Atypical nuclear envelope condensates linked to neurological disorders reveal nucleoporin-directed chaperone activities.
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
received:
26
10
2021
accepted:
26
08
2022
pubmed:
28
10
2022
medline:
11
11
2022
entrez:
27
10
2022
Statut:
ppublish
Résumé
DYT1 dystonia is a debilitating neurological movement disorder arising from mutation in the AAA+ ATPase TorsinA. The hallmark of Torsin dysfunction is nuclear envelope blebbing resulting from defects in nuclear pore complex biogenesis. Whether blebs actively contribute to disease manifestation is unknown. We report that FG-nucleoporins in the bleb lumen form aberrant condensates and contribute to DYT1 dystonia by provoking two proteotoxic insults. Short-lived ubiquitylated proteins that are normally rapidly degraded partition into the bleb lumen and become stabilized. In addition, blebs selectively sequester a specific HSP40-HSP70 chaperone network that is modulated by the bleb component MLF2. MLF2 suppresses the ectopic accumulation of FG-nucleoporins and modulates the selective properties and size of condensates in vitro. Our study identifies dual mechanisms of proteotoxicity in the context of condensate formation and establishes FG-nucleoporin-directed activities for a nuclear chaperone network.
Identifiants
pubmed: 36302970
doi: 10.1038/s41556-022-01001-y
pii: 10.1038/s41556-022-01001-y
pmc: PMC10041656
mid: NIHMS1878312
doi:
Substances chimiques
Nuclear Pore Complex Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1630-1641Subventions
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : NS105640
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : R01GM114401
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : 5T32GM007223-44
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
ID : F31MH116571
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
ID : R56MH122449
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
ID : R01MH115939
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : F31NS120528
Organisme : NIGMS NIH HHS
ID : R01 GM114401
Pays : United States
Organisme : NIH HHS
ID : S10 OD023651
Pays : United States
Organisme : NIH HHS
ID : S10 OD019967
Pays : United States
Organisme : NIH HHS
ID : S10 OD018034
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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