{"doi":"10.1101/2021.10.14.464447","title":"Heat shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition","abstract":"Summary While the RNA binding protein TDP-43 reversibly phase separates within nuclei into complex droplets (anisosomes) with TDP-43-containing liquid outer shells and liquid centers of HSP70 family chaperones, cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases, including ALS. Here we show that transient oxidative stress, proteasome inhibition, or inhibition of HSP70’s ATP-dependent chaperone activity provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independent of RNA binding or stress granules. Isotope labeling mass spectrometry is used to identify that phase separated cytoplasmic TDP-43 is primarily bound by the small heat shock protein HSPB1. Binding is direct, mediated through TDP-43’s RNA binding and low complexity domains. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and is essential for disassembly of stress-induced, TDP-43 droplets. Decrease of HSPB1 promotes cytoplasmic TDP-43 de-mixing and mislocalization. HSPB1 depletion is identified within ALS-patient spinal motor neurons containing aggregated TDP-43. These findings identify HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and aggregation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":215690,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"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":806812,"name":"Jiaojiao Hu","orcid":"0000-0003-3875-2868","position":1,"is_corresponding":false},{"id":807424,"name":"Bankhole Aladesuyi","orcid":null,"position":2,"is_corresponding":false},{"id":618882,"name":"Alexander Goginashvili","orcid":"0000-0002-3305-5898","position":3,"is_corresponding":false},{"id":705032,"name":"Sonia Vazquez‐Sanchez","orcid":"0000-0002-8107-5850","position":4,"is_corresponding":false},{"id":90672,"name":"Jolene K. Diedrich","orcid":"0000-0001-6489-4558","position":5,"is_corresponding":false},{"id":810584,"name":"Jinge Gu","orcid":"0000-0001-8990-2518","position":6,"is_corresponding":false},{"id":621943,"name":"Jacob A. Blum","orcid":"0000-0002-7015-6815","position":7,"is_corresponding":false},{"id":807425,"name":"Spencer Oung","orcid":null,"position":8,"is_corresponding":false},{"id":810585,"name":"Haiyang Yu","orcid":"0000-0003-3460-6716","position":9,"is_corresponding":false},{"id":241298,"name":"John Ravits","orcid":"0000-0001-6521-4649","position":10,"is_corresponding":false},{"id":236995,"name":"Cong Liu","orcid":"0000-0003-3425-6672","position":11,"is_corresponding":false},{"id":55408,"name":"John R. Yates","orcid":"0000-0001-5267-1672","position":12,"is_corresponding":false},{"id":227272,"name":"Don W. Cleveland","orcid":"0000-0002-1934-3682","position":13,"is_corresponding":false},{"id":550470,"name":"Shan Lu","orcid":"0000-0003-4740-0610","position":0,"is_corresponding":true}],"reference_count":127,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:52:55.971300Z","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":[]}