Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue EMBO Molecular Medicine Année : 2020

Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress

Corinne Stoetzel
  • Fonction : Auteur
  • PersonId : 1054987
Elise Schaefer
  • Fonction : Auteur
  • PersonId : 1055357
Sophie Scheidecker
  • Fonction : Auteur
  • PersonId : 1055358
Dan Lipsker
  • Fonction : Auteur
  • PersonId : 907546

Résumé

The ubiquitin-proteasome system degrades ubiquitin-modified proteins to maintain protein homeostasis and to control signalling. Whole-genome sequencing of patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cuta-neous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The protea-some content and activity in patient's fibroblasts was however unaffected. Nevertheless, patient's cells exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 tran-scriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient's fibroblasts. Upon chemical proteasome inhibition, this pathway was however impaired in patient's cells, which were unable to compensate for proteotoxic stress although a higher proteasome content and activity. Zebrafish modelling for knockout in PSMC3 remarkably reproduced the human phenotype with inner ear development anomalies as well as cataracts , suggesting that Rpt5 plays a major role in inner ear, lens and central nervous system development.
Fichier principal
Vignette du fichier
emmm.201911861.pdf (2.35 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte
Loading...

Dates et versions

hal-02903912 , version 1 (21-07-2020)

Identifiants

Citer

Ariane Kröll-Hermi, Frédéric Ebstein, Corinne Stoetzel, Véronique Geoffroy, Elise Schaefer, et al.. Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress. EMBO Molecular Medicine, 2020, 12 (7), ⟨10.15252/emmm.201911861⟩. ⟨hal-02903912⟩
89 Consultations
84 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More