Different membraneless organelles (MLOs) fulfill important biological functions under both normal and stress conditions. Dynamic assembly and disassembly of MLOs are under tight regulation, failure of which directly leads to various neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, it’s poorly understood how MLOs maintains its highly dynamics and reversible metastable functional state. Recently, researchers from Interdisciplinary Research Center of Biology and Chemistry (IRCBC) in Shanghai institute of Organic Chemistry (SIOC) and Shanghai Jiao Tong University revealed molecular chaperon Hsp40 as the key player in maintenance of membraneless organelles. Molecular chaperones are key components of the protein quality control system in cells to maintain protein homeostasis. Chaperones assist client proteins in folding and translocation, maintain clients in the native conformation and prevent them from misfolding and aggregation. In this study, the researcher found that class I and II Hsp40 (DNAJ) proteins possess a high ability of phase separation rendered by the shared intrinsically disordered G/F-rich region. Different Hsp40 proteins localize in different MLOs. Upon stress, both Hsp40 proteins transfer to stress granules (SGs). Mutation of the G/F-rich region not only markedly impaired Hdj1 phase separation and SG involvement, and also disrupted the synergistic phase separation and co-localization of Hdj1 with FUS in SGs. Being co-phase 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 work suggests that phase separation is an intrinsic property of Hsp40 proteins, which enables efficient incorporation and function of Hsp40 in MLOs, and may further mediate the buildup of chaperone network in MLOs.

Liu cong Ph.D. Professor
Tel: 021-68582528
Email: liulab@sioc.ac.cn