• 1
    Lu Y, Xiong X, Helm A, Kimani K, Bragin A & Skach WR (1998) Co- and posttranslational translocation mechanisms direct cystic fibrosis transmembrane conductance regulator N terminus transmembrane assembly. J Biol Chem 273, 568576.
  • 2
    Hammond C & Helenius A (1995) Quality control in the secretory pathway. Curr Opin Cell Biol 7, 523529.
  • 3
    Skach WR (2000) Defects in processing and trafficking of the cystic fibrosis transmembrane conductance regulator. Kidney Int 57, 825831.
  • 4
    Amaral MD (2004) CFTR and chaperones: processing and degradation. J Mol Neurosci 23, 4148.
  • 5
    Amaral MD (2005) Processing of CFTR: traversing the cellular maze – how much CFTR needs to go through to avoid cystic fibrosis? Ped Pulmonol 39, 479491.
  • 6
    Caramelo JJ & Parodi AJ (2007) How sugars convey information on protein conformation in the endoplasmic reticulum. Semin Cell Dev Biol 18, 732742.
  • 7
    Cheng SH, Gregory RJ, Marshall J, Paul S, Souza DW, White GA, O'Riordan CR & Smith AE (1990) Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 63, 827834.
  • 8
    Cioaca D, Ghenea S, Spiridon LN, Marin M, Petrescu AJ & Petrescu SM (2011) C-terminus glycans with critical functional role in the maturation of secretory glycoproteins. PLoS ONE 6, e19979.
  • 9
    Vashist S & Ng DT (2004) Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control. J Cell Biol 165, 4152.
  • 10
    Amaral MD & Farinha CM (2013) Rescuing mutant CFTR: a multi-task approach to a better outcome in treating cystic fibrosis. Curr Pharm Des 19, 34973508.
  • 11
    Farinha CM, Nogueira P, Mendes F, Penque D & Amaral MD (2002) The human DnaJ homologue (Hdj)-1/heat-shock protein (Hsp) 40 co-chaperone is required for the in vivo stabilization of the cystic fibrosis transmembrane conductance regulator by Hsp70. Biochem J 366, 797806.
  • 12
    Loo MA, Jensen TJ, Cui L, Hou Y, Chang XB & Riordan JR (1998) Perturbation of Hsp90 interaction with nascent CFTR prevents its maturation and accelerates its degradation by the proteasome. EMBO J 17, 68796887.
  • 13
    Meacham GC, Lu Z, King S, Sorscher E, Tousson A & Cyr DM (1999) The Hdj-2/Hsc70 chaperone pair facilitates early steps in CFTR biogenesis. EMBO J 18, 14921505.
  • 14
    Zhang Y, Nijbroek G, Sullivan ML, McCracken AA, Watkins SC, Michaelis S & Brodsky JL (2001) Hsp70 molecular chaperone facilitates endoplasmic reticulum-associated protein degradation of cystic fibrosis transmembrane conductance regulator in yeast. Mol Biol Cell 12, 13031314.
  • 15
    Coppinger JA, Hutt DM, Razvi A, Koulov AV, Pankow S, Yates JR 3rd & Balch WE (2012) A chaperone trap contributes to the onset of cystic fibrosis. PLoS ONE 7, e37682.
  • 16
    Scott-Ward TS & Amaral MD (2009) Deletion of Phe508 in the first nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator increases its affinity for the heat shock cognate 70 chaperone. FEBS J 276, 70977109.
  • 17
    Farinha CM & Amaral MD (2005) Most F508del-CFTR is targeted to degradation at an early folding checkpoint and independently of calnexin. Mol Cell Biol 25, 52425252.
  • 18
    Lewis HA, Zhao X, Wang C, Sauder JM, Rooney I, Noland BW, Lorimer D, Kearins MC, Conners K, Condon B et al. (2005) Impact of the deltaF508 mutation in first nucleotide-binding domain of human cystic fibrosis transmembrane conductance regulator on domain folding and structure. J Biol Chem 280, 13461353.
  • 19
    Serohijos AW, Hegedus T, Aleksandrov AA, He L, Cui L, Dokholyan NV & Riordan JR (2008) Phenylalanine-508 mediates a cytoplasmic–membrane domain contact in the CFTR 3D structure crucial to assembly and channel function. Proc Natl Acad Sci USA 105, 32563261.
  • 20
    Thibodeau PH, Richardson JM, Wang W, Millen L, Watson JM, Mendoza JL, Du K, Fischman S, Senderowitz H, Lukacs GL et al. (2010) The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis. J Biol Chem 285, 3582535835.
  • 21
    Meacham GC, Patterson C, Zhang W, Younger JM & Cyr DM (2001) The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol 3, 100105.
  • 22
    Roxo-Rosa M, Xu Z, Schmidt A, Neto M, Cai Z, Soares CM, Sheppard DN & Amaral MD (2006) Revertant mutants G550E and 4RK rescue cystic fibrosis mutants in the first nucleotide-binding domain of CFTR by different mechanisms. Proc Natl Acad Sci USA 103, 1789117896.
  • 23
    Chang X, Cui L, Hou Y, Jensen TJ, Aleksandrov AA, Mengos A & Riordan JR (1999) Removal of multiple arginine-framed trafficking signals overcomes misprocessing of delta F508 CFTR present in most patients with cystic fibrosis. Mol Cell 4, 137142.
  • 24
    Nishimura N & Balch WE (1997) A di-acidic signal required for selective export from the endoplasmic reticulum. Science 277, 556558.
  • 25
    Wang X, Matteson J, An Y, Moyer B, Yoo JS, Bannykh S, Wilson IA, Riordan JR & Balch WE (2004) COPII-dependent export of cystic fibrosis transmembrane conductance regulator from the ER uses a di-acidic exit code. J Cell Biol 167, 6574.
  • 26
    Bannykh SI, Bannykh GI, Fish KN, Moyer BD, Riordan JR & Balch WE (2000) Traffic pattern of cystic fibrosis transmembrane regulator through the early exocytic pathway. Traffic 1, 852870.
  • 27
    Yoo JS, Moyer BD, Bannykh S, Yoo HM, Riordan JR & Balch WE (2002) Non-conventional trafficking of the cystic fibrosis transmembrane conductance regulator through the early secretory pathway. J Biol Chem 277, 1140111409.
  • 28
    Bonifacino JS & Rojas R (2006) Retrograde transport from endosomes to the trans-Golgi network. Nat Rev Mol Cell Biol 7, 568579.
  • 29
    Gee HY, Noh SH, Tang BL, Kim KH & Lee MG (2011) Rescue of DeltaF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway. Cell 146, 746760.
  • 30
    Johnston JA, Ward CL & Kopito RR (1998) Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143, 18831898.
  • 31
    Luciani A, Villella VR, Esposito S, Gavina M, Russo I, Silano M, Guido S, Pettoello-Mantovani M, Carnuccio R, Scholte B et al. (2012) Targeting autophagy as a novel strategy for facilitating the therapeutic action of potentiators on DeltaF508 cystic fibrosis transmembrane conductance regulator. Autophagy 8, 16571672.
  • 32
    Luciani A, Villella VR, Esposito S, Brunetti-Pierri N, Medina D, Settembre C, Gavina M, Pulze L, Giardino I, Pettoello-Mantovani M et al. (2010) Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat Cell Biol 12, 863875.
  • 33
    Abdulrahman BA, Khweek AA, Akhter A, Caution K, Kotrange S, Abdelaziz DH, Newland C, Rosales-Reyes R, Kopp B, McCoy K et al. (2011) Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis. Autophagy 7, 13591370.
  • 34
    Okiyoneda T, Barriere H, Bagdany M, Rabeh WM, Du K, Hohfeld J, Young JC & Lukacs GL (2010) Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science 329, 805810.
  • 35
    Mitin N, Rossman KL & Der CJ (2005) Signaling interplay in Ras superfamily function. Curr Biol 15, R563R574.
  • 36
    Rojas AM, Fuentes G, Rausell A & Valencia A (2012) The Ras protein superfamily: evolutionary tree and role of conserved amino acids. J Cell Biol 196, 189201.
  • 37
    Ten Klooster JP & Hordijk PL (2007) Targeting and localized signalling by small GTPases. Biol Cell 99, 112.
  • 38
    Barr FA (2009) Rab GTPase function in Golgi trafficking. Semin Cell Dev Biol 20, 780783.
  • 39
    Mizuno-Yamasaki E, Rivera-Molina F & Novick P (2012) GTPase networks in membrane traffic. Annu Rev Biochem 81, 637659.
  • 40
    Ameen N, Silvis M & Bradbury NA (2007) Endocytic trafficking of CFTR in health and disease. J Cyst Fibros 6, 114.
  • 41
    Swiatecka-Urban A, Talebian L, Kanno E, Moreau-Marquis S, Coutermarsh B, Hansen K, Karlson KH, Barnaby R, Cheney RE, Langford GM et al. (2007) Myosin Vb is required for trafficking of the cystic fibrosis transmembrane conductance regulator in Rab11a-specific apical recycling endosomes in polarized human airway epithelial cells. J Biol Chem 282, 2372523736.
  • 42
    Prince LS, Peter K, Hatton SR, Zaliauskiene L, Cotlin LF, Clancy JP, Marchase RB & Collawn JF (1999) Efficient endocytosis of the cystic fibrosis transmembrane conductance regulator requires a tyrosine-based signal. J Biol Chem 274, 36023609.
  • 43
    Okiyoneda T & Lukacs GL (2007) Cell surface dynamics of CFTR: the ins and outs. Biochim Biophys Acta 1773, 476479.
  • 44
    Silvis MR, Bertrand CA, Ameen N, Golin-Bisello F, Butterworth MB, Frizzell RA & Bradbury NA (2009) Rab11b regulates the apical recycling of the cystic fibrosis transmembrane conductance regulator in polarized intestinal epithelial cells. Mol Biol Cell 20, 23372350.
  • 45
    Fukuda M (2008) Regulation of secretory vesicle traffic by Rab small GTPases. Cell Mol Life Sci 65, 28012813.
  • 46
    Saxena SK & Kaur S (2006) Rab27a negatively regulates CFTR chloride channel function in colonic epithelia: involvement of the effector proteins in the regulatory mechanism. Biochem Biophys Res Commun 346, 259267.
  • 47
    Saxena SK, Kaur S & George C (2006) Rab4GTPase modulates CFTR function by impairing channel expression at plasma membrane. Biochem Biophys Res Commun 341, 184191.
  • 48
    Gentzsch M, Chang XB, Cui L, Wu Y, Ozols VV, Choudhury A, Pagano RE & Riordan JR (2004) Endocytic trafficking routes of wild type and DeltaF508 cystic fibrosis transmembrane conductance regulator. Mol Biol Cell 15, 26842696.
  • 49
    Swiatecka-Urban A, Brown A, Moreau-Marquis S, Renuka J, Coutermarsh B, Barnaby R, Karlson KH, Flotte TR, Fukuda M, Langford GMA et al. (2005) The short apical membrane half-life of rescued {Delta}F508-cystic fibrosis transmembrane conductance regulator (CFTR) results from accelerated endocytosis of {Delta}F508-CFTR in polarized human airway epithelial cells. J Biol Chem 280, 3676236772.
  • 50
    Haggie PM, Kim JK, Lukacs GL & Verkman AS (2006) Tracking of quantum dot-labeled CFTR shows near immobilization by C-terminal PDZ interactions. Mol Biol Cell 17, 49374945.
  • 51
    Short DB, Trotter KW, Reczek D, Kreda SM, Bretscher A, Boucher RC, Stutts MJ & Milgram SL (1998) An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton. J Biol Chem 273, 1979719801.
  • 52
    Swiatecka-Urban A, Duhaime M, Coutermarsh B, Karlson KH, Collawn J, Milewski M, Cutting GR, Guggino WB, Langford G & Stanton BA (2002) PDZ domain interaction controls the endocytic recycling of the cystic fibrosis transmembrane conductance regulator. J Biol Chem 277, 4009940105.
  • 53
    Faria D, Dahimene S, Alessio L, Scott-Ward T, Schreiber R, Kunzelmann K & Amaral MD (2011) Effect of annexin A5 on CFTR: regulated traffic or scaffolding? Mol Membr Biol 28, 1429.
  • 54
    Ganeshan R, Nowotarski K, Di A, Nelson DJ & Kirk KL (2007) CFTR surface expression and chloride currents are decreased by inhibitors of N-WASP and actin polymerization. Biochim Biophys Acta 1773, 192200.
  • 55
    Jaffe AB & Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21, 247269.
  • 56
    Popoff MR & Geny B (2009) Multifaceted role of Rho, Rac, Cdc42 and Ras in intercellular junctions, lessons from toxins. Biochim Biophys Acta 1788, 797812.
  • 57
    Ridley AJ (2006) Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol 16, 522529.
  • 58
    Mertens AE, Pegtel DM & Collard JG (2006) Tiam1 takes PARt in cell polarity. Trends Cell Biol 16, 308316.
  • 59
    Nelson WJ (2009) Remodeling epithelial cell organization: transitions between front–rear and apical–basal polarity. Cold Spring Harb Perspect Biol 1, a000513.
  • 60
    Cheng J, Wang H & Guggino WB (2005) Regulation of cystic fibrosis transmembrane regulator trafficking and protein expression by a Rho family small GTPase TC10. J Biol Chem 280, 37313739.
  • 61
    Wolde M, Fellows A, Cheng J, Kivenson A, Coutermarsh B, Talebian L, Karlson K, Piserchio A, Mierke DF, Stanton BA et al. (2007) Targeting CAL as a negative regulator of DeltaF508-CFTR cell-surface expression: an RNA interference and structure-based mutagenetic approach. J Biol Chem 282, 80998109.
  • 62
    Cheng J, Wang H & Guggino WB (2004) Modulation of mature cystic fibrosis transmembrane regulator protein by the PDZ domain protein CAL. J Biol Chem 279, 18921898.
  • 63
    Moyer BD, Duhaime M, Shaw C, Denton J, Reynolds D, Karlson KH, Pfeiffer J, Wang S, Mickle JE, Milewski M et al. (2000) The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane. J Biol Chem 275, 2706927074.
  • 64
    Guerra L, Fanelli T, Favia M, Riccardi SM, Busco G, Cardone RA, Carrabino S, Weinman EJ, Reshkin SJ, Conese M et al. (2005) Na+/H+ exchanger regulatory factor isoform 1 overexpression modulates cystic fibrosis transmembrane conductance regulator (CFTR) expression and activity in human airway 16HBE14o- cells and rescues DeltaF508 CFTR functional expression in cystic fibrosis cells. J Biol Chem 280, 4092540933.
  • 65
    Penque D, Mendes F, Beck S, Farinha C, Pacheco P, Nogueira P, Lavinha J, Malh¢ R & Amaral MD (2000) Cystic fibrosis F508del patients have apically localized CFTR in a reduced number of airway cells. Lab Invest 80, 857868.
  • 66
    Kwon SH, Pollard H & Guggino WB (2007) Knockdown of NHERF1 enhances degradation of temperature rescued DeltaF508 CFTR from the cell surface of human airway cells. Cell Physiol Biochem 20, 763772.
  • 67
    Favia M, Guerra L, Fanelli T, Cardone RA, Monterisi S, Di Sole F, Castellani S, Chen M, Seidler U, Reshkin SJ et al. (2010) Na+/H+ exchanger regulatory factor 1 overexpression-dependent increase of cytoskeleton organization is fundamental in the rescue of F508del cystic fibrosis transmembrane conductance regulator in human airway CFBE41o- cells. Mol Biol Cell 21, 7386.
  • 68
    Castellani S, Guerra L, Favia M, Di Gioia S, Casavola V & Conese M (2012) NHERF1 and CFTR restore tight junction organisation and function in cystic fibrosis airway epithelial cells: role of ezrin and the RhoA/ROCK pathway. Lab Invest 92, 15271540.
  • 69
    Colas J, Faure G, Saussereau E, Trudel S, Rabeh WM, Bitam S, Guerrera IC, Fritsch J, Sermet-Gaudelus I, Davezac N et al. (2012) Disruption of cytokeratin-8 interaction with F508del-CFTR corrects its functional defect. Hum Mol Genet 21, 623634.
  • 70
    Moniz S, Sousa M, Moraes BJ, Mendes AI, Palma M, Barreto C, Fragata JI, Amaral MD & Matos P (2013) HGF stimulation of Rac1 signaling enhances pharmacological correction of the most prevalent cystic fibrosis mutant F508del-CFTR. ACS Chem Biol 8, 432442.
  • 71
    Janke M, Herrig A, Austermann J, Gerke V, Steinem C & Janshoff A (2008) Actin binding of ezrin is activated by specific recognition of PIP2-functionalized lipid bilayers. Biochemistry 47, 37623769.
  • 72
    Fievet BT, Gautreau A, Roy C, Del Maestro L, Mangeat P, Louvard D & Arpin M (2004) Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin. J Cell Biol 164, 653659.
  • 73
    Puchelle E, Gaillard D, Ploton D, Hinnrasky J, Fuchey C, Boutterin MC, Jacquot J, Dreyer D, Pavirani A & Dalemans W (1992) Differential localization of the cystic fibrosis transmembrane conductance regulator in normal and cystic fibrosis airway epithelium. Am J Respir Cell Mol Biol 7, 485491.
  • 74
    Dupuit F, Kalin N, Brezillon S, Hinnrasky J, Tåmmler B & Puchelle E (1995) CFTR and differentiation marker expression in non-CF and delta F 508 homozygous CF nasal epithelium. J Clin Invest 96, 16011611.
  • 75
    Hollande E, Fanjul M, Chemin-Thomas C, Devaux C, Demolombe S, Van Rietschoten J, Guy-Crotte O & Figarella C (1998) Targeting of CFTR protein is linked to the polarization of human pancreatic duct cells in culture. Eur J Cell Biol 76, 220227.
  • 76
    Trinh NT, Bardou O, Prive A, Maille E, Adam D, Lingee S, Ferraro P, Desrosiers MY, Coraux C & Brochiero E (2012) Improvement of defective cystic fibrosis airway epithelial wound repair after CFTR rescue. Eur Respir J 40, 13901400.