Weibel-Palade body localized syntaxin-3 modulates von Willebrand Factor secretion fom endothelial cells
Objective: Endothelial cells store VWF (von Willebrand factor) in rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs). WPB exocytosis is coordinated by a complex network of Rab GTPases, Rab effectors, and SNARE (soluble NSF attachment protein receptor) proteins. We have previously id...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
1 Jul 2018
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| In: |
Arteriosclerosis, thrombosis, and vascular biology
Year: 2018, Volume: 38, Issue: 7, Pages: 1549-1561 |
| ISSN: | 1524-4636 |
| DOI: | 10.1161/ATVBAHA.117.310701 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1161/ATVBAHA.117.310701
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| Author Notes: | Maaike Schillemans, Ellie Karampini, Bart L. van den Eshof, Anastasia Gangaev, Menno Hofman, Dorothee van Breevoort, Henriët Meems, Hans Janssen, Aat A. Mulder, Carolina R. Jost, Johanna C. Escher, Rüdiger Adam, Tom Carter, Abraham J. Koster, Maartje van den Biggelaar, Jan Voorberg, Ruben Bierings |
| Summary: | Objective: Endothelial cells store VWF (von Willebrand factor) in rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs). WPB exocytosis is coordinated by a complex network of Rab GTPases, Rab effectors, and SNARE (soluble NSF attachment protein receptor) proteins. We have previously identified STXBP1 as the link between the Rab27A-Slp4-a complex on WPBs and the SNARE proteins syntaxin-2 and -3. In this study, we investigate the function of syntaxin-3 in VWF secretion. Approach and Results: In human umbilical vein endothelial cells and in blood outgrowth endothelial cells (BOECs) from healthy controls, endogenous syntaxin-3 immunolocalized to WPBs. A detailed analysis of BOECs isolated from a patient with variant microvillus inclusion disease, carrying a homozygous mutation in STX3(STX3−/−), showed a loss of syntaxin-3 protein and absence of WPB-associated syntaxin-3 immunoreactivity. Ultrastructural analysis revealed no detectable differences in morphology or prevalence of immature or mature WPBs in control versus STX3−/− BOECs. VWF multimer analysis showed normal patterns in plasma of the microvillus inclusion disease patient, and media from STX3−/− BOECs, together indicating WPB formation and maturation are unaffected by absence of syntaxin-3. However, a defect in basal as well as Ca2+- and cAMP-mediated VWF secretion was found in the STX3−/− BOECs. We also show that syntaxin-3 interacts with the WPB-associated SNARE protein VAMP8 (vesicle-associated membrane protein-8). Conclusions: Our data reveal syntaxin-3 as a novel WPB-associated SNARE protein that controls WPB exocytosis. |
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| Item Description: | Gesehen am 27.06.2019 Originally published 1 Jul 2018 |
| Physical Description: | Online Resource |
| ISSN: | 1524-4636 |
| DOI: | 10.1161/ATVBAHA.117.310701 |