Weibel-Palade bodies (WPB) are specialized secretory organelles of endothelial cells that control vascular hemostasis by regulated, Ca²⁺-dependent exocytosis of the coagulation-promoting von-Willebrand factor. Some proteins of the WPB docking and fusion machinery have been identified but a role of membrane lipids in regulated WPB exocytosis has so far remained elusive. We show here that the plasma membrane phospholipid composition affects Ca²⁺-dependent WPB exocytosis and von-Willebrand factor release. Phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P₂] becomes enriched at WPB-plasma membrane contact sites at the time of fusion, most likely downstream of phospholipase D1-mediated production of phosphatidic acid (PA) that activates phosphatidylinositol 4-phosphate (PI4P) 5-kinase γ. Depletion of plasma membrane PI(4,5)P₂ or down-regulation of PI4P 5-kinase γ interferes with histamine-evoked and Ca²⁺-dependent WPB exocytosis and a mutant PI4P 5-kinase γ incapable of binding PA affects WPB exocytosis in a dominant-negative manner. This indicates that a unique PI(4,5)P₂-rich environment in the plasma membrane governs WPB fusion possibly by providing interaction sites for WPB-associated docking factors.

中文翻译：

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质膜磷脂酰肌醇（4,5）-双磷酸酯促进Weibel-Palade体胞吐作用。

Weibel-Palade体（WPB）是内皮细胞的专门分泌细胞器，通过调节促钙的von-Willebrand因子的Ca ²⁺依赖性胞吐作用来控制血管止血。已经发现了WPB对接和融合机制的某些蛋白质，但迄今为止，膜脂在调控WPB胞吐作用中的作用仍然难以捉摸。我们在这里显示质膜磷脂成分影响Ca ²⁺依赖性WPB胞吐作用和von-Willebrand因子释放。磷脂酰肌醇（4,5）-双磷酸[PI（4,5）P ₂在融合时，]在WPB-质膜接触位点富集，最有可能在磷脂酶D1介导的激活磷酸磷脂酰肌醇4-磷酸酯（PI4P）5-激酶γ的磷脂酸（PA）的下游。质膜PI（4,5）P ₂耗尽或PI4P 5激酶γ的下调会干扰组胺诱发和依赖Ca ^2+的WPB胞吐作用，而不能结合PA的突变PI4P 5激酶γ会影响WPB胞吐作用以显性负性方式 这表明质膜中独特的富含PI（4,5）P _2的环境可能通过提供与WPB相关的对接因子的相互作用位点来控制WPB融合。