Dynamin 2 orchestrates YAP/TAZ mechanotransduction via cortical actin remodeling

Mechanotransduction, the process by which cells sense and respond to mechanical stimuli, relies on cell adhesion, actin cytoskeleton remodeling, and biochemical signal integration. Here, we demonstrate that dynamin 2 (DNM2), clathrin plaques and surrounding branched actin filaments are mechanotransduction platforms that regulate YAP/TAZ signaling. We show that branched actin filaments surrounding clathrin plaques recruit TAZ, whereas contractile stress fibers associated with focal adhesions promote YAP localization. DNM2, the actin capping protein gelsolin, YAP and TAZ organize the cortical actin network around clathrin plaques while actin disorganization due to DNM2 or clathrin depletion delocalize both YAP and TAZ. In centronuclear myopathy models, DNM2 mutations impair actin remodeling, leading to aberrant YAP/TAZ nuclear translocation and altered gene expression of their transcriptional targets. Importantly, allele-specific mutant DNM2 silencing restores YAP/TAZ balance, actin organization and normalizes gene expression. Our findings establish clathrin plaques and DNM2 as central regulators of YAP/TAZ-mediated mechanotransduction.

机械转导（Mechanotransduction）是细胞感知并响应机械刺激的过程，其依赖于细胞黏附（cell adhesion）、肌动蛋白细胞骨架重塑（actin cytoskeleton remodeling）以及生化信号整合（biochemical signal integration）。本研究证实，动力蛋白2（Dynamin 2, DNM2）、网格蛋白斑（clathrin plaques）及其周围的分支状肌动蛋白丝（branched actin filaments）是调控YAP/TAZ信号通路（YAP/TAZ signaling）的机械转导平台（mechanotransduction platforms）。研究表明，网格蛋白斑周围的分支状肌动蛋白丝可招募TAZ，而与黏着斑（focal adhesions）相关的收缩性应力纤维（contractile stress fibers）则促进YAP的定位。动力蛋白2、肌动蛋白加帽蛋白凝溶胶蛋白（actin capping protein gelsolin）、YAP及TAZ可共同组装网格蛋白斑周围的皮层肌动蛋白网络（cortical actin network）；而因DNM2或网格蛋白耗竭引发的肌动蛋白紊乱（actin disorganization），则会导致YAP与TAZ均出现定位异常。在中央核肌病模型（centronuclear myopathy models）中，DNM2突变会损害肌动蛋白重塑（actin remodeling），进而引发YAP/TAZ的异常核转位（aberrant YAP/TAZ nuclear translocation），并改变其转录靶基因（transcriptional targets）的表达水平。值得注意的是，等位基因特异性突变型DNM2沉默（allele-specific mutant DNM2 silencing）可恢复YAP/TAZ的平衡状态、改善肌动蛋白的组织形式，并使基因表达恢复至正常水平。本研究结果确立了网格蛋白斑与DNM2作为YAP/TAZ介导的机械转导核心调控因子的地位。