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 "large number" symptom

acute rheumatic fever

adrenal incidentaloma

allergic bronchopulmonary aspergillosis

canavan disease

coats disease

cowden syndrome

dedifferentiated liposarcoma

dracunculiasis

epidermolysis bullosa simplex

fabry disease

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

kindler syndrome

legionellosis

malignant atrophic papulosis

neuralgic amyotrophy

phenylketonuria

pleomorphic liposarcoma

primary effusion lymphoma

scrub typhus

severe combined immunodeficiency

triple a syndrome

waldenström macroglobulinemia

well-differentiated liposarcoma

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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