The ubiquitin ligase CHIP/STUB1 targets mutant keratins for degradation.

[epidermolysis bullosa simplex]

Keratin (K ) intermediate filament proteins form cytoskeletal scaffolds in epithelia , the disruption of which leads to a large number of human disorders . KRT 5 or KRT 14 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 Hsp 70 and Hsp 90 in two EBS models , namely , in neonatal K 5 (-/-) mice and upon proteasome inhibition in cells that stably express the disease-causing mutation K 14 -p .Arg 125 C ys , both harboring keratin aggregates . Furthermore , proteasome inhibition caused nuclear translocation of pHSF-1 and an increase in K 14 -p .Arg 125 Cys-positive aggregates in cells . Overexpression of the chaperone-associated ubiquitin ligase CHIP /STUB 1 strongly reduced keratin aggregates through increased degradation of mutant K 14 . Using CHIP -p .Met 1 _Ala 142 del (DeltaTPR-CHIP ), we demonstrated the involvement of Hsc 70 and Hsp 70 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 .

Diseases
Validation

Diseases presenting "small molecules" symptom

epidermolysis bullosa simplex

erythropoietic protoporphyria

fabry disease

gm1 gangliosidosis

krabbe disease

phenylketonuria

werner syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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