Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, Bad Nauheim 61231, Germany.
Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, Bad Nauheim 61231, Germany.
Dev Cell. 2019 Oct 7;51(1):62-77.e5. doi: 10.1016/j.devcel.2019.08.006. Epub 2019 Sep 5.
Mechanical forces regulate cell behavior and tissue morphogenesis. During cardiac development, mechanical stimuli from the heartbeat are required for cardiomyocyte maturation, but the underlying molecular mechanisms remain unclear. Here, we first show that the forces of the contracting heart regulate the localization and activation of the cytoskeletal protein vinculin (VCL), which we find to be essential for myofilament maturation. To further analyze the role of VCL in this process, we examined its interactome in contracting versus non-contracting cardiomyocytes and, in addition to several known interactors, including actin regulators, identified the slingshot protein phosphatase SSH1. We show how VCL recruits SSH1 and its effector, the actin depolymerizing factor cofilin (CFL), to regulate F-actin rearrangement and promote cardiomyocyte myofilament maturation. Overall, our results reveal that mechanical forces generated by cardiac contractility regulate cardiomyocyte maturation through the VCL-SSH1-CFL axis, providing further insight into how mechanical forces are transmitted intracellularly to regulate myofilament maturation.
机械力调节细胞行为和组织形态发生。在心脏发育过程中，心跳产生的机械刺激对于心肌细胞成熟是必需的，但潜在的分子机制尚不清楚。在这里，我们首先表明，收缩心脏的力调节细胞骨架蛋白 vinculin（VCL）的定位和激活，我们发现它对于肌丝成熟是必不可少的。为了进一步分析 VCL 在这个过程中的作用，我们在收缩和非收缩心肌细胞中检查了它的相互作用组，除了几种已知的相互作用蛋白，包括肌动蛋白调节剂外，还鉴定了弹弓蛋白磷酸酶 SSH1。我们展示了 VCL 如何招募 SSH1 及其效应物、肌动蛋白解聚因子 cofilin（CFL），以调节 F-肌动蛋白重排并促进心肌细胞肌丝成熟。总的来说，我们的结果表明，心脏收缩产生的机械力通过 VCL-SSH1-CFL 轴调节心肌细胞成熟，为机械力如何在细胞内传递以调节肌丝成熟提供了进一步的见解。
