VAMP-7 links granule exocytosis to actin reorganization during platelet activation

• Published in: Blood Vol. 126; no. 5; pp. 651 - 660
• Main Authors: Koseoglu, Secil, Peters, Christian G., Fitch-Tewfik, Jennifer L., Aisiku, Omozuanvbo, Danglot, Lydia, Galli, Thierry, Flaumenhaft, Robert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.07.2015; American Society of Hematology
• Subjects: Actin Cytoskeleton - physiology; Actin-Related Protein 2-3 Complex - blood; Animals; Blood Platelets - physiology; Blood Platelets - ultrastructure; Cytoplasmic Granules - physiology; Exocytosis - physiology; Guanine Nucleotide Exchange Factors - blood; Hematology; Human health and pathology; Humans; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; P-Selectin - blood; Platelet Activation - physiology; Platelet Aggregation - physiology; Platelets and Thrombopoiesis; R-SNARE Proteins - blood; R-SNARE Proteins - deficiency; R-SNARE Proteins - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-12-618744

Platelet activation results in profound morphologic changes accompanied by release of granule contents. Recent evidence indicates that fusion of granules with the plasma membrane during activation provides auxiliary membrane to cover growing actin structures. Yet little is known about how membrane fusion is coupled with actin reorganization. Vesicle-associated membrane protein (VAMP)-7 is found on platelet vesicles and possesses an N-terminal longin domain capable of linking exocytosis to cytoskeletal remodeling. We have evaluated platelets from VAMP-7−/− mice to determine whether this VAMP isoform contributes to granule release and platelet spreading. VAMP-7−/− platelets demonstrated a partial defect in dense granule exocytosis and impaired aggregation. α Granule exocytosis from VAMP-7−/− platelets was diminished both in vitro and in vivo during thrombus formation. Consistent with a role of VAMP-7 in cytoskeletal remodeling, spreading on matrices was decreased in VAMP-7−/− platelets compared to wild-type controls. Immunoprecipitation of VAMP-7 revealed an association with VPS9-domain ankyrin repeat protein (VARP), an adaptor protein that interacts with both membrane-bound and cytoskeleton proteins and with Arp2/3. VAMP-7, VARP, and Arp2/3 localized to the platelet periphery during spreading. These studies demonstrate that VAMP-7 participates in both platelet granule secretion and spreading and suggest a mechanism whereby VAMP-7 links granule exocytosis with actin reorganization. •VAMP-7 functions in platelet granule exocytosis and spreading.•VAMP-7 associates with VARP and Arp2/3, thereby linking granule exocytosis and actin reorganization.