@article{36c2c59a9c2146f49ff150023423450b,
title = "WNK kinases sense molecular crowding and rescue cell volume via phase separation",
abstract = "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.",
keywords = "biomolecular condensates, cell volume regulation, hyperosmotic stress, K-Cl cotransport, macromolecular crowding, Na-K-2Cl cotransport, phase separation, SLC12 cotransporter, WNK kinase",
author = "Boyd-Shiwarski, {Cary R.} and Shiwarski, {Daniel J.} and Griffiths, {Shawn E.} and Beacham, {Rebecca T.} and Logan Norrell and Morrison, {Daryl E.} and Jun Wang and Jacob Mann and William Tennant and Anderson, {Eric N.} and Jonathan Franks and Michael Calderon and Connolly, {Kelly A.} and Cheema, {Muhammad Umar} and Weaver, {Claire J.} and Nkashama, {Lubika J.} and Weckerly, {Claire C.} and Querry, {Katherine E.} and Pandey, {Udai Bhan} and Donnelly, {Christopher J.} and Dandan Sun and Rodan, {Aylin R.} and Subramanya, {Arohan R.}",
note = "Funding Information: This work was supported by National Institutes of Health grants K08DK118211 (C.R.B.-S.); K99HL155777 (D.J.S.); R01DK098145 and R01DK119252 (A.R.S.); P30DK79307 , S10OD021627 , and S10OD028596 ( Pittsburgh Center for Kidney Research ); R01DK110358 (A.R.R.); R01NS105756 and R21NS098379 (C.J.D.), U.S. Department of Veterans Affairs grants I01BX002891 and IK6BX005647 (D.S.), and the LiveLikeLou Center for ALS Research at the University of Pittsburgh Brain Institute (C.J.D.). J.R.M. was supported by a fellowship from the Center for Protein Conformational Diseases at the University of Pittsburgh. We thank Ora Weisz, Catherine Baty, Gerard Apodaca, Manoj Puthenveedu, and Donna Stolz for imaging support; Gabrielle Pittman for technical assistance; and Ossama Kashlan, Seth Childers, Jeff Brodsky, Helbert Rondon, and Todd Lamitina for helpful discussions. This content is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. Department of Veterans Affairs. Funding Information: This work was supported by National Institutes of Health grants K08DK118211 (C.R.B.-S.); K99HL155777 (D.J.S.); R01DK098145 and R01DK119252 (A.R.S.); P30DK79307, S10OD021627, and S10OD028596 (Pittsburgh Center for Kidney Research); R01DK110358 (A.R.R.); R01NS105756 and R21NS098379 (C.J.D.), U.S. Department of Veterans Affairs grants I01BX002891 and IK6BX005647 (D.S.), and the LiveLikeLou Center for ALS Research at the University of Pittsburgh Brain Institute (C.J.D.). J.R.M. was supported by a fellowship from the Center for Protein Conformational Diseases at the University of Pittsburgh. We thank Ora Weisz, Catherine Baty, Gerard Apodaca, Manoj Puthenveedu, and Donna Stolz for imaging support; Gabrielle Pittman for technical assistance; and Ossama Kashlan, Seth Childers, Jeff Brodsky, Helbert Rondon, and Todd Lamitina for helpful discussions. This content is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. Department of Veterans Affairs. Conceptualization, C.R.B.-S. D.J.S. and A.R.S.; methodology, C.R.B.-S. D.J.S. C.J.D. D.S. A.R.R. and A.R.S.; investigation, C.R.B.-S. D.J.S. S.E.G. R.T.B. D.E.M. L.N. L.J.N. J.M. J.W. W.T. E.N.A. J.F. M.C. K.A.C. C.J.W. C.C.W. K.E.Q. and M.U.C.; resources, U.B.P. C.J.D. D.S. A.R.R. and A.R.S.; writing – original draft, C.R.B.-S. D.J.S. S.E.G. R.T.B. J.W. W.T. C.J.D. J.F. A.R.R. and A.R.S.; writing – review and editing, U.B.P. E.N.A. J.W. C.J.W. C.C.W. D.S. A.R.R. and A.R.S.; supervision, U.B.P. C.J.D. D.S. A.R.R. and A.R.S.; funding acquisition, C.R.B.-S. D.J.S. D.S. A.R.R. and A.R.S. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = nov,
day = "23",
doi = "10.1016/j.cell.2022.09.042",
language = "English (US)",
volume = "185",
pages = "4488--4506.e20",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "24",
}