title: Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion.
abstract: In humans, vWF levels predict the risk of myocardial infarction and thrombosis; however, the factors that influence vWF levels are not completely understood. Recent genome-wide association studies (GWAS) have identified syntaxin-binding protein 5 (STXBP5) as a candidate gene linked to changes in vWF plasma levels, though the functional relationship between STXBP5 and vWF is unknown. We hypothesized that STXBP5 inhibits endothelial cell exocytosis. We found that STXBP5 is expressed in human endothelial cells and colocalizes with and interacts with syntaxin 4. In human endothelial cells reduction of STXBP5 increased exocytosis of vWF and P-selectin. Mice lacking Stxbp5 had higher levels of vWF in the plasma, increased P-selectin translocation, and more platelet-endothelial interactions, which suggests that STXBP5 inhibits endothelial exocytosis. However, Stxbp5 KO mice also displayed hemostasis defects, including prolonged tail bleeding times and impaired mesenteric arteriole and carotid artery thrombosis. Furthermore, platelets from Stxbp5 KO mice had defects in platelet secretion and activation; thus, STXBP5 inhibits endothelial exocytosis but promotes platelet secretion. Our study reveals a vascular function for STXBP5, validates the functional relevance of a candidate gene identified by GWAS, and suggests that variation within STXBP5 is a genetic risk for venous thromboembolic disease.
authors.forename: Qiuyu
authors.initials: Q
authors.lastname: Zhu
authors.forename: Munekazu
authors.initials: M
authors.lastname: Yamakuchi
authors.forename: Sara
authors.initials: S
authors.lastname: Ture
authors.forename: Maria
authors.initials: M
authors.lastname: de la Luz Garcia-Hernandez
authors.forename: Kyung Ae
authors.initials: KA
authors.lastname: Ko
authors.forename: Kristina L
authors.initials: KL
authors.lastname: Modjeski
authors.forename: Michael B
authors.initials: MB
authors.lastname: LoMonaco
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Takai
authors.forename: Craig N
authors.initials: CN
authors.lastname: Morrell
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lowenstein
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071120:ADAMTS13 Protein; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology; D042783:Endothelial Cells / Q000166:cytology; D004727:Endothelium / Q000378:metabolism*; D005089:Exocytosis; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019007:P-Selectin / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000378:metabolism; D050683:R-SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D019007:P-Selectin; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; C484767:STXBP5 protein, human; C112618:tomosyn protein, mouse; D014841:von Willebrand Factor; D051722:ADAM Proteins; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human