Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 04 2023
13 04 2023
Historique:
received:
11
03
2022
accepted:
03
04
2023
medline:
17
4
2023
entrez:
13
4
2023
pubmed:
14
4
2023
Statut:
epublish
Résumé
Little is known about the mechanistic significance of the ubiquitin proteasome system (UPS) in a kidney autoimmune environment. In membranous nephropathy (MN), autoantibodies target podocytes of the glomerular filter resulting in proteinuria. Converging biochemical, structural, mouse pathomechanistic, and clinical information we report that the deubiquitinase Ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced by oxidative stress in podocytes and is directly involved in proteasome substrate accumulation. Mechanistically, this toxic gain-of-function is mediated by non-functional UCH-L1, which interacts with and thereby impairs proteasomes. In experimental MN, UCH-L1 becomes non-functional and MN patients with poor outcome exhibit autoantibodies with preferential reactivity to non-functional UCH-L1. Podocyte-specific deletion of UCH-L1 protects from experimental MN, whereas overexpression of non-functional UCH-L1 impairs podocyte proteostasis and drives injury in mice. In conclusion, the UPS is pathomechanistically linked to podocyte disease by aberrant proteasomal interactions of non-functional UCH-L1.
Identifiants
pubmed: 37055432
doi: 10.1038/s41467-023-37836-8
pii: 10.1038/s41467-023-37836-8
pmc: PMC10102022
doi:
Substances chimiques
Proteasome Endopeptidase Complex
EC 3.4.25.1
Ubiquitin
0
Ubiquitin Thiolesterase
EC 3.4.19.12
Ubiquitin carboxyl-Terminal Hydrolase L-1, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2114Commentaires et corrections
Type : ErratumIn
Type : CommentIn
Informations de copyright
© 2023. The Author(s).
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