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

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 un-derstood. 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 gran-ules 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.

Automated summary

This study investigates the effect of hyperosmotic stress on the liquid-liquid phase separation (LLPS) of amyotrophic lateral sclerosis (ALS)-related proteins. The results show that the dynamic and reversibility of FUS granules are sustained with increasing hypertonic stimulation time, while those of TDP-43 granules decrease significantly. FUS granules contain the essential chaperone Hsp40, capable of protecting amyloid proteins from aggregation. Additionally, FUS nuclear granules can co-localize with paraspeckles, but not with other nuclear bodies, while TDP-43 nuclear granules do not co-localize with any of the aforementioned nuclear bodies.