Syntaxin 8 Regulates Platelet Dense Granule Secretion, Aggregation, and Thrombus Stability

Platelet secretion not only drives thrombosis and hemostasis, but also mediates a variety of other physiological and pathological processes. The ubiquitous SNARE machinery and a number of accessory proteins have been implicated in regulating secretion in platelet. Although several platelet SNAREs have been identified, further members of the SNARE family may be needed to fine-tune platelet secretion. In this study we identified expression of the t-SNARE syntaxin 8 (STX8) (Qc SNARE) in mouse and human platelets. In mouse studies, whereas STX8 was not essential for α-granule or lysosome secretion, Stx8−/− platelets showed a significant defect in dense granule secretion in response to thrombin and CRP. This was most pronounced at intermediate concentrations of agonists. They also showed an aggregation defect that could be rescued with exogenous ADP and increased embolization in Stx8−/− mice in vivo consistent with an important autocrine and paracrine role for ADP in aggregation and thrombus stabilization. STX8 therefore specifically contributes to dense granule secretion and represents another member of a growing family of genes that play distinct roles in regulating granule release from platelets and thus platelet function in thrombosis and hemostasis. The molecular machinery controlling exocytosis of the three secretable granules types in platelets is not fully elucidated. ATP secretion, aggregation, and thrombus stability are defective in Stx8−/− mouse platelets. STX8 is involved in platelet dense granule secretion, and the STX8-mediated pathway contributes to thrombus stabilization. Identification of the novel functional SNARE STX8 suggests alternative mechanisms of granule secretion exist in platelets.