Heat-shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition

Shan Lu, Jiaojiao Hu, Olubankole Aladesuyi Arogundade, Alexander Goginashvili, Sonia Vazquez-Sanchez, Jolene K. Diedrich, Jinge Gu, Jacob Blum, Spencer Oung, Qiaozhen Ye, Haiyang Yu, John Ravits, Cong Liu, John R. Yates, Don W. Cleveland

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

While acetylated, RNA-binding-deficient TDP-43 reversibly phase separates within nuclei into complex droplets (anisosomes) comprised of TDP-43-containing liquid outer shells and liquid centres of HSP70-family chaperones, cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here we show that transient oxidative stress, proteasome inhibition or inhibition of the ATP-dependent chaperone activity of HSP70 provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independently of RNA binding or stress granules. Isotope labelling mass spectrometry was used to identify that phase-separated cytoplasmic TDP-43 is 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. A decrease in HSPB1 promotes cytoplasmic TDP-43 de-mixing and mislocalization. HSPB1 depletion was identified in spinal motor neurons of patients with ALS containing aggregated TDP-43. These findings identify HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and aggregation.

Original languageEnglish (US)
Pages (from-to)1378-1393
Number of pages16
JournalNature cell biology
Volume24
Issue number9
DOIs
StatePublished - Sep 2022

ASJC Scopus subject areas

  • Cell Biology

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