Hyperosmotic-stress-induced liquid-liquid phase separation of ALS-related proteins in the nucleus

Chao Gao; Jinge Gu; Hong Zhang; Kai Jiang; Linlin Tang; Ren Liu; Li Zhang; Pengfei Zhang; Cong Liu; Bin Dai; Jie Song

doi:10.1016/j.celrep.2022.111086

Hyperosmotic-stress-induced liquid-liquid phase separation of ALS-related proteins in the nucleus

Cell Rep. 2022 Jul 19;40(3):111086. doi: 10.1016/j.celrep.2022.111086.

Authors

Chao Gao¹, Jinge Gu², Hong Zhang¹, Kai Jiang¹, Linlin Tang¹, Ren Liu³, Li Zhang³, Pengfei Zhang³, Cong Liu⁴, Bin Dai⁵, Jie Song⁶

Affiliations

¹ Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
² Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
³ Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, The Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
⁴ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: liulab@sioc.ac.cn.
⁵ Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: daibin@sjtu.edu.cn.
⁶ Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, The Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China. Electronic address: sjie@sjtu.edu.cn.

PMID: 35858576
DOI: 10.1016/j.celrep.2022.111086

Abstract

Hyperosmotic stress as physiologic dysfunction can reduce the cell volume and then redistribute both protein concentration and ionic strength, but its effect on liquid-liquid phase separation (LLPS) is not well understood. Here, we map the hyperosmotic-stress-induced nuclear LLPS of amyotrophic lateral sclerosis (ALS)-related proteins (fused in sarcoma [FUS], TAR DNA-binding protein 43 [TDP-43]). The dynamic and reversibility of FUS granules are continuable with the increase of hypertonic stimulation time, but those of TDP-43 granules decrease significantly. Strikingly, FUS granules, but not TDP-43 granules, contain essential chaperone Hsp40, which can protect amyloid protein from solid aggregation. Moreover, FUS nuclear granules can co-localize with paraspeckles, but not promyelocytic leukemia (PML) bodies or nuclear speckles, while TDP-43 nuclear granules cannot co-localize with the above nuclear bodies. Together, these results may broaden our understanding of the LLPS of ALS-related proteins in response to cellular stress.

Keywords: ALS-related proteins; CP: Molecular biology; CP: Neuroscience; chaperones; hyperosmotic stress; liquid-liquid phase separation; nuclear granules; paraspeckles.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis* / metabolism
Cell Nucleus / metabolism
Humans
RNA-Binding Protein FUS / metabolism

Substances

RNA-Binding Protein FUS