Zhao Shuangshuang, Shi Xuemeng, Zhang Yue, Wen Zeyu, Cai Jinping, Gao Wei, Xu Jiayi, Zheng Yifei, Ji Baohua, Cui Yanqin, Shi Kun, Liu Yanjun, Li Hui, Jiu Yaming
The Joint Program in Infection and Immunity, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623; Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Yuquan Road No. 19(A), Shijingshan District, Beijing 100049, China.
iScience. 2020 Apr 24;23(4):100975. doi: 10.1016/j.isci.2020.100975. Epub 2020 Mar 11.
Actin stress fibers guide cell migration and morphogenesis. During centripetal flow, actin transverse arcs fuse accompanied by the formation of myosin II stacks to generate mechanosensitive actomyosin bundles. However, whether myosin II stack formation plays a role in cell mechano-sensing has remained elusive. Myosin-18B is a "glue" molecule for assembling myosin II stacks. By examining actin networks and traction forces, we find that cells abolishing myosin-18B resemble Ca∕calmodulin-dependent kinase kinase 2 (CaMKK2)-defective cells. Inhibition of CaMKK2 activity reverses the strong actin network to thin filaments in myosin-18B-overexpressing cells. Moreover, AMP-activated protein kinase (AMPK) activation is able to relieve the thin stress fibers by myosin-18B knockout. Importantly, lack of myosin-18B compromises AMPK-vasodilator-stimulated phosphoprotein and RhoA-myosin signaling, thereby leading to defective persistent migration, which can be rescued only by full-length and C-extension-less myosin-18B. Together, these results reveal a critical role of myosin-18B in the mechanosensitive regulation of migrating cells.
肌动蛋白应力纤维引导细胞迁移和形态发生。在向心流期间，肌动蛋白横向弧融合，伴随着肌球蛋白II堆栈的形成，以产生机械敏感的肌动球蛋白束。然而，肌球蛋白II堆栈的形成是否在细胞机械传感中发挥作用仍不清楚。肌球蛋白-18B是用于组装肌球蛋白II堆栈的“胶水”分子。通过检查肌动蛋白网络和牵引力，我们发现缺失肌球蛋白-18B的细胞类似于钙/钙调蛋白依赖性激酶激酶2（CaMKK2）缺陷细胞。抑制CaMKK2活性可使肌球蛋白-18B过表达细胞中强大的肌动蛋白网络逆转至细丝。此外，AMP激活的蛋白激酶（AMPK）激活能够通过敲除肌球蛋白-18B来缓解细应力纤维。重要的是，缺乏肌球蛋白-18B会损害AMPK-血管舒张剂刺激的磷蛋白和RhoA-肌球蛋白信号传导，从而导致持续性迁移缺陷，这只能通过全长和无C末端延伸的肌球蛋白-18B来挽救。总之，这些结果揭示了肌球蛋白-18B在迁移细胞的机械敏感调节中的关键作用。
