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

被引：110

作者：

Boyd-Shiwarski, Cary R. ^{[1
,8
]}

Shiwarski, Daniel J. ^{[9
]}

Griffiths, Shawn E. ^{[1
]}

Beacham, Rebecca T. ^{[1
]}

Norrell, Logan ^{[11
]}

Morrison, Daryl E. ^{[11
]}

Wang, Jun ^{[2
]}

Mann, Jacob ^{[3
]}

Tennant, William ^{[3
]}

Anderson, Eric N. ^{[4
]}

Franks, Jonathan ^{[5
]}

Calderon, Michael ^{[5
]}

Connolly, Kelly A. ^{[1
]}

Cheema, Muhammad Umar ^{[1
]}

Weaver, Claire J. ^{[1
]}

Nkashama, Lubika J. ^{[1
]}

Weckerly, Claire C. ^{[6
]}

Querry, Katherine E. ^{[1
]}

Pandey, Udai Bhan ^{[4
,7
]}

Donnelly, Christopher J. ^{[3
,7
]}

Sun, Dandan ^{[2
]}

Rodan, Aylin R. ^{[10
,11
,12
,13
]}

Subramanya, Arohan R. ^{[1
,6
,7
,8
]}

机构：

[1] Univ Pittsburgh, Dept Med, Renal Electrolyte Div, Sch Med, Pittsburgh, PA 15261 USA

[2] Univ Pittsburgh, Dept Neurol, Sch Med, Pittsburgh, PA 15261 USA

[3] Univ Pittsburgh, Dept Neurobiol, Sch Med, Pittsburgh, PA 15261 USA

[4] Univ Pittsburgh, Dept Pediat, Sch Med, Pittsburgh, PA 15261 USA

[5] Univ Pittsburgh, Ctr Biol Imaging, Sch Med, Pittsburgh, PA 15261 USA

[6] Univ Pittsburgh, Dept Cell Biol, Sch Med, Pittsburgh, PA 15261 USA

[7] Univ Pittsburgh, Ctr Prot Conformat Dis, Sch Med, Pittsburgh, PA 15261 USA

[8] Univ Pittsburgh, Pittsburgh Ctr Kidney Res, Sch Med, Pittsburgh, PA 15261 USA

[9] Carnegie Mellon Univ, Dept Biomed Engn, Pittsburgh, PA 15213 USA

[10] Univ Utah, Dept Human Genet, Salt Lake City, UT 84132 USA

[11] Univ Utah, Mol Med Program, Salt Lake City, UT 84132 USA

[12] Univ Utah, Dept Internal Med, Div Nephrol & Hypertens, Salt Lake City, UT 84132 USA

[13] VA Salt Lake City Hlth Care Syst, Med Serv, Salt Lake City, UT 84148 USA

来源：

CELL | 2022年 / 185卷 / 24期

基金：

美国国家卫生研究院;

关键词：

PROTEIN-KINASE; COILED COILS; COTRANSPORTER; PHOSPHORYLATION; ACTIVATION; MEMBRANE; MODEL; STIMULATION; TRANSITIONS; ENDOCYTOSIS;

D O I：

10.1016/j.cell.2022.09.042

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

When challenged by hypertonicity, dehydrated cells must recover their volume to survive. This process re-quires 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-depen-dent 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.

引用

页码：4488 / +

页数：40

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