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

共 92 条

[11] Role of WNK Kinases in the Modulation of Cell Volume [J].

de los Heros, Paola ;

Pacheco-Alvarez, Diana ;

Gamba, Gerardo .

CELL VOLUME REGULATION, 2018, 81 :207-235

[12] mTORC1 Controls Phase Separation and the Biophysical Properties of the Cytoplasm by Tuning Crowding [J].

Delarue, M. ;

Brittingham, G. P. ;

Pfeffer, S. ;

Surovtsev, I. V. ;

Pinglay, S. ;

Kennedy, K. J. ;

Schaffer, M. ;

Gutierrez, J. I. ;

Sang, D. ;

Poterewicz, G. ;

Chung, J. K. ;

Plitzko, J. M. ;

Groves, J. T. ;

Jacobs-Wagner, C. ;

Engel, B. D. ;

Holt, L. J. .

CELL, 2018, 174 (02) :338-+

[13] An HMM model for coiled-coil domains and a comparison with PSSM-based predictions [J].

Delorenzi, M ;

Speed, T .

BIOINFORMATICS, 2002, 18 (04) :617-625

[14] Water Homeostasis and Cell Volume Maintenance and Regulation [J].

Delpire, Eric ;

Gagnon, Kenneth B. .

CELL VOLUME REGULATION, 2018, 81 :3-52

[15] The Ion Transporter NKCC1 Links Cell Volume to Cell Mass Regulation by Suppressing mTORC1 [J].

Demian, Wael L. ;

Persaud, Avinash ;

Jiang, Chong ;

Coyaud, Etienne ;

Liu, Shixuan ;

Kapus, Andras ;

Kafri, Ran ;

Raught, Brian ;

Rotin, Daniela .

CELL REPORTS, 2019, 27 (06) :1886-+

[16]

Edelstein Arthur D, 2014, J Biol Methods, V1

[17] Essential Role of Coiled Coils for Aggregation and Activity of Q/N-Rich Prions and PolyQ Proteins [J].

Fiumara, Ferdinando ;

Fioriti, Luana ;

Kandel, Eric R. ;

Hendrickson, Wayne A. .

CELL, 2010, 143 (07) :1121-1135

[18] Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf [J].

Flagella, M ;

Clarke, LL ;

Miller, ML ;

Erway, LC ;

Giannella, RA ;

Andringa, A ;

Gawenis, LR ;

Kramer, J ;

Duffy, JJ ;

Doetschman, T ;

Lorenz, JN ;

Yamoah, EN ;

Cardell, EL ;

Shull, GE .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (38) :26946-26955

[19] Activation of the Na-K-Cl cotransporter NKM detected with a phospho-specific antibody [J].

Flemmer, AW ;

Giménez, I ;

Dowd, BFX ;

Darman, RB ;

Forbush, B .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (40) :37551-37558

[20] Coiled-Coil Motifs of RNA-Binding Proteins: Dynamicity in RNA Regulation [J].

Ford, Lenzie K. ;

Fioriti, Luana .

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 2020, 8

← 1 2 3 4 5 6 7 8 9 10 →