{"doi":"10.1101/2021.08.24.457459","title":"Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export","abstract":"Abstract Nuclear clearance of the DNA/RNA-binding protein TDP-43 is a pathologic hallmark of amyotrophic lateral sclerosis and frontotemporal dementia that remains unexplained. Moreover, our current understanding of TDP-43 nucleocytoplasmic shuttling does not fully explain the predominantly nuclear localization of TDP-43 in healthy cells. Here, we used permeabilized and live-cell models to investigate TDP-43 nuclear export and the role of RNA in TDP-43 localization. We show that TDP-43 nuclear efflux occurs in low-ATP conditions and independent of active mRNA export, consistent with export by passive diffusion through nuclear pore channels. TDP-43 nuclear residence requires binding to GU-rich nuclear intronic pre-mRNAs, based on the induction of TDP-43 nuclear efflux by RNase and GU-rich oligomers and TDP-43 nuclear retention conferred by pre-mRNA splicing inhibitors. Mutation of TDP-43 RNA recognition motifs disrupts TDP-43 nuclear accumulation and abolishes transcriptional blockade-induced TDP-43 nuclear efflux, demonstrating strict dependence of TDP-43 nuclear localization on RNA binding. Thus, the nuclear abundance of GU-rich intronic pre-mRNAs, as dictated by the balance of transcription and pre-mRNA processing, regulates TDP-43 nuclear sequestration and availability for passive nuclear export.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":216763,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":254051,"name":"Benjamin L. Zaepfel","orcid":"0000-0002-6822-7354","position":1,"is_corresponding":false},{"id":263041,"name":"Vasilisa Aksenova","orcid":"0000-0001-7325-3453","position":2,"is_corresponding":false},{"id":263050,"name":"Mary Dasso","orcid":"0000-0002-5410-1371","position":3,"is_corresponding":false},{"id":254058,"name":"Jeffrey D. Rothstein","orcid":"0000-0003-2001-8470","position":4,"is_corresponding":false},{"id":263127,"name":"Petr Kaláb","orcid":"0000-0002-8145-7728","position":5,"is_corresponding":false},{"id":254052,"name":"Lindsey R. Hayes","orcid":"0000-0003-4818-6054","position":6,"is_corresponding":false},{"id":251164,"name":"Lauren Duan","orcid":"0000-0002-0715-0824","position":0,"is_corresponding":true}],"reference_count":139,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:15.868165Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}