STXBP1 promotes Weibel-Palade body exocytosis through its interaction with the Rab27A effector Slp4-a
| Autor: | Kathinka W. E. M. van Hooren, Nicola Hellen, Dorothee van Breevoort, Sarah Weckhuysen, Jeroen Eikenboom, Jan Voorberg, Matthew J. Hannah, Karine M. Valentijn, Ambrosius P. Snijders, Peter De Jonghe, Mar Fernandez-Borja, Tom Carter, Berten Ceulemans, Ruben Bierings |
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| Přispěvatelé: | Landsteiner Laboratory, Amsterdam Cardiovascular Sciences, Experimental Vascular Medicine |
| Předmět: |
endocrine system
Immunology Vesicular Transport Proteins Syntaxin 1 Endogeny Biochemistry Exocytosis rab27 GTP-Binding Proteins chemistry.chemical_compound Munc18 Proteins Von Willebrand factor Weibel–Palade body Human Umbilical Vein Endothelial Cells Gene silencing Humans Secretion Protein Interaction Maps RNA Small Interfering Cells Cultured biology Weibel-Palade Bodies Effector Qa-SNARE Proteins Endothelial Cells Cell Biology Hematology 3. Good health Cell biology HEK293 Cells chemistry rab GTP-Binding Proteins biology.protein Cancer research RNA Interference Human medicine Histamine |
| Zdroj: | Europe PubMed Central Blood, 123(20), 3185-3194 Blood, 123(20), 3185-3194. American Society of Hematology Blood |
| ISSN: | 0006-4971 |
| Popis: | Vascular endothelial cells contain unique rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs), which contain the hemostatic protein von Willebrand factor (VWF) and a cocktail of angiogenic and inflammatory mediators. We have shown that the Rab27A effector synaptotagmin-like protein 4-a (Slp4-a) plays a critical role in regulating hormone-evoked WPB exocytosis. Using a nonbiased proteomic screen for targets for Slp4-a, we now identify syntaxin-binding protein 1 (STXBP1) and syntaxin-2 and -3 as endogenous Slp4-a binding partners in endothelial cells. Coimmunoprecipitations showed that STXBP1 interacts with syntaxin-2 and -3, but not with syntaxin-4. Small interfering RNA-mediated silencing of STXBP1 expression impaired histamine- and forskolin-induced VWF secretion. To further substantiate the role of STXBP1, we isolated blood outgrowth endothelial cells (BOECs) from an early infantile epileptic encephalopathy type 4 (EIEE4) patient carrying a de novo mutation in STXBP1. STXBP1-haploinsufficient EIEE4 BOECs contained similar numbers of morphologically normal WPBs compared with control BOECs of healthy donors; however, EIEE4 BOECs displayed significantly impaired histamine- and forskolin-stimulated VWF secretion. Based on these findings, we propose that the Rab27A-Slp4-a complex on WPB promotes exocytosis through an interaction with STXBP1, thereby controlling the release of vaso-active substances in the vasculature. |
| Databáze: | OpenAIRE |
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