{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Duan L"],"funding":["Intramural NIH HHS","NINDS NIH HHS","NIGMS NIH HHS"],"pagination":["111106"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9345261"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["40(3)"],"pubmed_abstract":["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."],"journal":["Cell reports"],"pubmed_title":["Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export."],"pmcid":["PMC9345261"],"funding_grant_id":["R01 NS123538","ZIA HD008954","T32 GM007445","R03 NS127011","K08 NS104273"],"pubmed_authors":["Zaepfel BL","Rothstein JD","Duan L","Dasso M","Hayes LR","Aksenova V","Kalab P"],"additional_accession":[]},"is_claimable":false,"name":"Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Jul","modification":"2026-06-01T02:18:21.993Z","creation":"2025-04-05T12:11:59.538Z"},"accession":"S-EPMC9345261","cross_references":{"pubmed":["35858577"],"doi":["10.1016/j.celrep.2022.111106"]}}