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Mechanosensing through Direct Binding of Tensed F-Actin by LIM Domains
Developmental Cell ( IF 10.7 ) Pub Date : 2020-10-14 , DOI: 10.1016/j.devcel.2020.09.022
Xiaoyu Sun 1 , Donovan Y Z Phua 1 , Lucas Axiotakis 2 , Mark A Smith 3 , Elizabeth Blankman 3 , Rui Gong 1 , Robert C Cail 2 , Santiago Espinosa de Los Reyes 1 , Mary C Beckerle 3 , Clare M Waterman 4 , Gregory M Alushin 5
Affiliation  

Mechanical signals transmitted through the cytoplasmic actin cytoskeleton must be relayed to the nucleus to control gene expression. LIM domains are protein-protein interaction modules found in cytoskeletal proteins and transcriptional regulators. Here, we identify three LIM protein families (zyxin, paxillin, and FHL) whose members preferentially localize to the actin cytoskeleton in mechanically stimulated cells through their tandem LIM domains. A minimal actin-myosin reconstitution system reveals that representatives of all three families directly bind F-actin only in the presence of mechanical force. Point mutations at a site conserved in each LIM domain of these proteins disrupt tensed F-actin binding in vitro and cytoskeletal localization in cells, demonstrating a common, avidity-based mechanism. Finally, we find that binding to tensed F-actin in the cytoplasm excludes the cancer-associated transcriptional co-activator FHL2 from the nucleus in stiff microenvironments. This establishes direct force-activated F-actin binding as a mechanosensing mechanism by which cytoskeletal tension can govern nuclear localization.



中文翻译:

通过 LIM 结构域直接结合拉紧的 F-肌动蛋白进行机械传感

通过细胞质肌动蛋白细胞骨架传输的机械信号必须传递到细胞核以控制基因表达。LIM 结构域是在细胞骨架蛋白和转录调节因子中发现的蛋白质-蛋白质相互作用模块。在这里,我们确定了三个 LIM 蛋白家族(zyxin、桩蛋白和 FHL),其成员通过其串联 LIM 域优先定位于机械刺激细胞中的肌动蛋白细胞骨架。最小肌动蛋白-肌球蛋白重建系统表明,所有三个家族的代表仅在存在机械力的情况下直接结合 F-肌动蛋白。在这些蛋白质的每个 LIM 结构域中保守的位点上的点突变破坏了体外紧张的 F-肌动蛋白结合和细胞中的细胞骨架定位,证明了一种常见的、基于亲和力的机制。最后,我们发现与细胞质中紧张的 F-肌动蛋白的结合将癌症相关的转录共激活因子 FHL2 从僵硬的微环境中的细胞核排除在外。这建立了直接力激活的 F-肌动蛋白结合作为一种机械传感机制,通过该机制细胞骨架张力可以控制核定位。

更新日期:2020-11-23
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