期刊
ISCIENCE
卷 25, 期 6, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2022.104356
关键词
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资金
- National Natural Science Foundation (NSF) of China [32170683, 82188101, 31872716, 32171236]
- Major State Basic Research Development Program [2019YFE0120600]
- Science and Technology Commission of Shanghai Municipality [20XD1425000, 2019SHZDZX02]
- CAS project for Young Scientists in Basic research [YSBR-009]
- Shanghai Pilot Program for Basic Research - Chinese Academy of Science, Shanghai Branch [CYJ-SHFY-2022-005]
The study reveals that Hsp70 plays a key role in preventing the pathological aggregation of different proteins through distinct mechanisms in cells, suggesting its important involvement in chaperoning the physiological dynamics of various membrane-less organelles.
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.
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