Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
The State Key Laboratory of Biomembrane and Membrane Biotechnology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Laboratory of Institute of Molecular Medicine, Peking University, Beijing 100871, China.
Nat Commun. 2017 Mar 3;8:14639. doi: 10.1038/ncomms14639.
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.
血管内皮细胞的 Weibel-Palade 体（WPB）胞吐是血管损伤的第一道防线。然而，控制 WPB 胞吐的最后阶段（包括颗粒的对接、引发和融合）的机制还知之甚少。在这里，我们发现粘着斑蛋白锌指蛋白（zyxin）在这个过程中至关重要。下调 zyxin 抑制了 cAMP 激动剂诱导的人原代内皮细胞（EC）中 von Willebrand 因子（VWF）的分泌，VWF 是 WPB 中含量最丰富的货物。缺乏 zyxin 的小鼠表现出肾上腺素刺激的 VWF 释放受损、出血时间延长和血栓形成，这主要是由于 VWF 的内皮分泌缺陷。使用活细胞超分辨率显微镜，我们可视化了以前未被认识到的融合前 WPB 周围预先存在的肌动蛋白丝的重新排列，这依赖于 zyxin 与肌动蛋白交联蛋白α-辅肌动蛋白的相互作用。我们的研究结果表明，zyxin 通过在胞吐的最后阶段重新组织局部肌动蛋白网络，成为内皮胞吐的生理调节剂。
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