RT Journal Article SR Electronic T1 Plasma membrane phosphatidylinositol (4,5)-bisphosphate promotes Weibel–Palade body exocytosis JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202000788 DO 10.26508/lsa.202000788 VO 3 IS 11 A1 Tu Thi Ngoc Nguyen A1 Sophia N Koerdt A1 Volker Gerke YR 2020 UL https://www.life-science-alliance.org/content/3/11/e202000788.abstract AB 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.