Syntaxin-binding protein 5 exocytosis regulation: differential role in endothelial cells and platelets
David Lillicrap
David Lillicrap
Published September 17, 2014
Citation Information: J Clin Invest. 2014;124(10):4231-4233. https://doi.org/10.1172/JCI77511.
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Commentary

Syntaxin-binding protein 5 exocytosis regulation: differential role in endothelial cells and platelets

Abstract

Details of the pathophysiologic mechanisms that underlie complex disorders, such as the thrombo-occlusive events associated with myocardial infarction, stroke, and venous thromboembolism, are challenging to address. Recent advances have been made through the application of genome-wide association studies (GWAS) to identify genetic loci associated with plasma levels of procoagulant proteins and risk of thrombotic disease. GWAS have consistently identified the gene encoding syntaxin-binding protein 5 (STXBP5) in this context. STXBP5 is expressed in both endothelium and platelets, and SNPs within the STXBP5 locus have been associated with plasma levels of vWF and increased venous thrombosis risk. In this issue of the JCI, two complementary reports from the laboratories of Charles Lowenstein and Sidney Whiteheart describe studies that highlight the complexity of the function of STXBP5 in control of storage granule development and exocytosis in platelets and endothelium. Together, these studies demonstrate that STXBP5 differentially regulates exocytosis in these two cell types. While STXBP5 facilitates granule release from platelets, it inhibits secretion from the Weibel-Palade bodies (WPBs) of endothelial cells.

Authors

David Lillicrap

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Figure 1

STXBP5 differentially influences exocytosis in platelets and endothelial cells.

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STXBP5 differentially influences exocytosis in platelets and endothelial...
(A) STXBP5 inhibits regulated exocytosis from endothelial cells, but promotes granule secretion from platelets. In both cell types, STXBP5 interacts with components of the SNARE machinery, but the details of these interactions appear distinct. In endothelial cells, there is no colocalization with WPBs, and the number, size, and morphology of these organelles is not influenced by STXBP5. In platelets, there is no colocalization of STXBP5 with α, dense, and lysosomal granules, but the granule cargo composition is altered. (B) Genetic associations and effects of STXBP5 deficiency. In humans, STXBP5 has consistently been identified in GWAS to be associated with the regulation the plasma levels of several coagulation factors, with bleeding, and with the risk of venous thrombosis. Stxbp5 KO mice exhibit a spectrum of hemostatic phenotypes that are consistent with the role of STXBP5 function in endothelial cells and platelets. FVIII, factor VIII; tPA, tissue plasminogen activator.