Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export.
CP: Molecular biology
RNA
TDP-43
amyotrophic lateral sclerosis
frontotemporal dementia
neurodegeneration
nuclear transport
splicing
transcription
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
19 07 2022
19 07 2022
Historique:
received:
27
09
2021
revised:
26
03
2022
accepted:
27
06
2022
entrez:
20
7
2022
pubmed:
21
7
2022
medline:
23
7
2022
Statut:
ppublish
Résumé
Nuclear clearance of the RNA-binding protein TDP-43 is a hallmark of neurodegeneration and an important therapeutic target. Our current understanding of TDP-43 nucleocytoplasmic transport does not fully explain its predominantly nuclear localization or mislocalization in disease. Here, we show that TDP-43 exits nuclei by passive diffusion, independent of facilitated mRNA export. RNA polymerase II blockade and RNase treatment induce TDP-43 nuclear efflux, suggesting that nuclear RNAs sequester TDP-43 in nuclei and limit its availability for passive export. Induction of TDP-43 nuclear efflux by short, GU-rich oligomers (presumably by outcompeting TDP-43 binding to endogenous nuclear RNAs), and nuclear retention conferred by splicing inhibition, demonstrate that nuclear TDP-43 localization depends on binding to GU-rich nuclear RNAs. Indeed, RNA-binding domain mutations markedly reduce TDP-43 nuclear localization and abolish transcription blockade-induced nuclear efflux. Thus, the nuclear abundance of GU-RNAs, dictated by the balance of transcription, pre-mRNA processing, and RNA export, regulates TDP-43 nuclear localization.
Identifiants
pubmed: 35858577
pii: S2211-1247(22)00908-1
doi: 10.1016/j.celrep.2022.111106
pmc: PMC9345261
mid: NIHMS1825578
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
RNA, Nuclear
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
111106Subventions
Organisme : NINDS NIH HHS
ID : R03 NS127011
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA HD008954
Pays : United States
Organisme : NINDS NIH HHS
ID : K08 NS104273
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS123538
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007445
Pays : United States
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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