Controlling the crowd with a WNK

Abstract

Volume control is a fundamental challenge for all cells, the mechanisms of which have been long debated. In this issue of Cell, Boyd-Shiwarski et al. find that increased molecular crowding drives condensation of WNK kinase, allowing cells to sense and respond to cell volume loss.

Figure 1:. WNK phase separation activates regulatory volume increase in response to hyperosmotic challenge.

A) At steady state, WNK kinases are diffusely localized and WNK pathway activity is low. Upon hyperosmotic challenge, increased crowding due to volume loss drives WNK phase separation and activation. WNK signaling activates transporters that allow ion influx, which draws water into the cell and restores volume/crowding. WNK then decondenses and activity is reduced to baseline. B) WNK knockout cells reconstituted with mutant or chimeric WNKs can rescue cell volume to varying degrees. The WNK kinase domain alone does not phase separate or function in RVI. The TDP-43 intrinsically disordered region (IDR) can rescue both WNK phase separation and RVI, while the FUS IDR shows partially impaired RVI rescue. Mutations targeting predicted coiled-coil regions in the WNK IDR impair both phase separation and RVI. C) The mechanisms that promote WNK signaling in condensates remain unclear. Possibilities include differences in ion content or hydration that alter WNK active site accessibility or induce conformational change. Condensates could also stimulate reaction kinetics or induce condensate-specific phosphorylation events by increasing substrate concentration. Additionally, the IDR properties that confer specificity to WNK condensate function remain unclear.