1. Heat-shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition.
- Author
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Lu S, Hu J, Arogundade OA, Goginashvili A, Vazquez-Sanchez S, Diedrich JK, Gu J, Blum J, Oung S, Ye Q, Yu H, Ravits J, Liu C, Yates JR 3rd, and Cleveland DW
- Subjects
- Adenosine Triphosphate, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, HSP70 Heat-Shock Proteins metabolism, Humans, Molecular Chaperones genetics, Proteasome Endopeptidase Complex, RNA metabolism, DNA-Binding Proteins chemistry, DNA-Binding Proteins metabolism, Heat-Shock Proteins chemistry, Heat-Shock Proteins metabolism, Heat-Shock Proteins, Small, Phase Transition
- 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., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
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