WNK kinases sense molecular crowding and rescue cell volume via phase separation

Cary R. Boyd-Shiwarski, Daniel J. Shiwarski, Shawn E. Griffiths, Rebecca T. Beacham, Logan Norrell, Daryl E. Morrison, Jun Wang, Jacob Mann, William Tennant, Eric N. Anderson, Jonathan Franks, Michael Calderon, Kelly A. Connolly, Muhammad Umar Cheema, Claire J. Weaver, Lubika J. Nkashama, Claire C. Weckerly, Katherine E. Querry, Udai Bhan Pandey, Christopher J. DonnellyDandan Sun, Aylin R. Rodan, Arohan R. Subramanya

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


When challenged by hypertonicity, dehydrated cells must recover their volume to survive. This process requires the phosphorylation-dependent regulation of SLC12 cation chloride transporters by WNK kinases, but how these kinases are activated by cell shrinkage remains unknown. Within seconds of cell exposure to hypertonicity, WNK1 concentrates into membraneless condensates, initiating a phosphorylation-dependent signal that drives net ion influx via the SLC12 cotransporters to restore cell volume. WNK1 condensate formation is driven by its intrinsically disordered C terminus, whose evolutionarily conserved signatures are necessary for efficient phase separation and volume recovery. This disorder-encoded phase behavior occurs within physiological constraints and is activated in vivo by molecular crowding rather than changes in cell size. This allows kinase activity despite an inhibitory ionic milieu and permits cell volume recovery through condensate-mediated signal amplification. Thus, WNK kinases are physiological crowding sensors that phase separate to coordinate a cell volume rescue response.

Original languageEnglish (US)
Pages (from-to)4488-4506.e20
Issue number24
StatePublished - Nov 23 2022
Externally publishedYes


  • biomolecular condensates
  • cell volume regulation
  • hyperosmotic stress
  • K-Cl cotransport
  • macromolecular crowding
  • Na-K-2Cl cotransport
  • phase separation
  • SLC12 cotransporter
  • WNK kinase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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