应力颗粒
细胞质
伴侣(临床)
化学
核糖核酸
蛋白酶体
热休克蛋白70
生物物理学
RNA结合蛋白
热休克蛋白
核心
蛋白质聚集
细胞生物学
生物化学
生物
信使核糖核酸
翻译(生物学)
医学
病理
基因
作者
Shan Lu,Jiaojiao Hu,Bankhole Aladesuyi,Alexander Goginashvili,Sonia Vazquez‐Sanchez,Jolene K. Diedrich,Jinge Gu,Jacob A. Blum,Spencer Oung,Haiyang Yu,John Ravits,Cong Liu,John R. Yates,Don W. Cleveland
标识
DOI:10.1101/2021.10.14.464447
摘要
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.
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