期刊
EMBO MOLECULAR MEDICINE
卷 12, 期 7, 页码 -出版社
WILEY
DOI: 10.15252/emmm.201911861
关键词
cataract; deafness; neurosensory disease; proteasome; PSMC3
资金
- Centre Regional de Genetique Medicale de Strasbourg (CREGEMES)
- Laboratory of Excellence GENMED (Medical Genomics) [ANR-10-LABX-0013]
- FritzThyssen Foundation [Az. 10.16.2.022MN]
- German Research Foundation [DFG SFBTRR186 A13, SFBTRR 167 A04]
- Molecular Medicine Research Consortium of the University of Greifswald [FOVB-2018-11]
- National BioResource Project (NBRP)
- NBRP/Fundamental Technologies Upgrading Program from AMED
- JED-Belgique foundation
- NBRP Fundamental Technologies Upgrading Program from AMED (Japan Agency for Medical Research and Development)
- Initiatives d'Excellence (IdEx) through the University of Strasbourg
- Franco-German University (UFA/DFH)
- CNRS/Universite de Strasbourg
- INSERM
- University of Strasbourg, IdEx Equipement mi-lourd 2015
- NBRP
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 cutaneous 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 proteasome 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 transcriptional 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.
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