• epidermolysis bullosa simplex;
  • EBS;
  • KRT5;
  • KRT14;
  • Hsp70;
  • Hsc70;
  • CHIP


Keratin (K) intermediate filament proteins form cytoskeletal scaffolds in epithelia, the disruption of which leads to a large number of human disorders. KRT5 or KRT14 mutations cause epidermolysis bullosa simplex (EBS). The considerable intra- and interfamilial variability in EBS suggests modifying loci, most of which are unknown. In many human disorders, chaperones and the ubiquitin–proteasome system have been found to modify disease severity, thereby providing novel therapy targets. Here, we demonstrate upregulation of stress-induced Hsp70 and Hsp90 in two EBS models, namely, in neonatal K5−/− mice and upon proteasome inhibition in cells that stably express the disease-causing mutation K14–p.Arg125Cys, both harboring keratin aggregates. Furthermore, proteasome inhibition caused nuclear translocation of pHSF-1 and an increase in K14–p.Arg125Cys-positive aggregates in cells. Overexpression of the chaperone-associated ubiquitin ligase CHIP/STUB1 strongly reduced keratin aggregates through increased degradation of mutant K14. Using CHIP–p.Met1_Ala142del (ΔTPR–CHIP), we demonstrated the involvement of Hsc70 and Hsp70 in mutant keratin degradation. Our data uncover common principles between EBS and other protein misfolding disorders, revealing that aggregation-prone keratins are targeted by components of the chaperone machinery. Thus, modulation of the chaperone machinery using small molecules may represent a novel therapeutic strategy for dominant EBS, allowing reformation of an intact keratin cytoskeleton. Hum Mutat 31:466–476, 2010. © 2010 Wiley-Liss, Inc.