• conformational disease;
  • cytoplasmic splicing;
  • ER stress response;
  • ER-associated protein degradation (ERAD);
  • Golgi stress response


  1. Top of page
  2. Abstract
  3. Introduction
  4. ER stress-inducing chemicals
  5. ER chaperones
  6. ERAD
  7. Response pathways for ER stress
  8. ER stress-related diseases
  9. Golgi stress response
  10. Conclusions and perspectives
  11. Acknowledgements
  12. References

Proteins synthesized in the endoplasmic reticulum (ER) are properly folded with the assistance of ER chaperones. Malfolded proteins are disposed of by ER-associated protein degradation (ERAD). When the amount of unfolded protein exceeds the folding capacity of the ER, human cells activate a defense mechanism called the ER stress response, which induces expression of ER chaperones and ERAD components and transiently attenuates protein synthesis to decrease the burden on the ER. It has been revealed that three independent response pathways separately regulate induction of the expression of chaperones, ERAD components, and translational attenuation. A malfunction of the ER stress response caused by aging, genetic mutations, or environmental factors can result in various diseases such as diabetes, inflammation, and neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and bipolar disorder, which are collectively known as ‘conformational diseases’. In this review, I will summarize recent progress in this field. Molecules that regulate the ER stress response would be potential candidates for drug targets in various conformational diseases.


axotomy-induced glyco/Golgi protein


amyloid precursor protein


apoptosis signal-regulating kinase 1


activating transcription factor


Bcl-2 homologous antagonist/killer


BiP-associated protein


B cell receptor-associated protein 31


Bcl2-associated X protein


B cell leukemia 2


Bax inhibitor 1


Bcl2-interacting mediator of cell death


binding protein


basic leucine zipper


Abelson murine leukemia viral oncogene homolog 1


CCAAT/enhancer-binding protein


C/EBP-homologous protein


cAMP response element-binding protein


cAMP response element-binding protein H


constitutive repressor of eIF2α phosphorylation


death-associated protein


degradation in the endoplasmic reticulum protein 1


Der1-like protein 1


degradation in the endoplasmic reticulum protein 10


death receptor 5


ER degradation enhancing α−mannosidase-like protein

eIF2 α

α-subunit of eukaryotic translational initiation factor 2


endoplasmic reticulum


ER-associated degradation


ER dnaJ


ER oxidoreductin


ER protein 72


ER stress response element


FK506-binding protein 13


growth arrest and DNA damage


glycoprotein 78


glucose-regulated protein


human ER-associated dnaJ


human inhibitor of apoptosis 2


HMG-CoA reductase degradation protein 1


heat shock protein


inhibitor of apoptosis


insulin-dependent diabetes mellitus


inositol requirement 1


Jun kinase


Kelch-like Ech-associated protein 1


basic leucine zipper protein


noninsulin-dependent diabetes mellitus


neutrophil NADPH oxidase factor


nuclear protein localization 4


nuclear respiratory factor


oxygen-regulated protein 150


osteosarcoma 9


58 kDa-inhibitor of protein kinase


the nuclear form of ATF6 protein


protein disulfide isomerase


PRKR-like endoplasmic reticulum kinase


double stranded RNA-dependent protein kinase


proteolipid protein 1




pion protein


cellular PrP


scrapie PrP


presenillin 1


p53 up-regulated modulator of apoptosis


the spliced form of XBP1 protein


the unspliced form of XBP1 protein


regulated intramembrane proteolysis


regulator of sE


site 1 protease


site 2 protease


stress-activated protein kinase


suppressor of lin12-like


sterol response element-binding protein


T cell death-associated gene 51


tumor necrosis factor


tumor necrosis factor receptor 1


TNF receptor-associated factor 2


Tribbles homolog 3


ubiquitin conjugase 6


ubiquitin conjugase 7


ubiquitin-activating enzyme 1


ubiquitin-activating enzyme 2G2


UBX domain-containing protein 2


ubiquitin C-terminal esterase L1


ubiquitin fusion degradation protein 1


unfolded protein response element


valocin-containing protein


Wolfram syndrome 1


x-box binding protein 1


inhibitor of apoptosis, x-linked


XTP3-transactivated gene B


  1. Top of page
  2. Abstract
  3. Introduction
  4. ER stress-inducing chemicals
  5. ER chaperones
  6. ERAD
  7. Response pathways for ER stress
  8. ER stress-related diseases
  9. Golgi stress response
  10. Conclusions and perspectives
  11. Acknowledgements
  12. References

The endoplasmic reticulum (ER) is an organelle where secretory or membrane proteins are synthesized. Nascent proteins are folded with the assistance of molecular chaperones and folding enzymes located in the ER (collectively called ER chaperones), and only correctly folded proteins are transported to the Golgi apparatus (Fig. 1). Unfolded or malfolded proteins are retained in the ER, retrotranslocated to the cytoplasm by the machinery of ER-associated degradation (ERAD), and degraded by the proteasome. ER chaperones and ERAD components are constitutively expressed in the ER to deal with nascent proteins. When cells synthesize secretory proteins in amounts that exceed the capacity of the folding apparatus and ERAD machinery, unfolded proteins are accumulated in the ER. Unfolded proteins expose hydrophobic amino-acid residues that should be located inside the protein and tend to form protein aggregates. Protein aggregates are so toxic that they induce apoptotic cell death and cause ‘conformational diseases’ such as neurodegenerative disorders and diabetes mellitus. To alleviate such a stressful situation (ER stress), eukaryotic cells activate a series of self-defense mechanisms referred to collectively as the ER stress response or unfolded protein response [1–4].


Figure 1.  Mammalian ER stress response. An accumulation of unfolded proteins in the ER evokes ER stress, and cells induce the ER stress response to cope. The mammalian ER stress response consists of four mechanisms: (1) translational attenuation; (2) expression of ER chaperones; (3) enhanced ERAD; (4) apoptosis.

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The mammalian ER stress response consists of four mechanisms. The first is attenuation of protein synthesis, which prevents any further accumulation of unfolded proteins. The second is the transcriptional induction of ER chaperone genes to increase folding capacity, and the third is the transcriptional induction of ERAD component genes to increase ERAD ability. The fourth is the induction of apoptosis to safely dispose of cells injured by ER stress to ensure the survival of the organism.

In this article, I will describe the basics of the mammalian ER stress response that are essential to understanding conformational diseases. I will review hot topics such as ERAD, regulated intramembrane proteolysis (RIP) and cytoplasmic splicing, and briefly summarize the ER stress-related diseases.

ER stress-inducing chemicals

  1. Top of page
  2. Abstract
  3. Introduction
  4. ER stress-inducing chemicals
  5. ER chaperones
  6. ERAD
  7. Response pathways for ER stress
  8. ER stress-related diseases
  9. Golgi stress response
  10. Conclusions and perspectives
  11. Acknowledgements
  12. References

Chemicals such as tunicamycin, thapsigargin, and dithiothreitol are usually used to evoke ER stress in cultured cells or animals for experimental purposes. I will briefly summarize the ER stress-inducing chemicals below.

The first group of ER stressors comprises glycosylation inhibitors. Most of the proteins synthesized in the ER are N-glycosylated, and the N-glycosylation is often essential for protein folding. Thus, chemicals that disturb N-glycosylation have the potential to induce ER stress. Tunicamycin is an antibiotic produced by Streptomyces lysosuperificus that inhibits N-glycosylation by preventing UDP-GlcNAc–dolichol phosphate GlcNAc-phosphate transferase activity [5,6]. 2-Deoxy-d-glucose is also used to inhibit N-glycosylation [7], but is less efficient than tunicamycin.

Another class of ER stressors is Ca2+ metabolism disruptors. As the concentration of Ca2+ ion in the ER is kept at a high level and ER chaperones such as BiP require Ca2+ ions, chemicals that perturb Ca2+ metabolism in the ER induce ER stress. Ca2+ ionophores such as A23187 and the Ca2+ pump inhibitor, thapsigargin, are often used to evoke ER stress [5,8].

The third category of ER stressors is reducing agents. As the lumen of the ER is highly oxidative, proteins synthesized there can form intermolecular or intramolecular disulfide bonds between their cysteine residues. As the formation of disulfide bonds is important for the folding of secretory proteins, reducing agents that disrupt disulfide bonds evoke ER stress. Dithiothreitol and 2-mercaptoethanol are often used to this end [9,10].

Hypoxia is also known to induce ER stress, although the underlying mechanism is unknown. It is speculated that a decrease in glucose concentration induced by hypoxia (because hypoxia induces glycolytic enzymes to sustain ATP production and then cells consume glucose) inhibits N-glycosylation, leading to ER stress [11].

ER chaperones

  1. Top of page
  2. Abstract
  3. Introduction
  4. ER stress-inducing chemicals
  5. ER chaperones
  6. ERAD
  7. Response pathways for ER stress
  8. ER stress-related diseases
  9. Golgi stress response
  10. Conclusions and perspectives
  11. Acknowledgements
  12. References

ER chaperones include molecular chaperones and folding enzymes located in the ER, which are responsible for the folding of nascent proteins [4,12]. They are also involved in the unfolding of malfolded proteins in ERAD. In this section, I will review mammalian ER chaperones, focusing on recent discoveries.

Binding protein (BiP)/glucose-regulated protein (GRP)78 is a well-known ER chaperone that belongs to the heat shock protein (HSP)70 family. BiP binds to the hydrophobic region of unfolded proteins via a substrate-binding domain and facilitates folding through conformational change evoked by the hydrolysis of ATP by the ATPase domain. Oxygen-regulated protein (ORP)150/GRP170 is an ER chaperone belonging to the HSP110 family (a HSP70 subfamily), and facilitates protein folding via a mechanism similar to that for BiP. It was originally identified as a protein expressed in response to hypoxia. ER dnaJ (ERdj)1, ERdj3/human ER-asociated dnaJ (HEDJ), ERdj4, ERdj5, SEC63, and p58IPK are ER chaperones belonging to the HSP40 family, and modulate the functions of BiP by regulating its ATPase activity as a cochaperone. BiP-associated protein (BAP), which is a member of the GrpE family, also modulates the functions of BiP by enhancing nucleotide exchange. GRP94 is an ER chaperone belonging to the HSP90 family, and facilitates folding through the hydrolysis of ATP. FKBP13 is a peptidyl-prolyl isomerase belonging to the FKBP family. These ER chaperones are involved in the general folding process of secretory proteins.

Calnexin and calreticulin are ER chaperones specifically involved in the folding of glycoprotein. High-mannose type oligosaccharide is attached en bloc to most proteins synthesized in the ER, and then trimmed sequentially (Fig. 2). When two glucose residues are trimmed by glucosidase I or II and the protein contains only one glucose residue, calnexin and calreticulin bind and fold the client protein. When the last glucose residue is trimmed by glucosidase II, the client is released from calnexin and calreticulin, and binds to UDP-glucose–glycoprotein glucosyltransferase. If the protein is folded, it is released from the enzyme and transported to the Golgi apparatus. If it is not folded, UDP-glucose–glycoprotein glucosyltransferase attaches one glucose residue and returns it to calnexin and calreticulin. This folding process is called the calnexin cycle [13]. Calnexin and calreticulin share a similar molecular structure and function, although they are transmembrane and luminal proteins, respectively.


Figure 2.  Folding and degradation of glycoprotein. Sugar chains of nascent glycoproteins synthesized in the ER are trimmed by glucosidase I or II, and polypeptides containing one glucose residue are folded by the calnexin cycle. One mannose residue of polypeptides that is unable to be folded by the calnexin cycle is removed by mannosidase I, and then the polypeptides are recognized by EDEM and degraded by ERAD.

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Numerous folding enzymes are involved in the formation of disulfide bonds in the ER, such as protein disulfide isomerase (PDI), ERp72, ERp61, GRP58/ERp57, ERp44, ERp29, and PDI-P5. These folding enzymes oxidize cysteine residues of nascent proteins and help proteins to form correct disulfide bonds. Reduced folding enzymes are reoxidized by ER oxidoreductin (ERO1), which can use molecular oxygen as a terminal electron acceptor [14].


  1. Top of page
  2. Abstract
  3. Introduction
  4. ER stress-inducing chemicals
  5. ER chaperones
  6. ERAD
  7. Response pathways for ER stress
  8. ER stress-related diseases
  9. Golgi stress response
  10. Conclusions and perspectives
  11. Acknowledgements
  12. References

Unfolded or malfolded proteins are trapped by the ERAD machinery and transported to the cytoplasm [15–17]. Retrotranslocated proteins are ubiquitinated and degraded by the proteasome in the cytosol. Thus, the process of ERAD can be divided into four steps, recognition, retrotranslocation, ubiquitination, and degradation (Fig. 3). As ERAD is one of the hottest topics in the study of ER stress, I will summarize our current understanding of mammalian ERAD systems.


Figure 3.  Mammalian ERAD machinery. Unfolded proteins released from the calnexin cycle are captured by a recognition complex containing EDEM and OS9, moved to the cytosol through retrotranslocation machinery, polyubiquitinated by the E1–E2–E3 system, and degraded by the proteasome. The precise function of each ERAD component is described in the text.

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During the calnexin cycle, the oligosaccharide of nascent polypeptides contains nine mannose residues. When one mannose residue is trimmed by α-mannosidase I, nascent polypeptides with eight mannose residues are released from calnexin or calreticulin and bind to ER degradation-enhancing α-mannosidase-like protein (EDEM) (Fig. 2), which discriminates unfolded proteins from folded proteins [18–22]. There are three genes for EDEM, and both EDEM1 and EDEM2 are involved in ERAD. EDEM1 is an ER membrane protein, whereas EDEM2 and EDEM3 are luminal proteins [23–25]. All EDEMs contain the mannosidase-like domain, which may be responsible for recognition of mannose residues.

Osteosarcoma 9 (OS9) and XTP3-transactivated gene B (XTP3B) are other ERAD components responsible for the recognition of unfolded proteins [26–28]. OS9 specifically binds to unfolded glycoproteins containing eight (or five) mannose residues. OS9 also binds to unglycosylated unfolded proteins, suggesting that it plays a critical role in the recognition of both glycosylated and unglycosylated proteins. OS9 and XTP3B [29] contain the mannose-6-phosphate receptor-like domain, which may be critical to the recognition of mannose residues.


Nascent glycoproteins recognized by EDEM and OS9 as malfolded are destined for the retrotranslocation machinery [30,31]. Before their retrotranslocation, nascent proteins associate with PDI and BiP to cleave disulfide bonds and to unfold the partially folded structure, respectively [32–34]. Although unfolded ER proteins were previously speculated to be retrotranslocated through the translocon containing Sec61, the molecular structure of the retrotranslocation machinery remains elusive. Derlin-1 is a mammalian homolog of yeast Der1, and thought to be a critical component of the machinery. Derlin-1 may form a retrotranslocation channel in the ER membrane and associates with p97 through an adaptor protein, valocin-containing protein (VCP)-interacting membrane protein 1 (VIMP1) [35]. Derlin-2 and Derlin-3, other Der1 homologs, are also involved in ERAD [35–37], although the exact underlying mechanism is still unclear.

p97/cdc48/VCP is a cytosolic AAA-ATPase and recruits unfolded ER proteins to the cytosol [38,39]. Ubiquitin fusion degradation protein 1 (Ufd1) and nuclear protein localization 4 (Npl4) bind to p97 as a cofactor and help p97 to extract unfolded proteins. The polypeptide portion of unfolded proteins interacts with p97, whereas the polyubiquitin chains attached to them are recognized by both p97 and Ufd1 and may activate the ATPase activity of p97 [40–42].


Retrotranslocated (or retrotranslocating) proteins are ubiquitinated by the E1–E2–E3 ubiquitin system. Ubiquitin is first conjugated to enzyme E2 by enzyme E1, and then transferred to ERAD substrates by enzyme E3. HMG-CoA reductase degradation protein 1 (HRD1), gp78, and TEB4/Doa10 are membrane-anchored E3 ligases involved in ERAD [43–46], whereas ubiquitin conjugase (UBC)6 and UBE2G2/UBC7 are E2 conjugase involved in ERAD. UBE1 is an E1 ubiquitin-activating enzyme that is ubiquitously involved in protein degradation by the proteasome. HRD1 shows a preference for substrates that contain misfolded luminal domains, whereas Doa10 prefers transmembrane proteins containing misfolded cytosolic domains (Doa10 also ubiquitinates cytosolic proteins). These two distinctive ERAD systems are called ERAD-L (luminal ERAD) and ERAD-C (cytosolic ERAD) [47,48]. EDEM and OS9 are thought to specifically recognize ERAD-L substrates. Actually, they form distinct ubiquitin–ligase complexes: the HRD1 complex contains HRD1, OS9, HRD3, Derlin-1, USA1, UBX2 and p97, whereas the Doa10 complex consists of Doa10, UBX2 and p97 [49–51]. Substrates containing misfolded transmembrane domains skip the interaction to OS9 and HRD3, and directly associate with the HRD1 complex, which is called the ERAD-M pathway [49].

However, there are a lot of other E3 ligases involved in the ERAD, and they preferentially recognize distinct ERAD substrates. FBX2 (F-box only protein 2) is another E3 ligase that specifically recognizes N-glycosylated proteins located in the cytosol [52,53]. Parkin is an E3 involved in Parkinson's disease (see below). In the case of cystic fibrosis transmembrane conductance regulator, its folding status is sequentially monitored by the two E3 ligase complexes, such as the RMA1 complex and the CHIP (C-terminus of Hsc70-interacting protein) complex [54].

Molecules other than E1–E2–E3 enzymes are also involved in ubiquitination. UBX2 binds to both p97 and E3 ligases such as HRD1 and Doa10 to recruit E3 to p97 [55], whereas gp78 directly associates with p97 [56]. The ubiquitin-domain protein, Herp (homocysteine-induced endoplasmic reticulum protein), associates with a complex containing HRD1, p97, Derlin-1, and VCP-interacting membrane protein [57,58].


Retrotranslocated and ubiquitinated proteins are deglycosylated by peptide–N-glycanase before their degradation by the proteasome, because bulky glycan chains may hamper the entrance of substrates into the proteasome pore. As peptide–N-glycanase is associated with Derlin-1, it is possible that deglycosylation occurs coretrotranslocationally [59]. Deglycosylated substrates are then delivered to the proteasome. Dsk2 and Rad23 facilitate this delivery of ERAD substrates [60].

Response pathways for ER stress

  1. Top of page
  2. Abstract
  3. Introduction
  4. ER stress-inducing chemicals
  5. ER chaperones
  6. ERAD
  7. Response pathways for ER stress
  8. ER stress-related diseases
  9. Golgi stress response
  10. Conclusions and perspectives
  11. Acknowledgements
  12. References

The mammalian ER stress response has four mechanisms: (1) translational attenuation; the enhanced expression of (2) ER chaperones and (3) ERAD components; (4) induction of apoptosis. These four responses are regulated by the regulatory pathways as described below (Fig. 4).


Figure 4.  Mammalian response pathways for ER stress. Three response pathways (PERK, ATF6, and IRE1 pathways) regulate the mammalian ER stress response. PERK, a transmembrane kinase, phosphorylates eIF2α to attenuate translation, and to up-regulate expression of ATF4, leading to enhanced transcription of target genes such as CHOP. ATF6, a transmembrane transcription factor, is translocated to the Golgi apparatus and cleaved by proteases such as S1P and S2P, leading to enhanced transcription of ER chaperone genes. IRE1, a transmembrane RNase, splices XBP1 pre-mRNA, and pXBP1(S) translated from mature XBP1 mRNA activates transcription of ERAD component genes.

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PERK pathway

PERK is a type I transmembrane protein located in the ER, which senses the accumulation of unfolded proteins in the ER lumen [61–63]. The luminal portion of PERK is involved in sensing unfolded proteins, whereas the cytoplasmic portion contains a kinase domain. In the absence of ER stress, BiP binds to the luminal domain of PERK and keeps it from being activated (Figs 4 and 5A). In response to ER stress, BiP is released from PERK, and PERK is activated through oligomerization and trans-phosphorylation [64]. Activated PERK phosphorylates and inactivates the α-subunit of eukaryotic translational initiation factor 2 (eIF2α), leading to translational attenuation. The phosphorylation of PERK is transient as the protein is dephosphorylated by specific phosphatases such as CReP (constitutive repressor of eIF2α phosphorylation), protein phosphatase 2C-GADD34, and p58IPK. CReP is constitutively expressed, whereas the expression of GADD34 and p58IPK is induced on ER stress by PERK and activating transcription factor (ATF)6 pathways, respectively.


Figure 5.  Activation of the PERK pathway. (A) Activation of PERK, IRE1, and ATF6. In the absence of ER stress, BiP prevents PERK, IRE1, and ATF6 from being activated by binding to these sensors. BiP prevents the activation of IRE1 and PERK by keeping them from being oligomerized, whereas BiP inhibits the translocation of ATF6 by masking the Golgi-localization signal (GLS). When BiP is sequestered from sensors by unfolded proteins, these sensor molecules are activated. (B) Regulation of ATF4 expression. In the absence of ER stress, most of the eIF2α is active (not phosphorylated), and translation starts at the small ORFs, leading to the release of ribosomes before they reach the ATF4 ORF. Upon ER stress, most of the eIF2α becomes inactive (phosphorylated), and translation rarely starts at the small ORFs, thus ribosomes can reach the ATF4 ORF and induce translation of ATF4 protein.

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Interestingly, translation of the transcription factor ATF4 is up-regulated by eIF2α-mediated translational attenuation. There are several small ORFs in the 5′-UTR of ATF4 mRNA (Fig. 5B). The ribosome first binds to a 5′-cap structure, slides on the ATF4 mRNA, and then starts translation at the small ORFs with unphosphorylated (active) eIF2α. As the ribosome is released from the ATF4 mRNA upon the termination of translation at the stop codon of small ORFs, the ATF4 ORF cannot be translated in the absence of ER stress. In contrast, as phosphorylated (inactive) eIF2α cannot start translation, the probability that the ribosome reaches the ATF4 ORF is increased in the presence of ER stress. Thus, the translation of ATF4 is remarkably enhanced in response to ER stress. The targets of ATF4 include CHOP (C/EBP homology protein), a transcription factor involved in the induction of apoptosis, and proteins involved in amino-acid metabolism such as asparagine synthetase or those involved in resistance to oxidative stress [65].

eIF2α is also phosphorylated by other kinases, such as dsRNA-dependent protein kinase (PKR), GCN2 (general control of amino-acid synthesis 2) and heme-regulated translational inhibitor. These kinases are activated by viral infections, amino-acid starvation, and heme deficiency, respectively, indicating that translational attenuation and ATF4 induction is induced by not only ER stress but also these physiological situations. Thus, the cellular response mediated by the phosphorylation of eIF2α is called the integrated stress response and is essential for cell survival [66].

ATF6 pathway

There is another sensor molecule, ATF6, on the ER membrane [67–70]. ATF6 is a type II transmembrane protein, the luminal domain of which is responsible for the sensing of unfolded proteins. The cytoplasmic portion of ATF6 has a DNA-binding domain containing the basic-leucine zipper motif (bZIP) and a transcriptional activation domain. In the absence of ER stress, BiP binds to the luminal domain of ATF6 and hinders the Golgi-localization signal, leading to inhibition of ATF6 translocation (Fig. 5A) [71–75]. In response to the accumulation of unfolded proteins, BiP dissociates from ATF6, and ATF6 is moved to the Golgi apparatus by vesicular transport (Fig. 4). In the Golgi apparatus, ATF6 is sequentially cleaved by a pair of processing proteases called site 1 protease (S1P) and site 2 protease (S2P), and the resultant cytoplasmic portion of ATF6 [pATF6(N)] translocates into the nucleus. In the nucleus, pATF6(N) binds to a cis-acting element, the ER stress response element (ERSE), and activates the transcription of ER chaperone genes such as BiP, GRP94 and calreticulin [68]. The consensus sequence of the ER stress response element is CCAAT-(N9)-CCACG, and ATF6 binds to the CCACG portion, whereas a general transcription factor, NF-Y (nuclear factor Y), binds to the CCAAT portion.

The cleavage of ATF6 is unique, especially as the second cleavage by S2P occurs in the transmembrane region [75]. This process is called regulated intramembrane proteolysis (RIP), which is well conserved from bacteria to mammals (Fig. 6). The most characterized substrate of RIP is sterol response element-binding protein (SREBP) [75]. SREBP is a transcription factor that is located in the ER membrane like ATF6. Upon a deficiency of sterol, SREBP is transported to the Golgi apparatus, cleaved by S1P and S2P, and activates the transcription of genes involved in the biosynthesis of sterol. Thus, the activation of ATF6 and SREBP is mainly regulated at the level of vesicular transport. The regulation of the transport of SREBP has been well characterized, and regulatory components such as the sensor-escort protein SCAP (SREBP cleavage-activating protein) and the anchor protein INSIG (insulin-induced gene 1) have been identified [76].


Figure 6.  Molecules regulated by RIP. RIP is conserved from bacteria to mammals, and is involved in various biological processes. SREBP senses a sterol deficiency and activates the transcription of genes involved in sterol synthesis. Cleavage of APP by RIP results in the production of antibody, which is responsible for the onset of Alzheimer's disease. Notch is a cell surface protein that is cleaved by RIP upon binding Delta, leading to the activation of target genes involved in differentiation. Bacterial RseA protein anchors a transcription factor, σE, to keep it inactive. In response to accumulation of unfolded proteins in the periplasm, RseA is cleaved by RIP, leading to transcriptional activation of periplasmic chaperones.

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There are two genes for ATF6, called ATF6α and ATF6β, which have a similar function and are ubiquitously expressed [68,77]. Recently, several bZIP transcription factors located in the ER and regulated by RIP have been reported. cAMP response element-binding protein H (CREBH) is specifically expressed in liver, and processed by S1P and S2P in response to ER stress [78]. CREBH activates the transcription of acute-phase response genes involved in acute inflammatory responses. OASIS (old astrocyte specifically induced substance) is also cleaved by S1P and S2P in response to ER stress in astrocytes and activates the transcription of BiP [79]. A spermatid-specific transcription factor, Tisp40 (transcript induced in spermiogenesis 40), is also severed by S1p and S2P and activates the transcription of EDEM [80]. These tissue-specific ATF6-like molecules may contribute to the ER stress response.

Luman/LZIP/CREB3 can be cut by S1P and S2P and activates the transcription of EDEM through a cis-acting element, unfolded protein response element (UPRE), although ER stress cannot induce Luman RIP [80–82]. CREB4 is transported to the Golgi apparatus in response to ER stress, is cleaved by S1P and S2P, and activates the transcription of BiP, although cleavage is not observed upon ER stress [83]. These ATF6-like molecules, which are insensitive to ER stress, might be activated in situations other than ER stress and activate transcription of ER chaperones.

IRE1 pathway

The third sensor molecule in the ER membrane is IRE1 (inositol requirement 1) [84–86]. The luminal domain of IRE1 is similar to that of PERK and involved in the sensing of unfolded proteins, whereas the cytoplasmic domain contains a kinase domain and an RNase domain. There are two genes for IRE1, IRE1α and IRE1β. Upon ER stress, BiP suppression of IRE1 activation is released, and IRE1 is activated through dimerization and transphosphorylation (Figs 4 and 5A) [64]. Activated IRE1α converts XBP1 (x-box binding protein 1) pre-mRNA into mature mRNA by an unconventional splicing mechanism [69,87]. As the DNA-binding domain and the activation domain are encoded in ORFs in XBP1 pre-mRNA, a protein translated from pre-mRNA [pXBP1(U)] cannot activate transcription. In contrast, a protein translated from mature mRNA [pXBP1(S)] activates the transcription of ERAD component genes such as EDEM, HRD1, Derlin-2, and Derlin-3 through a cis-acting element, unfolded protein response element, as these two ORFs are joined in mature mRNA [37,88,89]. pXBP1(S) also induces the expression of proteins involved in lipid synthesis and ER biogenesis, as well as the expression of ER chaperones such as BiP, p58IPK, ERdj4, PDI-P5 and HEDJ [90,91]. Thus, XBP1 is essential to the function of cells that produce large amounts of secretory proteins such as pancreatic β-cells, hepatocytes, and antibody-producing plasma cells [92–95].

The splicing of XBP1 pre-mRNA by IRE1α is quite different from conventional mRNA splicing (Fig. 7A) [69]. Conventional splicing is catalyzed by the spliceosome, and the consensus sequence at the exon–intron border is GU-AG or AU-AC (Chambon's rule). The splicing reaction is sequential: the 5′ site is cleaved first, then the 3′ site after a lariat structure is formed. In contrast, unconventional splicing of XBP1 pre-mRNA is catalyzed by IRE1α and RNA ligase, and there is a pair of stem–loop structures at the exon–intron border instead of GU-AG or AU-AC. Moreover, the splicing reaction is not sequential but random.


Figure 7.  Cytoplasmic splicing. (A) Comparison between nuclear and cytoplasmic splicing. Conventional splicing is catalyzed by the spliceosome in the nucleus, and there is a consensus sequence at the exon–intron boundary such as GU-AG or AU-AC. The splicing reaction is sequential: the 5′ site is cleaved first, the lariat structure is formed, and then the 3′ site is cleaved. In contrast, unconventional splicing is catalyzed by IRE1 and RNA ligase in the cytoplasm, there is a characteristic stem–loop structure at the boundary, and the splicing reaction is random without forming a lariat structure. (B) Biological significance of cytoplasmic splicing. As nuclear splicing cannot splice premRNA exported to the cytoplasm, de novo transcription is required to change the character of the protein encoded in the premRNA. In contrast, as cytoplasmic splicing can splice pre-mRNA that is translated in the cytoplasm, it can rapidly change the character of a protein in response to external or internal stimuli, without de novo transcription.

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The most important difference between conventional and unconventional splicing is where the reaction occurs (Fig. 7B). Conventional splicing (nuclear splicing) takes place in the nucleus, whereas unconventional splicing (cytoplasmic splicing) occurs in the cytoplasm. The biological significance of cytoplasmic splicing is that pre-mRNA used for translation in the cytoplasm can be spliced when it is necessary to change the nature of the protein translated from the mRNA, in response to extracellular or intracellular signaling. In contrast, as nuclear splicing cannot splice mRNA exported to the cytoplasm, it is necessary for pre-mRNA to be transcribed de novo and spliced. Thus, cytoplasmic splicing would be a very rapid, versatile, and energy-efficient mechanism with minimal waste as compared with conventional mRNA splicing. Recently, it was found that pXBP1(U) encoded in XBP1 pre-mRNA is a negative feedback regulator of pXBP1(S). Thus, in the case of XBP1, pre-mRNA and mature mRNA encode negative and positive regulators, respectively, and their expression is switched by cytoplasmic splicing in response to the situation in the ER [96].

IRE1β is specifically expressed in epithelial cells of the gastrointestinal tract, and thought to cleave rRNA to attenuate translation in response to ER stress [84]. When IRE1β–/– mice were exposed to an inducer of inflammatory bowel disease, they actually developed colitis, possibly because of the enhanced ER stress [97].

Recently, the crystal structure of the luminal domain of IRE1α was solved [98]. The luminal domain is similar in structure to the peptide-binding domain of major histocompatibility complexes, suggesting the interesting possibility that it directly senses ER stress by directly binding unfolded proteins.

Apoptosis-inducing pathways

The accumulation of unfolded proteins in the ER is toxic to cells. Thus, if the PERK, ATF6, and IRE1 pathways cannot suppress ER stress, an apoptotic pathway is triggered to ensure survival of the organism as a last line of defense. A number of pathways have been reported to be involved in ER stress-induced apoptosis, and the full induction of apoptosis seems to require the concomitant activation of several death pathways, although there remain many arguments over ER stress-induced apoptosis [99–105]. In this section, I will briefly summarize the known death pathways, focusing on recent progress (Fig. 8).


Figure 8.  ER stress-induced apoptotic pathways. The subcelluar distribution of factors involved in ER stress-induced cell death is shown. Pro-apoptotic and anti-apoptotic factors are indicated in black and white letters, respectively. Pro-apoptotic Bcl2 proteins positively regulate the IRE1 and caspase pathways, whereas anti-apoptotic Bcl2 proteins negatively regulate the latter. p53 enhances expression of pro-apoptotic Blc2 family proteins such as PUMA and NOXA. The IRE1 pathway activates JNK and SAPK, leading to apoptosis. c-Abl translocates from the ER to the mitochondria in response to ER stress. A fuller explanation is given in the text.

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The most characterized pathway is the CHOP pathway. CHOP/GADD153 (growth arrest and DNA damage 153) is a transcription factor, the expression of which is induced by the ATF6 and PERK pathways upon ER stress [70,106,107]. CHOP–/– cells exhibit less programmed cell death when faced with ER stress [108], suggesting that the CHOP pathway is a major regulator of ER stress-induced apoptosis. As for the target genes of CHOP, CHOP activates the transcription of GADD34, ERO1, DR5 (death receptor 5), and carbonic anhydrase VI, which seem to be responsible for apoptosis. GADD34 associated with protein phosphatase 2C enhances dephosphorylation of eIF2α and promotes ER client protein biosynthesis [109], whereas ERO1, which encodes an ER oxidase, makes the ER a more hyper-oxidizing environment [110]. DR5, which encodes a cell surface death receptor, may activate caspase cascades [111]. Carbonic anhydrase VI may change the cellular pH, affecting various cellular processes [112,113]. However, the exact signaling mechanism from CHOP to apoptosis is still unclear.

The second apoptotic pathway is the IRE1–TRAF2–ASK1 pathway. The cytoplasmic part of IRE1 binds to an adaptor protein, TRAF2 (tumor necrosis factor receptor-associated factor 2), which couples plasma membrane death receptor to Jun kinase (JNK) and stress-activated protein kinase (SAPK) [114]. IRE1 and TRAF2 form a complex with a mitogen-activated protein kinase kinase kinase, ASK1 (apoptosis signal-regulating kinase 1), and this IRE1–TRAF2–ASK1 complex is responsible for the phosphorylation and activation of JNK [115]. Actually, IRE1–/– cells as well as ASK1–/– cells are impaired in the activation of JNK and apoptosis by ER stress. In contrast, TRAF2–/– cells are more susceptible to apoptosis triggered by ER stress, which might be inconsistent with the above model [116]. TRAF2 also associates with caspase-12 and regulates its activation [117]. IRE1–TRAF2 activates the transcriptional repressor ATF3 as well, leading to the activation of apoptosis [118]. These suggest that the IRE1–TRAF2–ASK1 pathway is a major regulator of ER stress-induced apoptosis. TNFR1 (tumor necrosis factor receptor 1), a receptor for TNF-induced cell death, associates with IRE1α upon ER stress, and the activation of JNK by ER stress is impaired in TNFR1–/– cells. This suggests that TNFR1 mediates the ER stress-induced activation of JNK [119], possibly forming a complex with IRE1α, TRAF2, and ASK1. The expression of TNFα is up-regulated by the IRE1 pathway during ER stress [120,121], which may contribute to the activation of TNFR1.

Caspases are well-known pro-apoptotic components, and caspases 2, 3, 4, 7, 9 and 12 are reported to be involved in ER stress-induced cell death [122–131]. Caspase-12 is associated with the ER membrane, and activated by ER stress, possibly by calpain [132]. Then caspase-12 activates caspase-9, which in turn activates caspase-3 [133], leading to cell death. Caspase-12–/– mice are resistant to ER stress-induced apoptosis but sensitive to other death stimuli, suggesting that caspase-12 is a regulator specific to ER stress-induced apoptosis [134]. The activation of caspase-12 by ER stress is observed in models of various diseases such as Alzheimer's disease, polyglutamine disease, ischemia, and viral infection [135–139], suggesting that ER stress-induced apoptosis is closely involved in these diseases (see below). However, the involvement of caspase-12 in apoptosis of human cells is still open to question, as the human caspase-12 gene contains several mutations critical to function [140]. It is possible that an unidentified caspase other than caspase-12 is responsible in human cells.

Bcl2 family proteins are well-known components of the programmed cell death machinery, and some key components are involved in ER stress-induced apoptosis. In general, pro-apoptotic members of the Bcl2 family seem to be recruited to the ER surface and to activate caspase-12, whereas the anti-apoptotic members inhibit this recruitment, although the exact relationship between these factors is still unclear. So I will briefly describe our current understanding of Bcl2 family proteins. The anti-apoptotic factor Bcl2 is down-regulated by the transcription factor CHOP upon ER stress, which leads to enhanced oxidant injury and apoptosis [141]. Overexpression of Bcl2 inhibits the activation of caspase-12 and apoptosis during ER stress [142]. The pro-apoptotic factor, BAD (Bcl2 antagonist of cell death), is dephosphorylated and activated in response to ER stress [143], whereas other pro-apoptotic factors, Bax (Bcl2-associated X protein) and Bak (Bcl-2 homologous antagonist/killer), are present in the ER membrane as well as the mitochondrial membrane [144,145]. During ER stress, Bax and Bak oligomerize and activate caspase-12. Interestingly, Bax and Bak associate with IRE1α and modulate IRE1α function during ER stress [146]. Bax and Bak are required for most forms of apoptosis [147]. The transcription of PUMA (p53 up-regulated modulator of apoptosis) and NOXA (neutrophil NADPH oxidase factor), pro-apoptotic members of the BH3 (homology domain-3) domain-only family, is up-regulated by p53 during ER stress, and PUMA–/– cells and NOXA–/– cells are resistant to ER stress-induced apoptosis [148,149]. Another pro-apoptotic component, Bim (Bcl2-interacting mediator of cell death), translocates from the dynein-rich compartment to the ER membrane and activates caspase-12 in response to ER stress, whereas an anti-apoptotic factor, Bcl-xL (Bcl-2-like 1), binds to Bim and inhibits its translocation [150]. Bim-knockdown cells are resistant to ER stress. The ER-localized anti-apoptotic factor BI-1 (Bax inhibitor-1) inhibits the activation of Bax during ER stress, and BI-1–/– mice are sensitive to ER stress, whereas mice overexpressing BI-1 are resistant [151]. BIK (Bcl2-interacting killer) is an ER-localized pro-apoptotic component which enhances the recruitment of BAX and BAK to the ER [152]. Bap31 (B cell receptor-associated protein 31) is a pro-apoptotic factor that is cleaved and activated upon ER stress, its cleavage being dependent on calnexin [153]. In calnexin-deficient cells, the cleavage of Bap31 and ER stress-induced apoptosis are inhibited.

The inhibitor of apoptosis (IAP) family has also been reported to be involved in ER stress-induced apoptosis. Human inhibitor of apoptosis 2 (HIAP2) is an IAP that inhibits caspase-3 and caspase-7. Expression of HIAP2 is induced upon ER stress at the level of translation: caspases activated by ER stress cleave eukaryotic initiation factor, p97/DAP5/NAT1, and the cleavage product specifically activates the HIAP2 internal ribosome entry site, leading to enhanced translation of HIAP2 [131]. Transcription of IAP-2 and XIAP (inhibitor of apoptosis, X-linked), two other IAPs, is up-regulated during ER stress, and cells in which these IAPs have been knocked down are sensitive to ER stress-induced apoptosis [154]. Cells overexpressing XIAP or HIAP1 are resistant to ER stress [122,155]. These results suggest involvement of IAP proteins in ER stress-induced apoptosis.

c-Abl (Abelson murine leukemia viral oncogene homolog 1) is a protein tyrosine kinase distributed in the nucleus and cytoplasm, and c-Abl activated by a death signal induces phosphorylation and activation of pro-apoptotic JNK and SAPK. Interestingly, c-Abl is also located on the ER surface, and translocates to the mitochondria upon ER stress, where it induces the release of cytochrome c[156]. c-Abl–/– cells are resistant to ER stress-induced apoptosis. A c-Abl-interacting protein, Aph2 (anterior phalynx defective 2), is also located on the ER and shows pro-apoptotic activity [157], suggesting that c-Abl forms a distinct pathway leading to ER stress-induced apoptosis.

PKR is a dsRNA-dependent protein kinase which is activated upon viral infection, and its phosphorylation in the nucleus is up-regulated in response to ER stress. Interestingly, PKR-knockdown cells or PKR mutant cells are resistant to ER stress-induced apoptosis, suggesting that PKR is a pro-apoptotic factor during ER stress [158].

TDAG51 (T-cell death-associated gene 51) is a member of the pleckstrin homology-related domain family, and its transcription is induced by ER stress through the PERK pathway [159]. Overexpression of TDAG51 induces apoptosis, suggesting that TDAG51 is involved in ER stress-induced apoptosis and the development of atherosclerosis (see below).

Nuclear respiratory factor (NRF)1 and NRF2 are transcription factors that regulate the oxidative stress response. NRF2 is distributed in the cytoplasm through its association with the microtubule-associated protein Keap1 (Kelch-like Ech-associated protein 1). Upon ER stress, PERK phosphorylates NRF2 and dissociates it from Keap1, leading to the nuclear recruitment of NRF2 [160]. Remarkably, NRF2–/– cells are sensitive to ER stress-induced apoptosis, whereas NRF1 is located in the ER membrane, and translocates to the nucleus upon ER stress [161], suggesting that these proteins are involved in ER stress-specific apoptosis.

ATF6 is also involved in the apoptotic process during myogenesis. In differentiating myoblast, the ATF6 pathway is activated, and expression of BiP and CHOP is up-regulated, which may activate caspase-12. Moreover, AEBSF [4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride], an inhibitor of ATF6 activation, blocks apoptosis, suggesting that the ATF6 pathway contributes to apoptosis during myogenesis [162].

TRB3 (Tribbles homolog 3) is a human ortholog of Drosophila tribble, and its transcription is induced by ER stress through the PERK–ATF4–CHOP pathway. Interestingly, TRB3-knockdown cells are resistant to ER stress-induced apoptosis, suggesting that TRB3 is a pro-apoptotic factor during ER stress [163,164].

p53 is a transcription factor that induces growth arrest and apoptosis in response to various forms of cellular stress, such as DNA damage. There are several reports suggesting a connection between p53 and ER stress. Upon ER stress, p53 is phosphorylated by glycogen synthase kinase 3B, leading to the distribution of p53 in the cytoplasm and destabilization of p53, and attenuation of p53-dependent apoptosis [165–167]. Interestingly, Scotin and SCN3B (sodium channel subunit beta 3), p53-inducible pro-apoptotic proteins, are located in the ER [168,169]. Moreover, transcription of PUMA and NOXA, which are involved in ER stress-induced apoptosis, is up-regulated by p53 during ER stress [148], suggesting that the p53 pathway regulates the apoptotic pathway during ER stress.

Other components such as VCP and ALG-2 (apoptosis-linked-gene 2) [104], AIGP1 [170], elongation factor-1α[171], and NRADD (neurotrophin receptor associated death domain) [172] are also reported to be involved in ER stress-induced apoptosis. Their precise functions and working mechanisms are still to be clarified.

ER stress-related diseases

  1. Top of page
  2. Abstract
  3. Introduction
  4. ER stress-inducing chemicals
  5. ER chaperones
  6. ERAD
  7. Response pathways for ER stress
  8. ER stress-related diseases
  9. Golgi stress response
  10. Conclusions and perspectives
  11. Acknowledgements
  12. References

Unfolded or malfolded proteins readily form aggregates in the ER as well as the cytosol. Recent reports suggested that small aggregates are highly toxic, as they impair the ubiquitin proteasome pathway [173] and sequester transcription factors such as CREB-binding protein and TATA-binding protein [174,175], whereas large aggregates such as the aggresome and the inclusion body are cytoprotective [176]. Interestingly, molecular chaperones such as HSP70 and TRiC (TCP1- ring complex) can suppress the formation as well as toxicity of protein aggregates [174,177–181]. The diseases caused by the malfolding of cellular proteins are collectively called ‘conformational diseases’ or ‘folding diseases’. As malfolded proteins and protein aggregates can evoke ER stress, it has been speculated that ER stress is involved in most conformational diseases, particularly Alzheimer's disease and Parkinson's disease, although it is still heavily disputed whether ER stress (or protein aggregates) is a major cause of these diseases. In this section, I will briefly summarize recent findings on how ER stress is involved in conformational diseases.

Neurodegenerative diseases

Neurons are thought to be sensitive to protein aggregates, and there are many reports that ER stress is involved in neurodegenerative diseases [182–184]. In fact, disruption of SIL1/BAP, a cochaperone of BiP, results in the accumulation of protein aggregates and neurodegeneration [184]. Most of these diseases are caused by aging or genetic background, although several are assumed to be infectious, especially prion disease.

Alzheimer's disease is the most common neurodegenerative disease, and characterized by cerebral neuritic plaques of amyloid β-peptide [185–191]. Recent findings strongly suggest that one of the major causes of Alzheimer's disease is an accumulation of amyloid β-peptide, although tau also seems to be involved in the disease. Studies of patients with autosomal-dominant familial Alzheimer's disease have identified three genes responsible for the disease, amyloid precursor protein (APP), PS1 and PS2. The amyloid precursor protein encoded by APP is a transmembrane protein, the function of which is still unknown, whereas both PS1 and PS2 encode a protein called presenilin, which is an essential component of a protease called γ-secretase. APP is sequentially cleaved by a β-secretase called BACE (β-site amyloid β A4 precursor protein-cleaving enzyme 1) and γ-secretase, leading to the accumulation of amyloid β-peptide. Interestingly, cells expressing PS1 mutants show a waned ER stress response and are sensitive to ER stress [192]. The activation of ATF6, IRE1, and PERK is also disturbed in these mutant cells [193]. Moreover, proteins involved in ER stress-induced apoptosis, such as PKR and caspase-4, are involved in the onset of Alzheimer's disease [125,158]. Actually, the ER stress response is activated in patients with Alzheimer's disease [192,194,195], and polymorphism of SEL1, a component of ERAD, is linked to Alzheimer's disease [196]. These findings strongly suggest a strong causal relationship between ER stress and Alzheimer's disease, and it is highly possible that ER stress invoked by the accumulation of amyloid β-peptide is one of the key mechanisms of Alzheimer's disease.

Parkinson's disease is the second most common neurodegenerative disease, which is characterized by a loss of dopaminergic neurons [197]. Analyses of patients with familial Parkinson's disease have revealed three genes responsible for the disease, encoding α-synuclein, Parkin, and ubiquitin C-terminal esterase L1 (UCH-L1). α-synuclein is a cytoplasmic protein which forms aggregates, called Lewy bodies, characteristic of Parkinson's disease, but the link between α-synuclein and ER stress is unclear. In contrast, Parkin is a ubiquitin-protein ligase (E3) involved in ERAD [198]. One of the substrates of ERAD ubiquitinated by Parkin is Pael receptor, a homolog of endothelin receptor type B [199]. Interestingly, expression of Parkin is induced by ER stress, and neuronal cells overexpressing Parkin are resistant to ER stress [200]. As for UCH-L1, it is an abundant protein in neurons and stabilizes a monomeric ubiquitin [201,202]. It has been shown that UCH-L1 ubiquitinates unfolded proteins and might be involved in ERAD [203]. These findings strongly suggest the involvement of ER stress in Parkinson's disease. In addition, there are several other reports supporting the link between ER stress and Parkinson's disease. First, Parkinson's disease mimetics, such as 6-hydroxydopamine, specifically induce ER stress in neuronal cells [204,205]. Second, expression of ER chaperones such as PDI is up-regulated in the brain of Parkinson's disease patients, and PDI is accumulated in Lewy bodies [206]. The incidence of sporadic Parkinson's disease increases with age, but it is still unclear whether the ER stress response wanes in patients with Parkinson's disease.

Polyglutamine (polyQ) diseases are neurodegenerative disorders caused by duplications of the CAG-repeat in certain genes, and include Huntington's disease, spinobulbar muscular atrophy (Kennedy disease), Machado-Joseph disease, dentatorubral-pallidoluysian atrophy (Haw River Syndrome), and spinocerebellar ataxia. Large polyQ stretches translated from the CAG-repeat form insoluble protein aggregates, which are toxic to cells. Although the exact mechanism behind the toxicity of polyQ remains to be clarified, one possibility is that polyQ aggregates sequester other normal proteins, such as transcription factors, which are indispensable to cell function [174]. Another possibility is that the polyQ aggregate itself is toxic to cells. All known polyQ proteins causing neurodegenerative diseases are cytosolic, but they evoke ER stress, as polyQ proteins suppress the function of the proteasome, which is an essential component of ERAD [115,136,207]. Interestingly, p97, a component of the ERAD machinery, enhances degradation of polyQ proteins and suppresses polyQ protein-induced neurodegeneration [208]. Judging from these findings, it is probable that ER stress is involved in the onset of polyQ diseases.

Pelizaeus-Merzbacher disease is a progressive neurodegenerative disorder characterized by a loss of coordination, motor abilities, and intellectual function [209]. Currently, it is thought that the disease is caused by a mutation of the PLP1 gene which encodes a transmembrane proteolipid essential for the maintenance of myelin sheaths, as well as in oligodendrocyte development and axonal survival [210,211]. As a missense mutation causes a more severe phenotype than a null mutation, it is speculated that the missense mutant of PLP1 forms aggregates in the ER and evokes ER stress-induced cell death [212]. Actually, expression of CHOP, BiP, ERp59, and ERp72 is up-regulated in the brains of mice expressing missense PLP and the brains of patients with Pelizaeus-Merzbacher disease.

Prion disease, also called transmissible spongiform encephalopathy, encompasses Creutzfeldt-Jakob disease, Gerstmann–Straussler–Scheinker syndrome, fatal familial insomnia, Kuru, Alpers syndrome, bovine spongiform encephalopathy, transmissible milk encephalopathy, chronic wasting disease, and scrapie [213]. Characteristic features of the disease are a loss of motor control and dementia. The only gene to be identified so far as being responsible for prion disease is PrP, which encodes a protein anchored to the cell surface. There is no difference in amino-acid sequence between the normal protein PrPc and its pathological form PrPSc. PrPSc is rich in β-sheets, converts PrPc into PrPSc, and forms amyloid fibrils that are thought to be toxic to cells. Interestingly, in murine cells infected with PrPSc, the expression of ER chaperones such as GRP58 and GRP94 as well as caspase-12 is up-regulated [214]. Moreover, the expression of these chaperones is considerably increased in patients with Creutzfeldt-Jakob disease. Finally, overexpression of GRP58 protects cells from PrPSc-induced cell death, whereas inhibition of GRP58 expression with small interfering RNA results in a severe phenotype [215]. These findings strongly suggest that ER stress is involved in the pathology of prion disease.

Amyotrophic lateral sclerosis, also called Lou Gehrig's disease, is a progressive neuromuscular disease and shows characteristic pathological features such as a loss of motor neurons in the cerebral cortex and spinal cord. Analysis of patients with familial amyotrophic lateral sclerosis has revealed that superoxide dismutase-1 is responsible for the disease. Mutant superoxide dismutase-1 forms aggregates in the ER, evokes ER stress, induces the expression of BiP, and activates caspase-12, leading to neuronal cell death. These findings support the notion that ER stress induced by superoxide dismutase aggregates is a major cause of amyotrophic lateral sclerosis [216–218].

GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder characterized by an accumulation of GM1 gangliosides in the brain. The disease is caused by a mutation of lysosomal β-galactosidase that converts GM1 gangliosidosides to GM2 gangliosidosides. The analysis of β-galactosidase-knockout mice has revealed that the accumulation of GM1 gangliosidosides evokes ER stress, induces the expression of BiP and CHOP, activates JNK2 and caspase-12, and causes the apoptosis of neurons [219]. These findings suggest a strong correlation between ER stress and GM1 gangliosidosis.

Bipolar disorder

Bipolar disorder is a class of mood disorders where the person experiences recurrent episodes of mania and depression [220]. Genetic linkage studies suggest that genetic factors are involved in the disease. Microarray analyses of cells derived from twins discordant with respect to the disease revealed that the expression of XBP1 and BiP wanes in the affected twins. Recent reports showed that there are polymorphisms in the promoter regions of XBP1 and BiP that are common to patients [221–224], although this conclusion is still controversial [225]. It is interesting that mood-stabilizing drugs, such as valproate and lithium, which are highly effective in the treatment of bipolar disorder can increase the expression of ER chaperones such as BiP, GRP94, and calreticulin [226]. Further analyses are required to confirm that ER stress is involved in the onset of bipolar disorder.

Diabetes mellitus

Diabetes mellitus is a disease characterized by hyperglycemia caused by the impaired secretion or action of insulin [227–229]. Type I diabetes mellitus [insulin-dependent diabetes mellitus (IDDM)] results from selective destruction of insulin-secreting β-cells, whereas type II [noninsulin-dependent diabetes mellitus (NIDDM)] is characterized clinically by insulin resistance. As β-cells seem to suffer from ER stress caused by the production of a large amount of insulin, the link between ER stress and IDDM has been investigated thoroughly, especially the PERK pathway. PERK is responsible for an early infancy IDDM called Wolcott–Rallison syndrome [230], and PERK–/– mice show symptoms characteristic of IDDM [62,231]. Moreover, mice with a homozygous mutation at the eIF2α phosphorylation site (Ser51Ala) show similar pathological features [232,233], whereas the onset of diabetes is delayed in CHOP–/– mice [234]. Interestingly, components of ER stress pathways other than the PERK pathway are also involved in IDDM. First, the expression of BiP, GRP94, ORP150 and HRD1 is up-regulated, and both ATF6 and XBP1 are activated in the Akita diabetes mouse model [235,236]. Second, p58IPK–/– mice also show symptoms resembling IDDM [237]. Finally, the expression of WFS1, a gene responsible for the onset of Wolfman syndrome (juvenile diabetes), is induced by ER stress, and knockdown or knockout of WFS1 causes ER stress in pancreatic β-cells [238,239]. These findings strongly suggest that ER stress is deeply involved in the onset of IDDM.

There are several reports suggesting that ER stress is also involved in NIDDM. First, obesity, one of the causes of NIDDM, evokes ER stress, and XBP1–/– mice develop insulin resistance [240], although the underlying mechanism is unknown. Second, ectopic expression of ORP150 in β-cells improves insulin tolerance [240,241]. A possible explanation for this is that ORP150 expression may improve the folding capacity in the ER and protect cells from ER stress-induced apoptosis. Finally, a small nuclear polymorphism analysis revealed that a polymorphism in ATF6 is associated with NIDDM in Pima Indians [242].


Atherosclerosis is a disease wherein arteries harden and narrow because of the accumulation of fatty substances, cholesterol, cellular waste, Ca2+, and other substances in the arterial inner lining, leading to heart attack or stroke. One of the risk factors for atherosclerosis is the accumulation of homocysteine, which is an intermediate produced during the metabolism of sulfur amino acids [243,244]. Interestingly, homocysteine induces ER stress by an unknown mechanism, and then increases the expression of BiP, GRP94, CHOP, Herp, and TDAG51 [159,245,246]. The ER stress induced by homocysteine also increases cholesterol synthesis by activating the transcription factor SREBP. Both the induction of CHOP and TDAG51 (a member of the pleckstrin homology-related domain family) and the accumulation of cholesterol appear to promote the apoptosis of macrophages, leading to the deposition of macrophage debris in blood vessels that contributes to the development of the atherosclerosis observed in hyperhomocysteinemia [247–249]. Actually, CHOP–/– macrophages are less sensitive to cholesterol-induced apoptosis. These findings strongly support the notion that ER stress-induced apoptosis is one of the major factors that cause atherosclerosis.


Inflammation is the first response of the immune system to infection. Although the mechanism of inflammation is complicated, ER stress is involved in some types of inflammation. In inflammation of the central nervous system, interferon-γ induces ER stress and apoptosis of oligodendrocytes [250]. Interestingly, PERK+ mice show enhanced central nervous system hypomyelination and oligodendrocyte loss, suggesting that the PERK pathway has a protective role against interferon-γ-induced apoptosis. In the case of lipopolysaccharide-induced inflammation of the lungs, lipopolysaccharide induces ER stress and CHOP expression, leading to the apoptosis of lung cells [251]. Diclofenac, a nonsteroidal anti-inflammatory drug, suppresses ER stress-induced apoptosis [252], suggesting that ER stress is one of the major mediators of inflammation. Nitric oxide (NO) is another substance involved in the induction of apoptosis during inflammation. Although NO-induced apoptosis has been generally considered to be mediated by either DNA damage or mitochondrial damage, NO also induces apoptosis mediated by ER stress and CHOP in pancreatic β-cells, microglial cells, and macrophages [103,229,234,253–257]. Recently, it was reported that proinflammatory cytokines and lipopolysaccharide evoke ER stress and induce the transcription and activation of CREBH in the liver [78]. The transcription factor CREBH induces the expression of proteins involved in the acute inflammatory response such as serum amyloid P-component and C-reactive protein. As mentioned above, CREBH is structurally related to ATF6 and activated by a mechanism similar to ATF6. These findings suggest a strong link between ER stress and inflammation, although it should be clarified how ER stress is induced during inflammation.

ER stress is also involved in autoimmunity, and there are three reports supporting this notion. First, BiP associates with the clinically relevant autoantigen Ro52 (ribonucleoprotein autoantigen 52 kDa) [Sjoegren syndrome type A antigen (SS-A)], and is thought to be involved in autoimmunity and rheumatoid arthritis [258]. Second, a microarray analysis using muscle tissue of patients with myositis revealed that the expression of BiP, CHOP, GADD45 and asparagine synthetase is induced in the patients' cells, suggesting that the ER stress response is responsible for the skeletal muscle damage and dysfunction in autoimmune myositis [259]. Third, overexpression of synoviolin, an E3 ubiquitin ligase involved in ERAD, in mice causes arthropathy with synovial hyperplasia, whereas knockdown of synoviolin results in increased apoptosis of synovial cells and less sensitivity to collagen-induced arthritis [260].


As hypoxia induces ER stress as mentioned above, ER stress is an important cause of ischemia-related diseases. For instance, brain ischemia induces ER stress in neurons and activates the ATF6, IRE1 and PERK pathways [261], leading to the CHOP-mediated apoptosis of neurons [262]. Ischemia also induces ER stress and the expression of ER chaperones in the heart, leading to degeneration of cardiomyocytes [263], suggesting that ER stress is involved in the development of ischemic heart disease (see below).

Heart diseases

It has been reported that ER stress is involved in heart-related diseases. Pressure overload by transverse aortic constriction induces expression of ER chaperones and ER stress-induced apoptosis of cardiac myocytes, leading to cardiac hypertrophy [264]. Interestingly, transgenic mice expressing a mutant KDEL receptor, a retrieval receptor for ER chaperones in the early secretory pathway, developed dilated cardiomyopathy due to a malfunction of the ER quality control machinery and increased ER stress [265]. Moreover, up-regulation of ER chaperones protected cardiomyocytes from ER stress-induced apoptosis [266]. These findings strongly suggest that the ER stress response is essential for homeostasis of cardiomyocytes.

Liver diseases

Hepatocytes have a well-developed ER structure that is essential for the vigorous synthesis of secretory proteins, and it has been reported that ER stress is involved in liver-related diseases [267]. For instance, alcohol is known to cause liver injury by various mechanisms including ER stress [268,269]. Although exactly how alcohol causes ER stress remains unclear; one possible explanation is that alcohol inhibits the activity of the key enzymes for sulfur amino-acid metabolism such as methionine synthetase and betaine-homocysteine methyltransferase, leading to the accumulation of a potent ER stress inducer, homocysteine [121,270]. ER stress evoked by alcohol activates transcription factors such as CHOP, leading to CHOP-induced apoptosis of hepatocytes. ER stress also activates another transcription factor, SREBP, which is responsible for the up-regulation of fatty acid synthesis, resulting in lipid-induced apoptosis [268,271].

ER stress is also involved in hepatocarcinogenesis [272–274]. In human hepatocellular carcinoma, the ATF6 and IRE1 pathways are activated, and expression of BiP is markedly increased, suggesting that the transformation of hepatocytes induces ER stress, and cells cope with the stress by activating the ER stress response pathways.

Kidney diseases

Various factors are known to induce renal injury by evoking ER stress. First, the analgesic and antipyretic drug paracetamol (acetaminophen) causes renal tubular injury, and ER stress-induced apoptosis is one of the mechanisms involved [275]. Actually, paracetamol induces an ER stress response that includes the induction of CHOP and cleavage of caspase-12. Second, complement attack also induces ER stress and activates the PERK pathway, leading to glomerular epithelial cell injury [276]. Third, excessive accumulation of secretory proteins induces podocyte injury by evoking ER stress [277]. Fourth, overexpression of a kidney-specific serine protease inhibitor, megsin, induces ER stress and renal injury [278]. Interestingly, prior induction of BiP expression protects renal epithelial cells from chemicals inducing renal injury [279]. These findings suggest that ER stress is one of the major causes of chemically induced renal injury, and that the ER stress response is a defense mechanism against renal injury.

Viral infection

Infections caused by various viruses such as hepatitis B virus [280,281], hepatitis C virus [282], hepatitis D virus [283], flavivirus [284], Borna disease virus [285], murine leukemia virus [286] and Moloney murine leukemia virus [127] are known to induce ER stress, possibly because the vigorous synthesis of viral proteins makes the ER very busy. Upon viral infection, cells activate the ER stress response pathways to protect them from ER stress-induced apoptosis. ER stress induced by a viral infection is thought to cause various pathogenetic effects such as neurodegeneration, liver injury and carcinogenesis, depending on the cell types infected [267].

Hereditary tyrosinemia type I

Hereditary tyrosinemia type I is a metabolic disease affecting mainly the liver and renal functions, which is caused by a deficiency of fumarylacetate hydrolase which catalyzes the hydrolysis of fumarylacetate. In cells of patients with hereditary tyrosinemia type I, fumarylacetate is accumulated and evokes ER stress as well as mutagenic, cytostatic and apoptotic effects and chromosomal instability [287]. In hamster lung cells, fumarylacetate induces an ER stress response that includes the induction of BiP and CHOP expression and the cleavage of caspase-12, suggesting that ER stress is involved in this disease.

Golgi stress response

  1. Top of page
  2. Abstract
  3. Introduction
  4. ER stress-inducing chemicals
  5. ER chaperones
  6. ERAD
  7. Response pathways for ER stress
  8. ER stress-related diseases
  9. Golgi stress response
  10. Conclusions and perspectives
  11. Acknowledgements
  12. References

The Golgi apparatus is another organelle responsible for the production of secretory proteins [288]. Secretory proteins synthesized in the ER are transported to the Golgi apparatus and receive various modifications by enzymes located there, such as the modification of oligosaccharide chains and processing of peptide chains. Proteins properly processed in the Golgi apparatus are transported to the plasma membrane or secreted to the extracellular matrix. Thus, it is highly possible that the Golgi apparatus sends an emergency signal to the nucleus when the amount of client exceeds the capacity of its processing machinery, inducing the transcription of genes involved in Golgi apparatus function [289]. Although the mechanism of this response pathway (the Golgi apparatus stress response pathway) has not yet been clarified, it is worth investigating Golgi apparatus stress as it is probably correlated with various diseases.

Conclusions and perspectives

  1. Top of page
  2. Abstract
  3. Introduction
  4. ER stress-inducing chemicals
  5. ER chaperones
  6. ERAD
  7. Response pathways for ER stress
  8. ER stress-related diseases
  9. Golgi stress response
  10. Conclusions and perspectives
  11. Acknowledgements
  12. References

Clarification of the basic mechanisms of ER stress response has led to the discovery of a close relationship between ER stress and various diseases. As research on ER stress has expanded explosively, I hope this small review will help to give researchers a comprehensive view and to further develop this field academically and clinically.


  1. Top of page
  2. Abstract
  3. Introduction
  4. ER stress-inducing chemicals
  5. ER chaperones
  6. ERAD
  7. Response pathways for ER stress
  8. ER stress-related diseases
  9. Golgi stress response
  10. Conclusions and perspectives
  11. Acknowledgements
  12. References

We thank Ms. Kaoru Miyagawa for secretarial assistance. This work was supported by the PRESTO-SORST program of the Japan Science and Technology Agency, and grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (17026022, 17370061 and 18050013).


  1. Top of page
  2. Abstract
  3. Introduction
  4. ER stress-inducing chemicals
  5. ER chaperones
  6. ERAD
  7. Response pathways for ER stress
  8. ER stress-related diseases
  9. Golgi stress response
  10. Conclusions and perspectives
  11. Acknowledgements
  12. References
  • 1
    Harding HP, Calfon M, Urano F, Novoa I & Ron D (2002) Transcriptional and translational control in the Mammalian unfolded protein response. Annu Rev Cell Dev Biol 18, 575599.
  • 2
    Mori K (2000) Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101, 451454.
  • 3
    Patil C & Walter P (2001) Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals. Curr Opin Cell Biol 13, 349355.
  • 4
    Schroder M & Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569, 2963.
  • 5
    Dorner AJ, Wasley LC, Raney P, Haugejorden S, Green M & Kaufman RJ (1990) The stress response in Chinese hamster ovary cells. Regulation of ERp72 and protein disulfide isomerase expression and secretion. J Biol Chem 265, 2202922034.
  • 6
    Takatsuki A, Arima K & Tamura G (1971) Tunicamycin, a new antibiotic. I. Isolation and characterization of tunicamycin. J Antibiot (Tokyo) 24, 215223.
  • 7
    Lin HY, Masso-Welch PYP, Cai JW, Shen JW & Subjeck JR (1993) The 170-kDa glucose-regulated stress protein is an endoplasmic reticulum protein that binds immunoglobulin. Mol Biol Cell 4, 11091119.
  • 8
    Price BD, Mannheim-Rodman LA & Calderwood SK (1992) Brefeldin A, thapsigargin, and AIF4- stimulate the accumulation of GRP78 mRNA in a cycloheximide dependent manner, whilst induction by hypoxia is independent of protein synthesis. J Cell Physiol 152, 545552.
  • 9
    Brostrom MA, Prostko CR, Gmitter D & Brostrom CO (1995) Independent signaling of grp78 gene transcription and phosphorylation of eukaryotic initiator factor 2 alpha by the stressed endoplasmic reticulum. J Biol Chem 270, 41274132.
  • 10
    Fernandez F, Jannatipour M, Hellman U, Rokeach LA & Parodi AJ (1996) A new stress protein: synthesis of Schizosaccharomyces pombe UDP-Glc:glycoprotein glucosyltransferase mRNA is induced by stress conditions but the enzyme is not essential for cell viability. EMBO J 15, 705713.
  • 11
    Ikeda J, Kaneda S, Kuwabara K, Ogawa S, Kobayashi T, Matsumoto M, Yura T & Yanagi H (1997) Cloning and expression of cDNA encoding the human 150 kDa oxygen-regulated protein, ORP150. Biochem Biophys Res Commun 230, 9499.
  • 12
    Gething MJ (1997) Guidebook to Molecular Chaperones and Protein-Folding Catalysts. Oxford University Press, Oxford.
  • 13
    Deprez P, Gautschi M & Helenius A (2005) More than one glycan is needed for ER glucosidase II to allow entry of glycoproteins into the calnexin/calreticulin cycle. Mol Cell 19, 183195.
  • 14
    Gross E, Kastner DB, Kaiser CA & Fass D (2004) Structure of Ero1p, source of disulfide bonds for oxidative protein folding in the cell. Cell 117, 601610.
  • 15
    Ahner A & Brodsky JL (2004) Checkpoints in ER-associated degradation: excuse me, which way to the proteasome? Trends Cell Biol 14, 474478.
  • 16
    Hampton RY (2002) ER-associated degradation in protein quality control and cellular regulation. Curr Opin Cell Biol 14, 476482.
  • 17
    Jarosch E, Lenk U & Sommer T (2003) Endoplasmic reticulum-associated protein degradation. Int Rev Cytol 223, 3981.
  • 18
    Eriksson KK, Vago R, Calanca V, Galli C, Paganetti P & Molinari M (2004) EDEM contributes to maintenance of protein folding efficiency and secretory capacity. J Biol Chem 279, 4460044605.
  • 19
    Hosokawa N, Wada I, Hasegawa K, Yorihuzi T, Tremblay LO, Herscovics A & Nagata K (2001) A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation. EMBO Rep 2, 415422.
  • 20
    Hosokawa N, Wada I, Natsuka Y & Nagata K (2006) EDEM accelerates ERAD by preventing aberrant dimer formation of misfolded alpha1-antitrypsin. Genes Cells 11, 465476.
  • 21
    Molinari M, Calanca V, Galli C, Lucca P & Paganetti P (2003) Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle. Science 299, 13971400.
  • 22
    Oda Y, Hosokawa N, Wada I & Nagata K (2003) EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin. Science 299, 13941397.
  • 23
    Hirao K, Natsuka Y, Tamura T, Wada I, Morito D, Natsuka S, Romero P, Sleno B, Tremblay LO, Herscovics A, et al. (2006) EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming. J Biol Chem 281, 96509658.
  • 24
    Mast SW, Diekman K, Karaveg K, Davis A, Sifers RN & Moremen KW (2005) Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins. Glycobiology 15, 421436.
  • 25
    Olivari S, Galli C, Alanen H, Ruddock L & Molinari M (2005) A novel stress-induced EDEM variant regulating endoplasmic reticulum-associated glycoprotein degradation. J Biol Chem 280, 24242428.
  • 26
    Bhamidipati A, Denic V, Quan EM & Weissman JS (2005) Exploration of the topological requirements of ERAD identifies Yos9p as a lectin sensor of misfolded glycoproteins in the ER lumen. Mol Cell 19, 741751.
  • 27
    Buschhorn BA, Kostova Z, Medicherla B & Wolf DH (2004) A genome-wide screen identifies Yos9p as essential for ER-associated degradation of glycoproteins. FEBS Lett 577, 422426.
  • 28
    Szathmary R, Bielmann R, Nita-Lazar M, Burda P & Jakob CA (2005) Yos9 protein is essential for degradation of misfolded glycoproteins and may function as lectin in ERAD. Mol Cell 19, 765775.
  • 29
    Cruciat CM, Hassler C & Niehrs C (2006) The MRH protein Erlectin is a member of the endoplasmic reticulum synexpression group and functions in N-glycan recognition. J Biol Chem 281, 1298612993.
  • 30
    Lee RJ, Liu CW, Harty C, McCracken AA, Latterich M, Romisch K, DeMartino GN, Thomas PJ & Brodsky JL (2004) Uncoupling retro-translocation and degradation in the ER-associated degradation of a soluble protein. EMBO J 23, 22062215.
  • 31
    Spear ED & Ng DT (2005) Single, context-specific glycans can target misfolded glycoproteins for ER-associated degradation. J Cell Biol 169, 7382.
  • 32
    Kabani M, Kelley SS, Morrow MW, Montgomery DL, Sivendran R, Rose MD, Gierasch LM & Brodsky JL (2003) Dependence of endoplasmic reticulum-associated degradation on the peptide binding domain and concentration of BiP. Mol Biol Cell 14, 34373448.
  • 33
    Molinari M, Galli C, Piccaluga V, Pieren M & Paganetti P (2002) Sequential assistance of molecular chaperones and transient formation of covalent complexes during protein degradation from the ER. J Cell Biol 158, 247257.
  • 34
    Nishikawa SI, Fewell SW, Kato Y, Brodsky JL & Endo T (2001) Molecular chaperones in the yeast endoplasmic reticulum maintain the solubility of proteins for retrotranslocation and degradation. J Cell Biol 153, 10611070.
  • 35
    YeY, Shibata Y, Yun C, Ron D & Rapoport TA (2004) A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429, 841847.
  • 36
    Bordallo J, Plemper RK, Finger A & Wolf DH (1998) Der3p/Hrd1p is required for endoplasmic reticulum-associated degradation of misfolded lumenal and integral membrane proteins. Mol Biol Cell 9, 209222.
  • 37
    Oda Y, Okada T, Yoshida H, Kaufman RJ, Nagata K & Mori K (2006) Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J Cell Biol 172, 383393.
  • 38
    Rabinovich E, Kerem A, Frohlich KU, Diamant N & Bar-Nun S (2002) AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol Cell Biol 22, 626634.
  • 39
    YeY, Meyer HH & Rapoport TA (2001) The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414, 652656.
  • 40
    Elkabetz Y, Shapira I, Rabinovich E & Bar-Nun S (2004) Distinct steps in dislocation of luminal endoplasmic reticulum-associated degradation substrates: roles of endoplamic reticulum-bound p97/Cdc48p and proteasome. J Biol Chem 279, 39803989.
  • 41
    Richly H, Rape M, Braun S, Rumpf S, Hoege C & Jentsch S (2005) A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 120, 7384.
  • 42
    YeY, Meyer HH & Rapoport TA (2003) Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. J Cell Biol 162, 7184.
  • 43
    Bays NW, Gardner RG, Seelig LP, Joazeiro CA & Hampton RY (2001) Hrd1p/Der3p is a membrane-anchored ubiquitin ligase required for ER-associated degradation. Nat Cell Biol 3, 2429.
  • 44
    Hampton RY, Gardner RG & Rine J (1996) Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein. Mol Biol Cell 7, 20292044.
  • 45
    Ravid T, Kreft SG & Hochstrasser M (2006) Membrane and soluble substrates of the Doa10 ubiquitin ligase are degraded by distinct pathways. EMBO J 25, 533543.
  • 46
    Song BL, Sever N & DeBose-Boyd RA (2005) Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol Cell 19, 829840.
  • 47
    Huyer G, Piluek WF, Fansler Z, Kreft SG, Hochstrasser M, Brodsky JL & Michaelis S (2004) Distinct machinery is required in Saccharomyces cerevisiae for the endoplasmic reticulum-associated degradation of a multispanning membrane protein and a soluble luminal protein. J Biol Chem 279, 3836938378.
  • 48
    Kruse KB, Brodsky JL & McCracken AA (2006) Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways: one for soluble Z variant of human alpha-1 proteinase inhibitor (A1PiZ) and another for aggregates of A1PiZ. Mol Biol Cell 17, 203212.
  • 49
    Carvalho P, Goder V & Rapoport TA (2006) Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126, 361373.
  • 50
    Denic V, Quan EM & Weissman JS (2006) A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell 126, 349359.
  • 51
    Gauss R, Jarosch E, Sommer T & Hirsch C (2006) A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum quality control into the degradation machinery. Nat Cell Biol 8, 849854.
  • 52
    Yoshida Y, Adachi E, Fukiya K, Iwai K & Tanaka K (2005) Glycoprotein-specific ubiquitin ligases recognize N-glycans in unfolded substrates. EMBO Rep 6, 239244.
  • 53
    Yoshida Y, Chiba T, Tokunaga F, Kawasaki H, Iwai K, Suzuki T, Ito Y, Matsuoka K, Yoshida M, Tanaka K & Tai T (2002) E3 ubiquitin ligase that recognizes sugar chains. Nature 418, 438442.
  • 54
    Younger JM, Chen L, Ren HY, Rosser MF, Turnbull EL, Fan CY, Patterson C & Cyr DM (2006) Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator. Cell 126, 571582.
  • 55
    Schuberth C & Buchberger A (2005) Membrane-bound Ubx2 recruits Cdc48 to ubiquitin ligases and their substrates to ensure efficient ER-associated protein degradation. Nat Cell Biol 7, 9991006.
  • 56
    Zhong X, Shen Y, Ballar P, Apostolou A, Agami R & Fang S (2004) AAA ATPase p97/valosin-containing protein interacts with gp78, a ubiquitin ligase for endoplasmic reticulum-associated degradation. J Biol Chem 279, 4567645684.
  • 57
    Kokame K, Agarwala KL, Kato H & Miyata T (2000) Herp, a new ubiquitin-like membrane protein induced by endoplasmic reticulum stress. J Biol Chem 275, 3284632853.
  • 58
    Schulze A, Standera S, Buerger E, Kikkert M, van Voorden S, Wiertz E, Koning F, Kloetzel PM & Seeger M (2005) The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway. J Mol Biol 354, 10211027.
  • 59
    Katiyar S, Joshi S & Lennarz WJ (2005) The retrotranslocation protein Derlin-1 binds peptide: N-glycanase to the endoplasmic reticulum. Mol Biol Cell 16, 45844594.
  • 60
    Medicherla B, Kostova Z, Schaefer A & Wolf DH (2004) A genomic screen identifies Dsk2p and Rad23p as essential components of ER-associated degradation. EMBO Rep 5, 692697.
  • 61
    Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M & Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6, 10991108.
  • 62
    Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD & Ron D (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell 7, 11531163.
  • 63
    Harding HP, Zhang Y & Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271274.
  • 64
    Bertolotti A, Zhang Y, Hendershot LM, Harding HP & Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2, 326332.
  • 65
    Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, et al. (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11, 619633.
  • 66
    Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, et al. (2005) A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307, 935939.
  • 67
    Haze K, Yoshida H, Yanagi H, Yura T & Mori K (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10, 37873799.
  • 68
    Yoshida H, Haze K, Yanagi H, Yura T & Mori K (1998) Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem 273, 3374133749.
  • 69
    Yoshida H, Matsui T, Yamamoto A, Okada T & Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881891.
  • 70
    Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M & Mori K (2000) ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol 20, 67556767.
  • 71
    Chen X, Shen J & Prywes R (2002) The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. J Biol Chem 277, 1304513052.
  • 72
    Shen J, Chen X, Hendershot L & Prywes R (2002) ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 3, 99111.
  • 73
    Shen J & Prywes R (2004) Dependence of site-2 protease cleavage of ATF6 on prior site-1 protease digestion is determined by the size of the luminal domain of ATF6. J Biol Chem 279, 4304643051.
  • 74
    Shen J, Snapp EL, Lippincott-Schwartz J & Prywes R (2005) Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response. Mol Cell Biol 25, 921932.
  • 75
    YeJ, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS & Goldstein JL (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6, 13551364.
  • 76
    Anderson RG (2003) Joe Goldstein and Mike Brown: from cholesterol homeostasis to new paradigms in membrane biology. Trends Cell Biol 13, 534539.
  • 77
    Haze K, Okada T, Yoshida H, Yanagi H, Yura T, Negishi M & Mori K (2001) Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response. Biochem J 355, 1928.
  • 78
    Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT, Back SH & Kaufman RJ (2006) Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 124, 587599.
  • 79
    Kondo S, Murakami T, Tatsumi K, Ogata M, Kanemoto S, Otori K, Iseki K, Wanaka A & Imaizumi K (2005) OASIS, a CREB/ATF-family member, modulates UPR signalling in astrocytes. Nat Cell Biol 7, 186194.
  • 80
    Nagamori I, Yabuta N, Fujii T, Tanaka H, Yomogida K, Nishimune Y & Nojima H (2005) Tisp40, a spermatid specific bZip transcription factor, functions by binding to the unfolded protein response element via the Rip pathway. Genes Cells 10, 575594.
  • 81
    DenBoer LM, Hardy-Smith PW, Hogan MR, Cockram GP, Audas TE & Lu R (2005) Luman is capable of binding and activating transcription from the unfolded protein response element. Biochem Biophys Res Commun 331, 113119.
  • 82
    Raggo C, Rapin N, Stirling J, Gobeil P, Smith-Windsor E, O'Hare P & Misra V (2002) Luman, the cellular counterpart of herpes simplex virus VP16, is processed by regulated intramembrane proteolysis. Mol Cell Biol 22, 56395649.
  • 83
    Stirling J & O'Hare P (2006) CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P. Mol Biol Cell 17, 413426.
  • 84
    Iwawaki T, Hosoda A, Okuda T, Kamigori Y, Nomura-Furuwatari C, Kimata Y, Tsuru A & Kohno K (2001) Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress. Nat Cell Biol 3, 158164.
  • 85
    Tirasophon W, Welihinda AA & Kaufman RJ (1998) A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 12, 18121824.
  • 86
    Wang XZ, Harding HP, Zhang Y, Jolicoeur EM, Kuroda M & Ron D (1998) Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J 17, 57085717.
  • 87
    Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG & Ron D (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 9296.
  • 88
    Kaneko M & Nomura Y (2003) ER signaling in unfolded protein response. Life Sci 74, 199205.
  • 89
    Yoshida H, Matsui T, Hosokawa N, Kaufman RJ, Nagata K & Mori K (2003) A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell 4, 265271.
  • 90
    Lee AH, Iwakoshi NN & Glimcher LH (2003) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23, 74487459.
  • 91
    Sriburi R, Jackowski S, Mori K & Brewer JW (2004) XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol 167, 3541.
  • 92
    Lee AH, Chu GC, Iwakoshi NN & Glimcher LH (2005) XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J 24, 43684380.
  • 93
    Reimold AM, Etkin A, Clauss I, Perkins A, Friend DS, Zhang J, Horton HF, Scott A, Orkin SH, Byrne MC, et al. (2000) An essential role in liver development for transcription factor XBP-1. Genes Dev 14, 152157.
  • 94
    Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, Friend D, Grusby MJ, Alt F & Glimcher LH (2001) Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300307.
  • 95
    Zhang K, Wong HN, Song B, Miller CN, Scheuner D & Kaufman RJ (2005) The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest 115, 268281.
  • 96
    Yoshida H, Oku M, Suzuki M & Mori K (2006) pXBP1 (U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1 (S) in mammalian ER stress response. J Cell Biol 172, 565575.
  • 97
    Bertolotti A, Wang X, Novoa I, Jungreis R, Schlessinger K, Cho JH, West AB & Ron D (2001) Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest 107, 585593.
  • 98
    Credle JJ, Finer-Moore JS, Papa FR, Stroud RM & Walter P (2005) On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc Natl Acad Sci USA 102, 1877318784.
  • 99
    Breckenridge DG, Germain M, Mathai JP, Nguyen M & Shore GC (2003) Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 22, 86088618.
  • 100
    Ferri KF & Kroemer G (2001) Organelle-specific initiation of cell death pathways. Nat Cell Biol 3, E255E263.
  • 101
    Kadowaki H, Nishitoh H & Ichijo H (2004) Survival and apoptosis signals in ER stress: the role of protein kinases. J Chem Neuroanat 28, 93100.
  • 102
    Kim R, Emi M, Tanabe K & Murakami S (2006) Role of the unfolded protein response in cell death. Apoptosis 11, 513.
  • 103
    Oyadomari S & Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11, 381389.
  • 104
    Rao RV, Ellerby HM & Bredesen DE (2004) Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ 11, 372380.
  • 105
    Szegezdi E, Fitzgerald U & Samali A (2003) Caspase-12 and ER-stress-mediated apoptosis: the story so far. Ann N Y Acad Sci 1010, 186194.
  • 106
    Ma Y, Brewer JW, Diehl JA & Hendershot LM (2002) Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol 318, 13511365.
  • 107
    Ron D & Habener JF (1992) CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant- negative inhibitor of gene transcription. Genes Dev 6, 439453.
  • 108
    Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL & Ron D (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12, 982995.
  • 109
    Novoa I, Zeng H, Harding HP & Ron D (2001) Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 153, 10111022.
  • 110
    Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP & Ron D (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18, 30663077.
  • 111
    Yamaguchi H & Wang HG (2004) CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 279, 4549545502.
  • 112
    Sok J, Wang XZ, Batchvarova N, Kuroda M, Harding H & Ron D (1999) CHOP-Dependent stress-inducible expression of a novel form of carbonic anhydrase VI. Mol Cell Biol 19, 495504.
  • 113
    Wang XZ, Kuroda M, Sok J, Batchvarova N, Kimmel R, Chung P, Zinszner H & Ron D (1998) Identification of novel stress-induced genes downstream of chop. EMBO J 17, 36193630.
  • 114
    Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP & Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287, 664666.
  • 115
    Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A & Ichijo H (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 16, 13451355.
  • 116
    Mauro C, Crescenzi E, De Mattia R, Pacifico F, Mellone S, Salzano S, de Luca C, D'Adamio L, Palumbo G, Formisano S, et al. (2006) Central role of the scaffold protein tumor necrosis factor receptor-associated factor 2 in regulating endoplasmic reticulum stress-induced apoptosis. J Biol Chem 281, 26312638.
  • 117
    Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T & Tohyama M (2001) Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem 276, 1393513940.
  • 118
    Zhang C, Kawauchi J, Adachi MT, Hashimoto Y, Oshiro S, Aso T & Kitajima S (2001) Activation of JNK and transcriptional repressor ATF3/LRF1 through the IRE1/TRAF2 pathway is implicated in human vascular endothelial cell death by homocysteine. Biochem Biophys Res Commun 289, 718724.
  • 119
    Yang Q, Kim YS, Lin Y, Lewis J, Neckers L & Liu ZG (2006) Tumour necrosis factor receptor 1 mediates endoplasmic reticulum stress-induced activation of the MAP kinase JNK. EMBO Rep 7, 622627.
  • 120
    Hu P, Han Z, Couvillon AD, Kaufman RJ & Exton JH (2006) Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol 26, 30713084.
  • 121
    Ji C, Deng Q & Kaplowitz N (2004) Role of TNF-alpha in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury. Hepatology 40, 442451.
  • 122
    Cheung HH, Lynn Kelly N, Liston P & Korneluk RG (2006) Involvement of caspase-2 and caspase-9 in endoplasmic reticulum stress-induced apoptosis: A role for the IAPs. Exp Cell Res 312, 23472357.
  • 123
    Dahmer MK (2005) Caspases-2, -3, and -7 are involved in thapsigargin-induced apoptosis of SH-SY5Y neuroblastoma cells. J Neurosci Res 80, 576583.
  • 124
    Di Sano F, Ferraro E, Tufi R, Achsel T, Piacentini M & Cecconi F (2006) Endoplasmic reticulum stress induces apoptosis by an apoptosome-dependent but caspase 12-independent mechanism. J Biol Chem 281, 26932700.
  • 125
    Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, et al. (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol 165, 347356.
  • 126
    Kim SJ, Zhang Z, Hitomi E, Lee YC & Mukherjee AB (2006) Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL. Hum Mol Genet 15, 18261834.
  • 127
    Liu N, Scofield VL, Qiang W, Yan M, Kuang X & Wong PK (2006) Interaction between endoplasmic reticulum stress and caspase 8 activation in retrovirus MoMuLV-ts1-infected astrocytes. Virology 348, 398405.
  • 128
    Rao RV, Hermel E, Castro-Obregon S, del Rio G, Ellerby LM, Ellerby HM & Bredesen DE (2001) Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation. J Biol Chem 276, 3386933874.
  • 129
    Reddy RK, Mao C, Baumeister P, Austin RC, Kaufman RJ & Lee AS (2003) Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. J Biol Chem 278, 2091520924.
  • 130
    Song L, De Sarno P & Jope RS (2002) Central role of glycogen synthase kinase-3beta in endoplasmic reticulum stress-induced caspase-3 activation. J Biol Chem 277, 4470144708.
  • 131
    Warnakulasuriyarachchi D, Cerquozzi S, Cheung HH & Holcik M (2004) Translational induction of the inhibitor of apoptosis protein HIAP2 during endoplasmic reticulum stress attenuates cell death and is mediated via an inducible internal ribosome entry site element. J Biol Chem 279, 1714817157.
  • 132
    Tan Y, Dourdin N, Wu C, De Veyra T, Elce JS & Greer PA (2006) Ubiquitous calpains promote caspase-12 and Jnk activation during ER stress-induced apoptosis. J Biol Chem 281, 1601616024.
  • 133
    Morishima N, Nakanishi K, Takenouchi H, Shibata T & Yasuhiko Y (2002) An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem 277, 3428734294.
  • 134
    Nakagawa T & Yuan J (2000) Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol 150, 887894.
  • 135
    Bitko V & Barik S (2001) An endoplasmic reticulum-specific stress-activated caspase (caspase-12) is implicated in the apoptosis of A549 epithelial cells by respiratory syncytial virus. J Cell Biochem 80, 441454.
  • 136
    Kouroku Y, Fujita E, Jimbo A, Kikuchi T, Yamagata T, Momoi MY, Kominami E, Kuida K, Sakamaki K, Yonehara S, et al. (2002) Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation. Hum Mol Genet 11, 15051515.
  • 137
    Mouw G, Zechel JL, Gamboa J, Lust WD, Selman WR & Ratcheson RA (2003) Activation of caspase-12, an endoplasmic reticulum resident caspase, after permanent focal ischemia in rat. Neuroreport 14, 183186.
  • 138
    Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA & Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98103.
  • 139
    Shibata M, Hattori H, Sasaki T, Gotoh J, Hamada J & Fukuuchi Y (2003) Activation of caspase-12 by endoplasmic reticulum stress induced by transient middle cerebral artery occlusion in mice. Neuroscience 118, 491499.
  • 140
    Fischer H, Koenig U, Eckhart L & Tschachler E (2002) Human caspase 12 has acquired deleterious mutations. Biochem Biophys Res Commun 293, 722726.
  • 141
    McCullough KD, Martindale JL, Klotz LO, Aw TY & Holbrook NJ (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21, 12491259.
  • 142
    Contreras JL, Smyth CA, Bilbao G, Eckstein C, Young CJ, Thompson JA, Curiel DT & Eckhoff DE (2003) Coupling endoplasmic reticulum stress to cell death program in isolated human pancreatic islets: effects of gene transfer of Bcl-2. Transpl Int 16, 537542.
  • 143
    Elyaman W, Terro F, Suen KC, Yardin C, Chang RC & Hugon J (2002) BAD and Bcl-2 regulation are early events linking neuronal endoplasmic reticulum stress to mitochondria-mediated apoptosis. Brain Res Mol Brain Res 109, 233238.
  • 144
    Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T & Korsmeyer SJ (2003) BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300, 135139.
  • 145
    Zong WX, Li C, Hatzivassiliou G, Lindsten T, Yu QC, Yuan J & Thompson CB (2003) Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol 162, 5969.
  • 146
    Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B, Brandt GS, Iwakoshi NN, Schinzel A, Glimcher LH, et al. (2006) Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 312, 572576.
  • 147
    Zong WX, Lindsten T, Ross AJ, MacGregor GR & Thompson CB (2001) BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 15, 14811486.
  • 148
    Li J, Lee B & Lee AS (2006) Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. J Biol Chem 281, 72607270.
  • 149
    Reimertz C, Kogel D, Rami A, Chittenden T & Prehn JH (2003) Gene expression during ER stress-induced apoptosis in neurons: induction of the BH3-only protein Bbc3/PUMA and activation of the mitochondrial apoptosis pathway. J Cell Biol 162, 587597.
  • 150
    Morishima N, Nakanishi K, Tsuchiya K, Shibata T & Seiwa E (2004) Translocation of Bim to the endoplasmic reticulum (ER) mediates ER stress signaling for activation of caspase-12 during ER stress-induced apoptosis. J Biol Chem 279, 5037550381.
  • 151
    Chae HJ, Kim HR, Xu C, Bailly-Maitre B, Krajewska M, Krajewski S, Banares S, Cui J, Digicaylioglu M, Ke N, et al. (2004) BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Mol Cell 15, 355366.
  • 152
    Mathai JP, Germain M & Shore GC (2005) BH3-only BIK regulates BAX,BAK-dependent release of Ca2+ from endoplasmic reticulum stores and mitochondrial apoptosis during stress-induced cell death. J Biol Chem 280, 2382923836.
  • 153
    Zuppini A, Groenendyk J, Cormack LA, Shore G, Opas M, Bleackley RC & Michalak M (2002) Calnexin deficiency and endoplasmic reticulum stress-induced apoptosis. Biochemistry 41, 28502858.
  • 154
    Hu P, Han Z, Couvillon AD & Exton JH (2004) Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death. J Biol Chem 279, 4942049429.
  • 155
    Wootz H, Hansson I, Korhonen L & Lindholm D (2006) XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS transgenic mice. Exp Cell Res 312, 18901898.
  • 156
    Ito Y, Pandey P, Mishra N, Kumar S, Narula N, Kharbanda S, Saxena S & Kufe D (2001) Targeting of the c-Abl tyrosine kinase to mitochondria in endoplasmic reticulum stress-induced apoptosis. Mol Cell Biol 21, 62336242.
  • 157
    Li B, Cong F, Tan CP, Wang SX & Goff SP (2002) Aph2, a protein with a zf-DHHC motif, interacts with c-Abl and has pro-apoptotic activity. J Biol Chem 277, 2887028876.
  • 158
    Onuki R, Bando Y, Suyama E, Katayama T, Kawasaki H, Baba T, Tohyama M & Taira K (2004) An RNA-dependent protein kinase is involved in tunicamycin-induced apoptosis and Alzheimer's disease. EMBO J 23, 959968.
  • 159
    Hossain GS, van Thienen JV, Werstuck GH, Zhou J, Sood SK, Dickhout JG, de Koning AB, Tang D, Wu D, Falk E, et al. (2003) TDAG51 is induced by homocysteine, promotes detachment-mediated programmed cell death, and contributes to the cevelopment of atherosclerosis in hyperhomocysteinemia. J Biol Chem 278, 3031730327.
  • 160
    Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ & Diehl JA (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23, 71987209.
  • 161
    Wang W & Chan JY (2006) Nrf1 is targeted to the ER membrane by a N-terminal transmembrane domain: inhibition of nuclear translocation and transacting function. J Biol Chem 281, 1967619687.
  • 162
    Nakanishi K, Sudo T & Morishima N (2005) Endoplasmic reticulum stress signaling transmitted by ATF6 mediates apoptosis during muscle development. J Cell Biol 169, 555560.
  • 163
    Corcoran CA, Luo X, He Q, Jiang C, Huang Y & Sheikh MS (2005) Genotoxic and endoplasmic reticulum stresses differentially regulate TRB3 expression. Cancer Biol Ther 4, 10631067.
  • 164
    Ohoka N, Yoshii S, Hattori T, Onozaki K & Hayashi H (2005) TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J 24, 12431255.
  • 165
    Pluquet O, Qu LK, Baltzis D & Koromilas AE (2005) Endoplasmic reticulum stress accelerates p53 degradation by the cooperative actions of Hdm2 and glycogen synthase kinase 3beta. Mol Cell Biol 25, 93929405.
  • 166
    Qu L, Huang S, Baltzis D, Rivas-Estilla AM, Pluquet O, Hatzoglou M, Koumenis C, Taya Y, Yoshimura A & Koromilas AE (2004) Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3beta. Genes Dev 18, 261277.
  • 167
    Qu L & Koromilas AE (2004) Control of tumor suppressor p53 function by endoplasmic reticulum stress. Cell Cycle 3, 567570.
  • 168
    Adachi K, Toyota M, Sasaki Y, Yamashita T, Ishida S, Ohe-Toyota M, Maruyama R, Hinoda Y, Saito T, Imai K, et al. (2004) Identification of SCN3B as a novel p53-inducible proapoptotic gene. Oncogene 23, 77917798.
  • 169
    Bourdon JC, Renzing J, Robertson PL, Fernandes KN & Lane DP (2002) Scotin, a novel p53-inducible proapoptotic protein located in the ER and the nuclear membrane. J Cell Biol 158, 235246.
  • 170
    Aoki S, Su Q, Li H, Nishikawa K, Ayukawa K, Hara Y, Namikawa K, Kiryu-Seo S, Kiyama H & Wada K (2002) Identification of an axotomy-induced glycosylated protein, AIGP1, possibly involved in cell death triggered by endoplasmic reticulum-Golgi stress. J Neurosci 22, 1075110760.
  • 171
    Talapatra S, Wagner JD & Thompson CB (2002) Elongation factor-1 alpha is a selective regulator of growth factor withdrawal and ER stress-induced apoptosis. Cell Death Differ 9, 856861.
  • 172
    Wang X, Shao Z, Zetoune FS, Zeidler MG, Gowrishankar K & Vincenz C (2003) NRADD, a novel membrane protein with a death domain involved in mediating apoptosis in response to ER stress. Cell Death Differ 10, 580591.
  • 173
    Bence NF, Sampat RM & Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292, 15521555.
  • 174
    Schaffar G, Breuer P, Boteva R, Behrends C, Tzvetkov N, Strippel N, Sakahira H, Siegers K, Hayer-Hartl M & Hartl FU (2004) Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol Cell 15, 95105.
  • 175
    Sugars KL & Rubinsztein DC (2003) Transcriptional abnormalities in Huntington disease. Trends Genet 19, 233238.
  • 176
    Kopito RR (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10, 524530.
  • 177
    Behrends C, Langer CA, Boteva R, Bottcher UM, Stemp MJ, Schaffar G, Rao BV, Giese A, Kretzschmar H, Siegers K, et al. (2006) Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers. Mol Cell 23, 887897.
  • 178
    Chan HY, Warrick JM, Gray-Board GL, Paulson HL & Bonini NM (2000) Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum Mol Genet 9, 28112820.
  • 179
    Cummings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr HT & Zoghbi HY (1998) Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 19, 148154.
  • 180
    Muchowski PJ, Schaffar G, Sittler A, Wanker EE, Hayer-Hartl MK & Hartl FU (2000) Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc Natl Acad Sci USA 97, 78417846.
  • 181
    Nollen EA, Garcia SM, van Haaften G, Kim S, Chavez A, Morimoto RI & Plasterk RH (2004) Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc Natl Acad Sci USA 101, 64036408.
  • 182
    Forman MS, Lee VM & Trojanowski JQ (2003) ‘Unfolding’ pathways in neurodegenerative disease. Trends Neurosci 26, 407410.
  • 183
    Gow A & Sharma R (2003) The unfolded protein response in protein aggregating diseases. Neuromolecular Med 4, 7394.
  • 184
    Zhao L, Longo-Guess C, Harris BS, Lee JW & Ackerman SL (2005) Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP. Nat Genet 37, 974979.
  • 185
    Imaizumi K, Katayama T & Tohyama M (2001) Presenilin and the UPR. Nat Cell Biol 3, E104.
  • 186
    Lindholm D, Wootz H & Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13, 385392.
  • 187
    Mattson MP, Gary DS, Chan SL & Duan W (2001) Perturbed endoplasmic reticulum function, synaptic apoptosis and the pathogenesis of Alzheimer's disease. Biochem Soc Symp 151162.
  • 188
    Mattson MP, Guo Q, Furukawa K & Pedersen WA (1998) Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer's disease. J Neurochem 70, 114.
  • 189
    Paschen W & Mengesdorf T (2005) Endoplasmic reticulum stress response and neurodegeneration. Cell Calcium 38, 409415.
  • 190
    Pereira C, Ferreiro E, Cardoso SM & de Oliveira CR (2004) Cell degeneration induced by amyloid-beta peptides: implications for Alzheimer's disease. J Mol Neurosci 23, 97104.
  • 191
    Zhang K & Kaufman RJ (2006) The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology 66, S102S109.
  • 192
    Katayama T, Imaizumi K, Sato N, Miyoshi K, Kudo T, Hitomi J, Morihara T, Yoneda T, Gomi F, Mori Y, et al. (1999) Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat Cell Biol 1, 479485.
  • 193
    Katayama T, Imaizumi K, Honda A, Yoneda T, Kudo T, Takeda M, Mori K, Rozmahel R, Fraser P, George-Hyslop PS, et al. (2001) Disturbed activation of endoplasmic reticulum stress transducers by familial Alzheimer's disease-linked presenilin-1 mutations. J Biol Chem 276, 4344643454.
  • 194
    Hoozemans JJ, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P & Scheper W (2005) The unfolded protein response is activated in Alzheimer's disease. Acta Neuropathol (Berl) 110, 165172.
  • 195
    Unterberger U, Hoftberger R, Gelpi E, Flicker H, Budka H & Voigtlander T (2006) Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo. J Neuropathol Exp Neurol 65, 348357.
  • 196
    Saltini G, Dominici R, Lovati C, Cattaneo M, Michelini S, Malferrari G, Caprera A, Milanesi L, Finazzi D, Bertora P, et al. (2006) A novel polymorphism in SEL1L confers susceptibility to Alzheimer's disease. Neurosci Lett 398, 5358.
  • 197
    Kahle PJ & Haass C (2004) How does parkin ligate ubiquitin to Parkinson's disease? EMBO Rep 5, 681685.
  • 198
    Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, et al. (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25, 302305.
  • 199
    Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y & Takahashi R (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891902.
  • 200
    Imai Y, Soda M & Takahashi R (2000) Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem 275, 3566135664.
  • 201
    Osaka H, Wang YL, Takada K, Takizawa S, Setsuie R, Li H, Sato Y, Nishikawa K, Sun YJ, Sakurai M, et al. (2003) Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron. Hum Mol Genet 12, 19451958.
  • 202
    Saigoh K, Wang YL, Suh JG, Yamanishi T, Sakai Y, Kiyosawa H, Harada T, Ichihara N, Wakana S, Kikuchi T & Wada K (1999) Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nat Genet 23, 4751.
  • 203
    Liu Y, Fallon L, Lashuel HA, Liu Z & Lansbury PT Jr (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell 111, 209218.
  • 204
    Holtz WA & O'Malley KL (2003) Parkinsonian mimetics induce aspects of unfolded protein response in death of dopaminergic neurons. J Biol Chem 278, 1936719377.
  • 205
    Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, Ron D & Greene LA (2002) Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson's disease. J Neurosci 22, 1069010698.
  • 206
    Conn KJ, Gao W, McKee A, Lan MS, Ullman MD, Eisenhauer PB, Fine RE & Wells JM (2004) Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson's disease and Lewy body pathology. Brain Res 1022, 164172.
  • 207
    Thomas MYuZ, Dadgar N, Varambally SYuJ, Chinnaiyan AM & Lieberman AP (2005) The unfolded protein response modulates toxicity of the expanded glutamine androgen receptor. J Biol Chem 280, 2126421271.
  • 208
    Kobayashi T, Tanaka K, Inoue K & Kakizuka A (2002) Functional ATPase activity of p97/valosin-containing protein (VCP) is required for the quality control of endoplasmic reticulum in neuronally differentiated mammalian PC12 cells. J Biol Chem 277, 4735847365.
  • 209
    Southwood C & Gow A (2001) Molecular pathways of oligodendrocyte apoptosis revealed by mutations in the proteolipid protein gene. Microsc Res Tech 52, 700708.
  • 210
    Gow A & Lazzarini RA (1996) A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease. Nat Genet 13, 422428.
  • 211
    Osaka H, Inoue K, Kawanishi C, Yamada Y, Onishi H, Sugiyama N, Suzuki K, Nezu A, Kimura S & Kosaka K (1995) MvaI polymorphism in the proteolipid protein (PLP) gene. Hum Genet 95, 461.
  • 212
    Southwood CM, Garbern J, Jiang W & Gow A (2002) The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher disease. Neuron 36, 585596.
  • 213
    Castilla J, Hetz C & Soto C (2004) Molecular mechanisms of neurotoxicity of pathological prion protein. Curr Mol Med 4, 397403.
  • 214
    Hetz C, Russelakis-Carneiro M, Maundrell K, Castilla J & Soto C (2003) Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J 22, 54355445.
  • 215
    Hetz C, Russelakis-Carneiro M, Walchli S, Carboni S, Vial-Knecht E, Maundrell K, Castilla J & Soto C (2005) The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity. J Neurosci 25, 27932802.
  • 216
    Kikuchi H, Almer G, Yamashita S, Guegan C, Nagai M, Xu Z, Sosunov AA, McKhann GM, 2nd & Przedborski S (2006) Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc Natl Acad Sci USA 103, 60256030.
  • 217
    Tobisawa S, Hozumi Y, Arawaka S, Koyama S, Wada M, Nagai M, Aoki M, Itoyama Y, Goto K & Kato T (2003) Mutant SOD1 linked to familial amyotrophic lateral sclerosis, but not wild-type SOD1, induces ER stress in COS7 cells and transgenic mice. Biochem Biophys Res Commun 303, 496503.
  • 218
    Wootz H, Hansson I, Korhonen L, Napankangas U & Lindholm D (2004) Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS. Biochem Biophys Res Commun 322, 281286.
  • 219
    Tessitore APMM, Sano R, Ma Y, Mann L, Ingrassia A, Laywell ED, Steindler DA, Hendershot LM & d'Azzo A (2004) GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. Mol Cell 15, 753766.
  • 220
    Bown CD, Wang JF, Chen B & Young LT (2002) Regulation of ER stress proteins by valproate: therapeutic implications. Bipolar Disord 4, 145151.
  • 221
    Kakiuchi C, Ishiwata M, Nanko S, Kunugi H, Minabe Y, Nakamura K, Mori N, Fujii K, Umekage T, Tochigi M, et al. (2005) Functional polymorphisms of HSPA5: possible association with bipolar disorder. Biochem Biophys Res Commun 336, 11361143.
  • 222
    Kakiuchi C, Ishiwata M, Umekage T, Tochigi M, Kohda K, Sasaki T & Kato T (2004) Association of the XBP1–116C/G polymorphism with schizophrenia in the Japanese population. Psychiatry Clin Neurosci 58, 438440.
  • 223
    Kakiuchi C, Iwamoto K, Ishiwata M, Bundo M, Kasahara T, Kusumi I, Tsujita T, Okazaki Y, Nanko S, Kunugi H, et al. (2003) Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat Genet 35, 171175.
  • 224
    Kusumi I, Masui T, Kakiuchi C, Suzuki K, Akimoto T, Hashimoto R, Kunugi H, Kato T & Koyama T (2005) Relationship between XBP1 genotype and personality traits assessed by TCI and NEO-FFI. Neurosci Lett 391, 710.
  • 225
    Cichon S, Buervenich S, Kirov G, Akula N, Dimitrova A, Green E, Schumacher J, Klopp N, Becker T, Ohlraun S, et al. (2004) Lack of support for a genetic association of the XBP1 promoter polymorphism with bipolar disorder in probands of European origin. Nat Genet 36, 783784; author reply 784–785.
  • 226
    Shao L, Sun X, Xu L, Young LT & Wang JF (2006) Mood stabilizing drug lithium increases expression of endoplasmic reticulum stress proteins in primary cultured rat cerebral cortical cells. Life Sci 78, 13171323.
  • 227
    Araki E, Oyadomari S & Mori M (2003) Endoplasmic reticulum stress and diabetes mellitus. Intern Med 42, 714.
  • 228
    Harding HP & Ron D (2002) Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 51 (Suppl. 3), S455S461.
  • 229
    Oyadomari S, Araki E & Mori M (2002) Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis 7, 335345.
  • 230
    Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM & Julier C (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott–Rallison syndrome. Nat Genet 25, 406409.
  • 231
    Zhang P, McGrath B, Li S, Frank A, Zambito F, Reinert J, Gannon M, Ma K, McNaughton K & Cavener DR (2002) The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol Cell Biol 22, 38643874.
  • 232
    Scheuner D, Mierde DV, Song B, Flamez D, Creemers JW, Tsukamoto K, Ribick M, Schuit FC & Kaufman RJ (2005) Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nat Med 11, 757764.
  • 233
    Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P, Saunders T, Bonner-Weir S & Kaufman RJ (2001) Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol Cell 7, 11651176.
  • 234
    Oyadomari S, Koizumi A, Takeda K, Gotoh T, Akira S, Araki E & Mori M (2002) Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Invest 109, 525532.
  • 235
    Allen JR, Nguyen LX, Sargent KE, Lipson KL, Hackett A & Urano F (2004) High ER stress in beta-cells stimulates intracellular degradation of misfolded insulin. Biochem Biophys Res Commun 324, 166170.
  • 236
    Nozaki J, Kubota H, Yoshida H, Naitoh M, Goji J, Yoshinaga T, Mori K, Koizumi A & Nagata K (2004) The endoplasmic reticulum stress response is stimulated through the continuous activation of transcription factors ATF6 and XBP1 in Ins2+/Akita pancreatic beta cells. Genes Cells 9, 261270.
  • 237
    Ladiges WC, Knoblaugh SE, Morton JF, Korth MJ, Sopher BL, Baskin CR, MacAuley A, Goodman AG, LeBoeuf RC & Katze MG (2005) Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes 54, 10741081.
  • 238
    Fonseca SG, Fukuma M, Lipson KL, Nguyen LX, Allen JR, Oka Y & Urano F (2005) WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem 280, 3960939615.
  • 239
    Yamada T, Ishihara H, Tamura A, Takahashi R, Yamaguchi S, Takei D, Tokita A, Satake C, Tashiro F, Katagiri H, et al. (2006) WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet 15, 16001609.
  • 240
    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH & Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457461.
  • 241
    Nakatani Y, Kaneto H, Kawamori D, Yoshiuchi K, Hatazaki M, Matsuoka TA, Ozawa K, Ogawa S, Hori M, Yamasaki Y, et al. (2005) Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J Biol Chem 280, 847851.
  • 242
    Thameem F, Farook VS, Bogardus C & Prochazka M (2006) Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians. Diabetes 55, 839842.
  • 243
    Austin RC, Lentz SR & Werstuck GH (2004) Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ 11 (Suppl. 1), S56S64.
  • 244
    Lawrence de Koning AB, Werstuck GH, Zhou J & Austin RC (2003) Hyperhomocysteinemia and its role in the development of atherosclerosis. Clin Biochem 36, 431441.
  • 245
    Werstuck GH, Lentz SR, Dayal S, Hossain GS, Sood SK, Shi YY, Zhou J, Maeda N, Krisans SK, Malinow MR, et al. (2001) Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest 107, 12631273.
  • 246
    Zhou J, Werstuck GH, Lhotak S, de Koning AB, Sood SK, Hossain GS, Moller J, Ritskes-Hoitinga M, Falk E, Dayal S, et al. (2004) Association of multiple cellular stress pathways with accelerated atherosclerosis in hyperhomocysteinemic apolipoprotein E-deficient mice. Circulation 110, 207213.
  • 247
    Devries-Seimon T, Li Y, Yao PM, Stone E, Wang Y, Davis RJ, Flavell R & Tabas I (2005) Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. J Cell Biol 171, 6173.
  • 248
    Feng B, Yao PM, Li Y, Devlin CM, Zhang D, Harding HP, Sweeney M, Rong JX, Kuriakose G, Fisher EA, et al. (2003) The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol 5, 781792.
  • 249
    Han S, Liang CP, DeVries-Seimon T, Ranalletta M, Welch CL, Collins-Fletcher K, Accili D, Tabas I & Tall AR (2006) Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell Metab 3, 257266.
  • 250
    Lin W, Harding HP, Ron D & Popko B (2005) Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-gamma. J Cell Biol 169, 603612.
  • 251
    Endo M, Mori M, Akira S & Gotoh T (2006) C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation. J Immunol 176, 62456253.
  • 252
    Yamazaki T, Muramoto M, Oe T, Morikawa N, Okitsu O, Nagashima T, Nishimura S, Katayama Y & Kita Y (2006) Diclofenac, a non-steroidal anti-inflammatory drug, suppresses apoptosis induced by endoplasmic reticulum stresses by inhibiting caspase signaling. Neuropharmacology 50, 558567.
  • 253
    Gotoh T & Mori M (1999) Arginase II downregulates nitric oxide (NO) production and prevents NO-mediated apoptosis in murine macrophage-derived RAW 264.7 cells. J Cell Biol 144, 427434.
  • 254
    Gotoh T & Mori M (2006) Nitric oxide and endoplasmic reticulum stress. Arterioscler Thromb Vasc Biol 26, 14391446.
  • 255
    Gotoh T, Oyadomari S, Mori K & Mori M (2002) Nitric oxide-induced apoptosis in RAW 264.7 macrophages is mediated by endoplasmic reticulum stress pathway involving ATF6 and CHOP. J Biol Chem 277, 1234312350.
  • 256
    Gotoh T, Terada K, Oyadomari S & Mori M (2004) hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria. Cell Death Differ 11, 390402.
  • 257
    Oyadomari S, Takeda K, Takiguchi M, Gotoh T, Matsumoto M, Wada I, Akira S, Araki E & Mori M (2001) Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway. Proc Natl Acad Sci USA 98, 1084510850.
  • 258
    Purcell AW, Todd A, Kinoshita G, Lynch TA, Keech CL, Gething MJ & Gordon TP (2003) Association of stress proteins with autoantigens: a possible mechanism for triggering autoimmunity? Clin Exp Immunol 132, 193200.
  • 259
    Nagaraju K, Casciola-Rosen L, Lundberg I, Rawat R, Cutting S, Thapliyal R, Chang J, Dwivedi S, Mitsak M, Chen YW, et al. (2005) Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum 52, 18241835.
  • 260
    Yamasaki S, Yagishita N, Tsuchimochi K, Nishioka K & Nakajima T (2005) Rheumatoid arthritis as a hyper-endoplasmic-reticulum-associated degradation disease. Arthritis Res Ther 7, 181186.
  • 261
    Rissanen A, Sivenius J & Jolkkonen J (2006) Prolonged bihemispheric alterations in unfolded protein response related gene expression after experimental stroke. Brain Res 1087, 6066.
  • 262
    Tajiri S, Oyadomari S, Yano S, Morioka M, Gotoh T, Hamada JI, Ushio Y & Mori M (2004) Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ 11, 403415.
  • 263
    Azfer A, Niu J, Rogers LM, Adamski FM & Kolattukudy PE (2006) Activation of endoplasmic reticulum stress response during the development of ischemic heart disease. Am J Physiol Heart Circ Physiol 291, H1411H1420.
  • 264
    Okada K, Minamino T, Tsukamoto Y, Liao Y, Tsukamoto O, Takashima S, Hirata A, Fujita M, Nagamachi Y, Nakatani T, et al. (2004) Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 110, 705712.
  • 265
    Hamada H, Suzuki M, Yuasa S, Mimura N, Shinozuka N, Takada Y, Suzuki M, Nishino T, Nakaya H, Koseki H, et al. (2004) Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice. Mol Cell Biol 24, 80078017.
  • 266
    Martindale JJ, Fernandez R, Thuerauf D, Whittaker R, Gude N, Sussman MA & Glembotski CC (2006) Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6. Circ Res 98, 11861193.
  • 267
    Ji C & Kaplowitz N (2006) ER stress: can the liver cope? J Hepatol 45, 321333.
  • 268
    Ji C & Kaplowitz N (2004) Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury. World J Gastroenterol 10, 16991708.
  • 269
    Kaplowitz N & Ji C (2006) Unfolding new mechanisms of alcoholic liver disease in the endoplasmic reticulum. J Gastroenterol Hepatol 21, S7S9.
  • 270
    Ji C & Kaplowitz N (2003) Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology 124, 14881499.
  • 271
    Ji C, Mehrian-Shai R, Chan C, Hsu YH & Kaplowitz N (2005) Role of CHOP in hepatic apoptosis in the murine model of intragastric ethanol feeding. Alcohol Clin Exp Res 29, 14961503.
  • 272
    Arai M, Kondoh N, Imazeki N, Hada A, Hatsuse K, Kimura F, Matsubara O, Mori K, Wakatsuki T & Yamamoto M (2006) Transformation-associated gene regulation by ATF6alpha during hepatocarcinogenesis. FEBS Lett 580, 184190.
  • 273
    Chiang PC, Chien CL, Pan SL, Chen WP, Teng CM, Shen YC & Guh JH (2005) Induction of endoplasmic reticulum stress and apoptosis by a marine prostanoid in human hepatocellular carcinoma. J Hepatol 43, 679686.
  • 274
    Shuda M, Kondoh N, Imazeki N, Tanaka K, Okada T, Mori K, Hada A, Arai M, Wakatsuki T, Matsubara O, et al. (2003) Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 38, 605614.
  • 275
    Lorz C, Justo P, Sanz A, Subira D, Egido J & Ortiz A (2004) Paracetamol-induced renal tubular injury: a role for ER stress. J Am Soc Nephrol 15, 380389.
  • 276
    Cybulsky AV, Takano T, Papillon J & Bijian K (2005) Role of the endoplasmic reticulum unfolded protein response in glomerular epithelial cell injury. J Biol Chem 280, 2439624403.
  • 277
    Inagi R, Nangaku M, Onogi H, Ueyama H, Kitao Y, Nakazato K, Ogawa S, Kurokawa K, Couser WG & Miyata T (2005) Involvement of endoplasmic reticulum (ER) stress in podocyte injury induced by excessive protein accumulation. Kidney Int 68, 26392650.
  • 278
    Miyata T, Inagi R, Sugiyama S & Usuda N (2005) Serpinopathy and endoplasmic reticulum stress. Med Mol Morph 38, 7378.
  • 279
    Asmellash S, Stevens JL & Ichimura T (2005) Modulating the endoplasmic reticulum stress response with trans-4,5-dihydroxy-1,2-dithiane prevents chemically induced renal injury in vivo. Toxicol Sci 88, 576584.
  • 280
    Wang HC, Chang WT, Chang WW, Wu HC, Huang W, Lei HY, Lai MD, Fausto N & Su IJ (2005) Hepatitis B virus pre-S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes. Hepatology 41, 761770.
  • 281
    Wang HC, Wu HC, Chen CF, Fausto N, Lei HY & Su IJ (2003) Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific pre-S mutants that may induce endoplasmic reticulum stress. Am J Pathol 163, 24412449.
  • 282
    Benali-Furet NL, Chami M, Houel L, De Giorgi F, Vernejoul F, Lagorce D, Buscail L, Bartenschlager R, Ichas F, Rizzuto R, et al. (2005) Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion. Oncogene 24, 49214933.
  • 283
    Huang IC, Chien CY, Huang CR & Lo SJ (2006) Induction of hepatitis D virus large antigen translocation to the cytoplasm by hepatitis B virus surface antigens correlates with endoplasmic reticulum stress and NF-kappaB activation. J Gen Virol 87, 17151723.
  • 284
    Yu CY, Hsu YW, Liao CL & Lin YL (2006) Flavivirus infection activates XBP1 pathway of the unfolded protein response to cope with endoplasmic reticulum stress. J Virol 80, 1186811880.
  • 285
    Williams BL & Lipkin WI (2006) Endoplasmic reticulum stress and neurodegeneration in rats neonatally infected with borna disease virus. J Virol 80, 86138626.
  • 286
    Dimcheff DE, Volkert LG, Li Y, DeLucia AL & Lynch WP (2006) Gene expression profiling of microglia infected by a highly neurovirulent murine leukemia virus: implications for neuropathogenesis. Retrovirology 3, 26.
  • 287
    Bergeron A, Jorquera R, Orejuela D & Tanguay RM (2006) Involvement of endoplasmic reticulum stress in hereditary tyrosinemia type I. J Biol Chem 281, 53295334.
  • 288
    Berger EG & Roth J (1997) The Golgi Apparatus. Birkhauser-Verlag, Basel.
  • 289
    Hicks SW & Machamer CE (2005) Golgi structure in stress sensing and apoptosis. Biochim Biophys Acta 1744, 406414.