TY - JOUR T1 - Plasma membrane phosphatidylinositol (4,5)-bisphosphate promotes Weibel–Palade body exocytosis JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202000788 VL - 3 IS - 11 SP - e202000788 AU - Tu Thi Ngoc Nguyen AU - Sophia N Koerdt AU - Volker Gerke Y1 - 2020/11/01 UR - https://www.life-science-alliance.org/content/3/11/e202000788.abstract N2 - 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. ER -