Munc18b/STXBP2 is required for platelet secretion.
Platelets are vital for hemostasis because they release their granule contents in response to vascular damage. Platelet exocytosis is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), whose interactions are governed by regulators, eg, Sec/Munc18 proteins. These proteins chaperone syntaxin t-SNAREs and are required for exocytosis. Platelets contain 3 Munc18 isoforms: Munc18a, Munc18b, and Munc18c. We report that Munc18b is the major isoform and is required for platelet secretion. Familial hemophagocytic lymphohistiocytosis type 5 (FHL5) is caused by defects in the Munc18b/STXBP2 gene. We confirm a previous report showing that platelets from FHL5 patients have defective secretion. Serotonin, ADP/ATP, and platelet factor 4 release was profoundly affected in the 2 biallelic patients and partially in a heterozygous patient. Release of lysosomal contents was only affected in the biallelic platelets. Platelets from the FHL5 biallelic patients showed decreased Munc18b and syntaxin-11 levels were significantly reduced; other syntaxins were unaffected. Munc18b formed complexes with syntaxin-11, SNAP-23, and vesicle-associated membrane protein-8 in human platelets. Other potential secretion regulators, Munc13-4 and Rab27, were also found associated. These data demonstrate a key role for Munc18b, perhaps as a limiting factor, in platelet exocytosis and suggest that it regulates syntaxin-11.
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Rania
R
Al Hawas
Qiansheng
Q
Ren
Shaojing
S
Ye
Zubair A
ZA
Karim
Alexandra H
AH
Filipovich
Sidney W
SW
Whiteheart
D001792:Blood Platelets / Q000378:metabolism* / Q000648:ultrastructure; D015153:Blotting, Western; D016022:Case-Control Studies; D003594:Cytoplasmic Granules / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051938:Munc18 Proteins / Q000378:metabolism*; D010974:Platelet Aggregation / Q000502:physiology; D050765:Qa-SNARE Proteins / Q000378:metabolism; D050600:SNARE Proteins / Q000378:metabolism*
D051938:Munc18 Proteins; D050765:Qa-SNARE Proteins; D050600:SNARE Proteins; C541732:STX11 protein, human