Mechanoadaptation and Caveolae Biology Laboratory, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.
Proteomics Unit, Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.
Nat Commun. 2019 Dec 20;10(1):5828. doi: 10.1038/s41467-019-13782-2.
Cells remodel their structure in response to mechanical strain. However, how mechanical forces are translated into biochemical signals that coordinate the structural changes observed at the plasma membrane (PM) and the underlying cytoskeleton during mechanoadaptation is unclear. Here, we show that PM mechanoadaptation is controlled by a tension-sensing pathway composed of c-Abl tyrosine kinase and membrane curvature regulator FBP17. FBP17 is recruited to caveolae to induce the formation of caveolar rosettes. FBP17 deficient cells have reduced rosette density, lack PM tension buffering capacity under osmotic shock, and cannot adapt to mechanical strain. Mechanistically, tension is transduced to the FBP17 F-BAR domain by direct phosphorylation mediated by c-Abl, a mechanosensitive molecule. This modification inhibits FBP17 membrane bending activity and releases FBP17-controlled inhibition of mDia1-dependent stress fibers, favoring membrane adaptation to increased tension. This mechanoprotective mechanism adapts the cell to changes in mechanical tension by coupling PM and actin cytoskeleton remodeling.
细胞会根据机械应变来重塑其结构。然而，机械力如何被转化为生化信号，从而协调在机械适应过程中观察到的质膜（PM）和下伏细胞骨架的结构变化，目前还不清楚。在这里，我们表明 PM 的机械适应受由 c-Abl 酪氨酸激酶和膜曲率调节剂 FBP17 组成的张力感应途径控制。FBP17 被募集到 caveolae 以诱导 caveolar rosette 的形成。缺乏 FBP17 的细胞，其 rosette 密度降低，在渗透压冲击下缺乏 PM 张力缓冲能力，并且无法适应机械应变。在机制上，张力通过 c-Abl 介导的直接磷酸化传递到 FBP17 的 F-BAR 结构域，c-Abl 是一种机械敏感分子。这种修饰抑制了 FBP17 对膜弯曲的活性，并释放了由 FBP17 控制的对 mDia1 依赖性应力纤维的抑制，有利于膜适应增加的张力。这种机械保护机制通过耦合 PM 和肌动蛋白细胞骨架重塑来适应机械张力的变化。
