WNK kinases sense molecular crowding and rescue cell volume via phase separation.
WNK kinases sense molecular crowding and rescue cell volume via phase separation.
复制标题
DOI：
10.1016/j.cell.2022.09.042
复制
发表时间：
2022-11-23
期刊：
影响因子：
64.5
通讯作者：
Subramanya, Arohan R.
中科院分区：
文献类型：
--
作者：
Boyd-Shiwarski, Cary R.;Shiwarski, Daniel J.;Griffiths, Shawn E.;Beacham, Rebecca T.;Norrell, Logan;Morrison, Daryl E.;Wang, Jun;Mann, Jacob;Tennant, William;Anderson, Eric N.;Franks, Jonathan;Calderon, Michael;Connolly, Kelly A.;Cheema, Muhammad Umar;Weaver, Claire J.;Nkashama, Lubika J.;Weckerly, Claire C.;Querry, Katherine E.;Pandey, Udai Bhan;Donnelly, Christopher J.;Sun, Dandan;Rodan, Aylin R.;Subramanya, Arohan R.
当受到高渗性的挑战时，脱水的细胞必须恢复其体积才能存活。这一过程需要WNK激酶对SLC 12阳离子氯转运蛋白的磷酸化依赖性调节，但这些激酶如何被细胞收缩激活仍不清楚。在细胞暴露于高渗的几秒钟内，WNK 1浓缩成无膜浓缩物，启动磷酸化依赖性信号，通过SLC 12协同转运蛋白驱动净离子流入，以恢复细胞体积。WNK 1冷凝物的形成是由其本质上无序的C-末端驱动的，其进化上保守的特征对于有效的相分离和体积恢复是必要的。这种疾病编码的相行为发生在生理限制范围内，并在体内通过分子拥挤而不是细胞大小的变化来激活。这允许激酶活性，尽管抑制性离子环境，并允许通过冷凝物介导的信号放大的细胞体积恢复。因此，WNK激酶是生理拥挤传感器，其相分离以协调细胞体积拯救响应。WNK 1是一种分子拥挤传感器，其经历细胞收缩依赖性相分离并恢复细胞体积。这项研究提供了一个明确的内在无序区域介导的蛋白质相分离和细胞生理学之间的联系。
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. WNK1 is a molecular crowding sensor that undergoes cell shrinkage dependent phase separation and restores cell volume. This study provides a clear link between intrinsically disordered region mediated phase-separation of a protein and cell physiology.
登录
查看更多内容
DOI：
10.1083/jcb.121.1.61
发表时间：
1993-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hansen SH;Sandvig K;van Deurs B
通讯作者：
van Deurs B
钾调节的远端小管WNK体是肾脏特异性的WNK1。
影响因子：
3.3
作者：
Boyd-Shiwarski CR;Shiwarski DJ;Roy A;Namboodiri HN;Nkashama LJ;Xie J;McClain KL;Marciszyn A;Kleyman TR;Tan RJ;Stolz DB;Puthenveedu MA;Huang CL;Subramanya AR
通讯作者：
Subramanya AR
影响因子：
5.3
作者：
Acevedo, Summer F.;de Portugal, Raniero L. Peru y Colon;Rothenfluh, Adrian
通讯作者：
Rothenfluh, Adrian
影响因子：
5.8
作者：
Delorenzi, M;Speed, T
通讯作者：
Speed, T
影响因子：
64.5
作者：
Fiumara F;Fioriti L;Kandel ER;Hendrickson WA
通讯作者：
Hendrickson WA