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
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.