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

Lillicrap, David

doi:10.1172/jci77511

Cited by 7 publications

(5 citation statements)

References 16 publications

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“…Interestingly, STXBP5 has also been shown to differentially regulate exocytosis in endothelial cells and platelets [44, 45]. While STXBP5 facilitates granule release from platelets, it inhibits secretion from the WPB of endothelial cells [46]. Recently, Torisu et al observed another novel type of regulation of VWF release through an observation that WPBs are often in close proximity of autophagosomes [47].…”

Section: Regulation Of Vwf Protein Secretionmentioning

confidence: 99%

Regulation of VWF expression, and secretion in health and disease

Xiang

Hwa

2016

Current Opinion in Hematology

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PURPOSE OF REVIEW VWF is a large multi-domain, multimeric glycoprotein that plays an essential role in regulating the balance between blood clotting and bleeding. Aberrant VWF regulation can lead to a spectrum of diseases extending from bleeding disorders (VWD) to aberrant thrombosis (TTP). Understanding the biology of VWF expression and secretion is essential for developing novel targeted therapies for VWF related hemostasis disorders. RECENT FINDINGS A number of recent elegant in vitro and in vivo studies will be highlighted including the discovery of intronic splicing in the VWF gene, miRNA regulated VWF gene expression, and syntaxin binding protein and autophagy mediated VWF secretion. Compared with the already established critical role of VWF in VWD and TTP pathophysiology, additional clinical studies have clarified and reinforced the association of increased plasma levels of VWF with an increased risk of stroke, myocardial infarction, venous thrombosis and diabetic thrombotic complications. Moreover, experimental mouse models of ischaemic stroke and myocardial infarction have further support VWF as a potential therapeutic target. SUMMARY VWF biosynthesis, maturation, and secretion is a complex process, which mandates tight regulation. Significant progress has been made in our understandings of VWF expression and secretion and its association with thrombotic diseases, contributing to the development of novel targeting VWF drugs for prevention and treatment of deficient and enhanced hemostasis.

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Section: Regulation Of Vwf Protein Secretionmentioning

confidence: 99%

Regulation of VWF expression, and secretion in health and disease

Xiang

Hwa

2016

Current Opinion in Hematology

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“…4, 8, 9 More recently, we and others found STXBP5 is a novel regulator of platelet granule exocytosis and thrombosis. 10–12 …”

Section: Introductionmentioning

confidence: 99%

Novel Thrombotic Function of a Human SNP in STXBP5 Revealed by CRISPR/Cas9 Gene Editing in Mice

Zhu

Ture

et al. 2017

ATVB

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Objective To identify and characterize the effect of a single nucleotide polymorphism (SNP) in the STXBP5 locus that is associated with altered thrombosis in humans. Genome wide association studies (GWAS) have identified numerous SNPs associated with human thrombotic phenotypes, but determining the functional significance of an individual candidate SNP can be challenging, particularly when in vivo modeling is required. Recent GWAS led to the discovery of STXBP5 as a regulator of platelet secretion in humans. Further clinical studies have identified genetic variants of STXBP5 that are linked to altered plasma von Willebrand factor (VWF) levels and thrombosis in humans, but the functional significance of these variants in STXBP5 is not understood. Approach and Results We used CRISPR-Cas9 techniques to produce a precise mouse model carrying a human coding SNP rs1039084 (encoding human p. N436S) in the STXBP5 locus associated with decreased thrombosis. Mice carrying the orthologous human mutation (encoding p. N437S in mouse STXBP5) have lower plasma VWF levels, decreased thrombosis, and decreased platelet secretion compared to wild-type mice. This thrombosis phenotype recapitulates the phenotype of humans carrying the minor allele of rs1039084. Decreased plasma VWF and platelet activation may partially explain the decreased thrombotic phenotype in mutant mice. Conclusions Using precise mammalian genome editing, we have identified a human non-synonymous SNP rs1039084 in the STXBP5 locus as a causal variant for a decreased thrombotic phenotype. CRISPR-Cas9 genetic editing facilitates the rapid and efficient generation of animals to study the function of human genetic variation in vascular diseases.

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“…58,[73][74][75][76][77][78] These loci may modulate VWF plasma levels either by involvement in intracellular trafficking and exocytosis of VWF (e.g., STX2 and STXBP5 genes) or through cellular uptake and clearance of VWF from plasma (e.g., STAB2, SCARA5, CLEC4M, and LRP1). 78,79 Further ex vivo gene expression and in vivo mouse studies of CLEC4M provided additional evidence that a variable number of tandem repeat (VNTR) polymorphisms in CLEC4M gene influence VWF levels in plasma. The CLEC4M protein is a lectin receptor possessing an N-terminal cytoplasmic domain, a transmembrane domain and an extracellular neck region which is highly polymorphic possessing three to nine VNTRs of a conserved 23-aa sequence.…”

Section: Genetic Determinants Outside Vwf Contributing To Variabilitymentioning

confidence: 99%

The Current Understanding of Molecular Pathogenesis of Quantitative von Willebrand Disease, Types 1 and 3

Yadegari¹,

Oldenburg²

2020

Hamostaseologie

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Von Willebrand disease (VWD), the most prevalent congenital bleeding disorder, arises from deficiencies in quantity or quality of von Willebrand factor (VWF). The quantitative deficiencies of VWF are considered to be either VWD type 1 (mild/moderate reduction of VWF) or type 3 (virtual absence of VWF). Following cloning of the VWF gene (VWF) in the 1980s, significant progress has been made in our understanding of the pathogenesis of VWD. The genetic basis of type 3 VWD is well defined. VWF causative variations comprising predominantly null alleles have been identified in more than 85% of cases. In contrast, the molecular mechanisms in type 1 disease are only partially characterized. The VWF sequence variations, including mostly missense alterations, are found in only approximately 65% of type 1 VWD patients. It appears that genetic elements outside of VWF may contribute to the pathophysiology of type 1 VWD. This review discusses in detail the current understandings of the genetic basis and molecular mechanisms causing quantitative deficiencies of VWF.

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

Abstract: C o m m e n t a r y 4 2 3 1

Cited by 7 publications

References 16 publications

Regulation of VWF expression, and secretion in health and disease

Regulation of VWF expression, and secretion in health and disease

Novel Thrombotic Function of a Human SNP in STXBP5 Revealed by CRISPR/Cas9 Gene Editing in Mice

The Current Understanding of Molecular Pathogenesis of Quantitative von Willebrand Disease, Types 1 and 3

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