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2018 ; 38
(7
): 1549-1561
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Weibel-Palade Body Localized Syntaxin-3 Modulates Von Willebrand Factor Secretion
From Endothelial Cells
#MMPMID29880488
Schillemans M
; Karampini E
; van den Eshof BL
; Gangaev A
; Hofman M
; van Breevoort D
; Meems H
; Janssen H
; Mulder AA
; Jost CR
; Escher JC
; Adam R
; Carter T
; Koster AJ
; van den Biggelaar M
; Voorberg J
; Bierings R
Arterioscler Thromb Vasc Biol
2018[Jul]; 38
(7
): 1549-1561
PMID29880488
show ga
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 Ca(2+)- 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.