Rare Diseases Symptoms Automatic Extraction

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. 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 (DeltaTPR-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.

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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