PT  - JOURNAL ARTICLE
AU  - Tu Thi Ngoc Nguyen
AU  - Sophia N Koerdt
AU  - Volker Gerke
TI  - Plasma membrane phosphatidylinositol (4,5)-bisphosphate promotes Weibel–Palade body exocytosis
AID  - 10.26508/lsa.202000788
DP  - 2020 Nov 01
TA  - Life Science Alliance
PG  - e202000788
VI  - 3
IP  - 11
4099  - https://www.life-science-alliance.org/content/3/11/e202000788.short
4100  - https://www.life-science-alliance.org/content/3/11/e202000788.full
SO  - Life Sci. Alliance2020 Nov 01; 3
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.