A Mechanosensitive RhoA Pathway that Protects Epithelia against Acute Tensile Stress
A Mechanosensitive RhoA Pathway that Protects Epithelia against Acute Tensile Stress
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DOI：
10.1016/j.devcel.2018.09.016
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发表时间：
2018-11-19
影响因子：
11.8
通讯作者：
Yap, Alpha S.
中科院分区：
文献类型：
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作者：
Acharya, Bipul R.;Nestor-Bergmann, Alexander;Yap, Alpha S.
粘附连接是将上皮细胞连接在一起的拉伸结构。连接张力可由细胞内在收缩力的应用或组织运动的细胞外在力产生。在这里，我们报告了一种机械敏感信号通路，该通路可激活粘附连接处的 RhoA，以响应急性拉伸应力来保持上皮完整性。我们将肌球蛋白 VI 确定为力传感器，当机械单层应力增加连接张力时，其与 E-钙粘蛋白的关联会增强。肌球蛋白 VI 促进异源三聚体 G α 12 蛋白募集至 E-钙粘蛋白，在此向 p114 RhoGEF 发出信号以激活 RhoA。尽管张力激活的 RhoA 信号传导具有刺激连接肌动球蛋白并进一步增加收缩性的潜力，但它对于保持上皮完整性是必要的。这可以通过抗拉强度的增加来解释，尤其是在连接的多细胞顶点，这是由于 mDia1 介导的肌动蛋白组装所致。
Adherens junctions are tensile structures that couple epithelial cells together. Junctional tension can arise from cell-intrinsic application of contractility or from the cell-extrinsic forces of tissue movement. Here, we report a mechanosensitive signaling pathway that activates RhoA at adherens junctions to preserve epithelial integrity in response to acute tensile stress. We identify Myosin VI as the force sensor, whose association with E-cadherin is enhanced when junctional tension is increased by mechanical monolayer stress. Myosin VI promotes recruitment of the heterotrimeric G alpha 12 protein to E-cadherin, where it signals for p114 RhoGEF to activate RhoA. Despite its potential to stimulate junctional actomyosin and further increase contractility, tension-activated RhoA signaling is necessary to preserve epithelial integrity. This is explained by an increase in tensile strength, especially at the multicellular vertices of junctions, that is due to mDia1-mediated actin assembly.