期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 49, 页码 31123-31133出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2002437117
关键词
Hsp40; stress granule; ALS; FUS; LLPS
资金
- Major State Basic Research Development Program [2016YFA0501902]
- National Natural Science Foundation (NSF) of China [91853113, 31872716]
- Science and Technology Commission of Shanghai Municipality [18JC1420500]
- Shanghai Municipal Education Commission, Shanghai Municipal Science and Technology Major Project [2019SHZDZX02]
- Innovation Program of Shanghai Municipal Education Commission [2019-01-0700-02-E00037]
- Eastern Scholar Project
Membraneless organelles contain a wide spectrum of molecular chaperones, indicating their important roles in modulating the metastable conformation and biological function of membraneless organelles. Here we report that class I and II Hsp40 (DNAJ) proteins possess a high ability of phase separation rendered by the flexible G/F-rich region. Different Hsp40 proteins localize in different membraneless organelles. Specifically, human Hdj1 (DNAJB1), a class II Hsp40 protein, condenses in ubiquitin (Ub)-rich nuclear bodies, while Hdj2 (DNAJA1), a class I Hsp40 protein, condenses in nucleoli. Upon stress, both Hsp40 proteins incorporate into stress granules (SGs). Mutations of the G/F-rich region not only markedly impaired Hdj1 phase separation and SG involvement and disrupted the synergistic phase separation and colocalization of Hdj1 and fused in sarcoma (FUS) in cells. Being cophase separated with FUS, Hdj1 stabilized the liquid phase of FUS against proceeding into amyloid aggregation in vitro and alleviated abnormal FUS aggregation in cells. Moreover, Hdj1 uses different domains to chaperone FUS phase separation and amyloid aggregation. This paper suggests that phase separation is an intrinsic property of Hsp40 proteins, which enables efficient incorporation and function of Hsp40 in membraneless organelles and may further mediate the buildup of chaperone network in membraneless organelles.
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