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. Donnelly; Dandan Sun; Aylin R. Rodan; Arohan R. Subramanya

doi:10.1016/j.cell.2022.09.042

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 journal › Article › peer-review

41 Scopus citations

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.

Original language	English (US)
Pages (from-to)	4488-4506.e20
Journal	Cell
Volume	185
Issue number	24
DOIs	https://doi.org/10.1016/j.cell.2022.09.042
State	Published - Nov 23 2022
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2022.09.042

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Boyd-Shiwarski, C. R., Shiwarski, D. J., Griffiths, S. E., Beacham, R. T., Norrell, L., Morrison, D. E., Wang, J., Mann, J., Tennant, W., Anderson, E. N., Franks, J., Calderon, M., Connolly, K. A., Cheema, M. U., Weaver, C. J., Nkashama, L. J., Weckerly, C. C., Querry, K. E., Pandey, U. B., ... Subramanya, A. R. (2022). WNK kinases sense molecular crowding and rescue cell volume via phase separation. Cell, 185(24), 4488-4506.e20. https://doi.org/10.1016/j.cell.2022.09.042

Boyd-Shiwarski, CR, Shiwarski, DJ, Griffiths, SE, Beacham, RT, Norrell, L, Morrison, DE, Wang, J, Mann, J, Tennant, W, Anderson, EN, Franks, J, Calderon, M, Connolly, KA, Cheema, MU, Weaver, CJ, Nkashama, LJ, Weckerly, CC, Querry, KE, Pandey, UB, Donnelly, CJ, Sun, D, Rodan, AR & Subramanya, AR 2022, 'WNK kinases sense molecular crowding and rescue cell volume via phase separation', Cell, vol. 185, no. 24, pp. 4488-4506.e20. https://doi.org/10.1016/j.cell.2022.09.042

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

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 = "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",

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T1 - WNK kinases sense molecular crowding and rescue cell volume via phase separation

AU - Boyd-Shiwarski, Cary R.

AU - Shiwarski, Daniel J.

AU - Griffiths, Shawn E.

AU - Beacham, Rebecca T.

AU - Norrell, Logan

AU - Morrison, Daryl E.

AU - Wang, Jun

AU - Mann, Jacob

AU - Tennant, William

AU - Anderson, Eric N.

AU - Franks, Jonathan

AU - Calderon, Michael

AU - Connolly, Kelly A.

AU - Cheema, Muhammad Umar

AU - Weaver, Claire J.

AU - Nkashama, Lubika J.

AU - Weckerly, Claire C.

AU - Querry, Katherine E.

AU - Pandey, Udai Bhan

AU - Donnelly, Christopher J.

AU - Sun, Dandan

AU - Rodan, Aylin R.

AU - Subramanya, Arohan R.

PY - 2022/11/23

Y1 - 2022/11/23

N2 - 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.

AB - 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.

KW - K-Cl cotransport

KW - Na-K-2Cl cotransport

KW - SLC12 cotransporter

KW - WNK kinase

KW - biomolecular condensates

KW - cell volume regulation

KW - hyperosmotic stress

KW - macromolecular crowding

KW - phase separation

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U2 - 10.1016/j.cell.2022.09.042

DO - 10.1016/j.cell.2022.09.042

M3 - Article

C2 - 36318922

AN - SCOPUS:85142152862

SN - 0092-8674

VL - 185

SP - 4488-4506.e20

JO - Cell

JF - Cell

IS - 24

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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