Li Yichen, Gu Jinge, Wang Chen, Hu Jiaojiao, Zhang Shenqing, Liu Cong, Zhang Shengnan, Fang Yanshan, Li Dan
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China.
Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China.
iScience. 2022 May 5;25(6):104356. doi: 10.1016/j.isci.2022.104356. eCollection 2022 Jun 17.
Hsp70 is a key molecular chaperone in the protein quality control system to safeguard protein homeostasis in cells. Previous studies have shown that Hsp70 chaperones TDP-43, a pathogenic protein associated with amyotrophic lateral sclerosis (ALS), in nuclear bodies and prevents it from the pathological aggregation. In this work, we report that Hsp70 undergoes liquid-liquid phase separation, chaperones FUS, another ALS-linked pathogenic protein, in stress granules (SGs), and prevents condensed FUS from amyloid aggregation. Knock-down of Hsp70 does not influence SG assembly but results in the liquid-to-solid transition in SGs. NMR experiments further reveal Hsp70 predominantly uses its C-terminal substrate-binding domain to interact with the low complexity domain of FUS, which represents a mechanism distinct from that interacting with TDP-43. These findings suggest that Hsp70 is widely involved in chaperoning the physiological dynamics of various membrane-less organelles and adopts different mechanisms to prevent the pathological aggregation of different proteins.
热休克蛋白70（Hsp70）是蛋白质质量控制系统中的关键分子伴侣，可维护细胞内的蛋白质稳态。先前的研究表明，Hsp70在核小体中对与肌萎缩侧索硬化症（ALS）相关的致病蛋白TDP - 43起分子伴侣作用，并防止其发生病理性聚集。在这项研究中，我们报告Hsp70会发生液 - 液相分离，在应激颗粒（SGs）中对另一种与ALS相关的致病蛋白FUS起分子伴侣作用，并防止凝聚的FUS发生淀粉样聚集。敲低Hsp70并不影响SG的组装，但会导致SGs发生从液相到固相的转变。核磁共振实验进一步揭示，Hsp70主要利用其C端底物结合结构域与FUS的低复杂性结构域相互作用，这代表了一种不同于其与TDP - 43相互作用的机制。这些发现表明，Hsp70广泛参与各种无膜细胞器生理动态的分子伴侣作用，并采用不同机制防止不同蛋白质的病理性聚集。
