Zyxin regulates endothelial von Willebrand factor secretion by reorganizing actin filaments around exocytic granules.
Zyxin regulates endothelial von Willebrand factor secretion by reorganizing actin filaments around exocytic granules.
复制标题
Zyxin 通过重组胞吐颗粒周围的肌动蛋白丝来调节内皮血管性血友病因子分泌
DOI：
10.1038/ncomms14639
复制
发表时间：
2017-03-03
影响因子：
16.6
通讯作者：
Luo J
中科院分区：
文献类型：
--
作者：
Han X;Li P;Yang Z;Huang X;Wei G;Sun Y;Kang X;Hu X;Deng Q;Chen L;He A;Huo Y;Li D;Betzig E;Luo J
内皮细胞胞吐韦伯-帕拉德小体（WPB）是防御血管损伤的第一道防线之一。然而，WPB胞吐作用的最后阶段（包括颗粒的对接、引发和融合）的控制机制还知之甚少。在这里，我们表明，粘着斑蛋白zyxin在这个过程中是至关重要的。Zyxin下调抑制cAMP激动剂诱导的人原代内皮细胞（EC）分泌血管性血友病因子（VWF），VWF是WPB中最丰富的货物。Zyxin缺陷小鼠表现出受损的肾上腺素刺激的VWF释放，出血时间延长和血栓形成，主要是由于VWF的内皮分泌缺陷。使用活细胞超分辨率显微镜，我们可视化了融合前WPB周围预先存在的肌动蛋白丝的先前未被欣赏的重组，依赖于zyxin和与肌动蛋白交联剂α-辅肌动蛋白的相互作用。我们的研究结果表明，zyxin作为一个生理调节内皮细胞胞吐作用，通过重组局部肌动蛋白网络在最后阶段的胞吐。接头蛋白zyxin在维持肌动蛋白网络中具有机械感应功能。在这里，作者表明，zyxin是血液稳态和血栓形成的关键，通过控制血管性血友病因子的内皮释放和肌动蛋白支架的形成外泌颗粒。
Endothelial exocytosis of Weibel–Palade body (WPB) is one of the first lines of defence against vascular injury. However, the mechanisms that control WPB exocytosis in the final stages (including the docking, priming and fusion of granules) are poorly understood. Here we show that the focal adhesion protein zyxin is crucial in this process. Zyxin downregulation inhibits the secretion of von Willebrand factor (VWF), the most abundant cargo in WPBs, from human primary endothelial cells (ECs) induced by cAMP agonists. Zyxin-deficient mice exhibit impaired epinephrine-stimulated VWF release, prolonged bleeding time and thrombosis, largely due to defective endothelial secretion of VWF. Using live-cell super-resolution microscopy, we visualize previously unappreciated reorganization of pre-existing actin filaments around WPBs before fusion, dependent on zyxin and an interaction with the actin crosslinker α-actinin. Our findings identify zyxin as a physiological regulator of endothelial exocytosis through reorganizing local actin network in the final stage of exocytosis. The adaptor protein zyxin is known for its mechanosensing function in the maintenance of actin network. Here the authors show that zyxin is key to blood homeostasis and thrombosis by controlling the endothelial release of von Willebrand factor and the formation of actin scaffolds on exocytic granules.