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Double agent

In patients, abnormalities in the circulating levels of von Willebrand factor (vWF) are predictive of heart attack and thrombosis. vWF regulates coagulation and influences blood flow and vessel wall characteristics; however, it is not clear how vWF levels are modulated. Recent GWAS have linked the gene encoding syntaxin binding protein 5 (STXBP5), which participates in the docking and fusion of exocytic vesicles, with alterations in vWF plasma levels. Qiuyu Zhu and colleagues at the University of Rochester Medical Center determined that STXBP5 inhibits exocytosis in human endothelial cells, reducing secretion of vWF and the adhesion factor P-selectin. STXBP5-deficient mice had increased plasma levels of vWF, a greater occurrence of platelet-endothelial cell interactions, and hemostasis defects. A companion article in this issue from Shaojing Ye and colleagues at the University of Kentucky found that platelets from Stxbp5 KO mice exhibit decreased granule secretion and granule cargo levels, both of which are required for clotting. Ye and colleagues also confirmed that hemostasis is defective in Stxbp5 KO mice. Together, these studies reveal a differential role for STXBP5 in endothelial cells and platelets that influences vascular disease. In the accompanying commentary, David Lillicrap discusses how these studies validate GWAS that identified STXBP5 as a cardiovascular disease risk factor. The accompanying image from Qiuyu Zhu and colleagues shows that STXBP5 (green) and vWF (red) do not colocalize in human endothelial cells. Nuclei are stained with DAPI (blue)

 

Published September 17, 2014, by Corinne Williams

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Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion
Qiuyu Zhu, … , Craig N. Morrell, Charles J. Lowenstein
Qiuyu Zhu, … , Craig N. Morrell, Charles J. Lowenstein
Published September 17, 2014
Citation Information: J Clin Invest. 2014;124(10):4503-4516. https://doi.org/10.1172/JCI71245.
View: Text | PDF
Research Article

Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion

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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

Qiuyu Zhu, Munekazu Yamakuchi, Sara Ture, Maria de la Luz Garcia-Hernandez, Kyung Ae Ko, Kristina L. Modjeski, Michael B. LoMonaco, Andrew D. Johnson, Christopher J. O’Donnell, Yoshimi Takai, Craig N. Morrell, Charles J. Lowenstein

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Platelet secretion and hemostasis require syntaxin-binding protein STXBP5
Shaojing Ye, … , Yoshimi Takai, Sidney W. Whiteheart
Shaojing Ye, … , Yoshimi Takai, Sidney W. Whiteheart
Published September 17, 2014
Citation Information: J Clin Invest. 2014;124(10):4517-4528. https://doi.org/10.1172/JCI75572.
View: Text | PDF
Research Article

Platelet secretion and hemostasis require syntaxin-binding protein STXBP5

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Abstract

Genome-wide association studies (GWAS) have linked genes encoding several soluble NSF attachment protein receptor (SNARE) regulators to cardiovascular disease risk factors. Because these regulatory proteins may directly affect platelet secretion, we used SNARE-containing complexes to affinity purify potential regulators from human platelet extracts. Syntaxin-binding protein 5 (STXBP5; also known as tomosyn-1) was identified by mass spectrometry, and its expression in isolated platelets was confirmed by RT-PCR analysis. Coimmunoprecipitation studies showed that STXBP5 interacts with core secretion machinery complexes, such as syntaxin-11/SNAP23 heterodimers, and fractionation studies suggested that STXBP5 also interacts with the platelet cytoskeleton. Platelets from Stxbp5 KO mice had normal expression of other key secretory components; however, stimulation-dependent secretion from each of the 3 granule types was markedly defective. Secretion defects in STXBP5-deficient platelets were confirmed via lumi-aggregometry and FACS analysis for P-selectin and LAMP-1 exposure. Interestingly, STXBP5-deficient platelets had altered granule cargo levels, despite having normal morphology and granule numbers. Consistent with secretion and cargo deficiencies, Stxbp5 KO mice showed dramatic bleeding in the tail transection model and defective hemostasis in the FeCl3-induced carotid injury model. Transplantation experiments indicated that these defects were due to loss of STXBP5 in BM-derived cells. Our data demonstrate that STXBP5 is required for normal arterial hemostasis, due to its contributions to platelet granule cargo packaging and secretion.

Authors

Shaojing Ye, Yunjie Huang, Smita Joshi, Jinchao Zhang, Fanmuyi Yang, Guoying Zhang, Susan S. Smyth, Zhenyu Li, Yoshimi Takai, Sidney W. Whiteheart

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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

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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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