近日，美国匹兹堡大学医学院Arohan R. Subramanya及其研究团队发现，WNK激酶通过相分离感知分子拥挤并拯救细胞体积。相关论文于2022年10月31日在线发表在《细胞》杂志上。
研究人员发现，在细胞暴露于高渗状态的几秒钟内，WNK1集中到无膜凝集物中，启动一个磷酸化依赖性信号，通过SLC12共转运体驱动净离子流入来恢复细胞体积。WNK1凝集物的形成是由其本质上无序的C端驱动的，其演化上保守的特征是有效的相分离和体积恢复所必需的。这种无序编码的相行为是在生理限制下发生的，在体内被分子拥挤而不是细胞大小的变化所激活。这使得激酶在抑制性的离子环境中仍有活性，并通过凝集物介导的信号放大使细胞体积恢复。因此，WNK激酶是生理上的拥挤传感器，其通过相分离来协调细胞体积救援反应。
据介绍，当受到高渗的挑战时，脱水的细胞必须恢复其体积才能生存。这一过程需要WNK激酶对SLC12阳离子氯化物转运体进行磷酸化依赖性调节，但这些激酶如何被细胞收缩激活仍是未知数。
附：英文原文
Title: WNK kinases sense molecular crowding and rescue cell volume via phase separation
Author: 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
Issue&Volume: 2022-10-31
Abstract: When challenged by hypertonicity, dehydrated cells must recover their volume to survive.This process requires the phosphorylation-dependent regulation of SLC12 cation chloridetransporters by WNK kinases, but how these kinases are activated by cell shrinkageremains unknown. Within seconds of cell exposure to hypertonicity, WNK1 concentratesinto membraneless condensates, initiating a phosphorylation-dependent signal thatdrives net ion influx via the SLC12 cotransporters to restore cell volume. WNK1 condensateformation is driven by its intrinsically disordered C terminus, whose evolutionarilyconserved signatures are necessary for efficient phase separation and volume recovery.This disorder-encoded phase behavior occurs within physiological constraints and isactivated in vivo by molecular crowding rather than changes in cell size. This allows kinase activitydespite an inhibitory ionic milieu and permits cell volume recovery through condensate-mediatedsignal amplification. Thus, WNK kinases are physiological crowding sensors that phaseseparate to coordinate a cell volume rescue response.
DOI: 10.1016/j.cell.2022.09.042
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01261-2