School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom.
Blood Adv. 2018 Dec 26;2(24):3627-3636. doi: 10.1182/bloodadvances.2018023291.
Platelet secretion is central to physiological and pathophysiological platelet function. SNAP23 has long been implicated as being a principal SNARE protein regulating platelet granule secretion, although this has not been definitively demonstrated in genetic models. Here, using a platelet-specific conditional SNAP23 knockout mouse, we show that absence of SNAP23 results in complete ablation of dense granule, α granule, and lysosomal secretion. Measured granule cargo content and granule numbers were normal, suggesting SNAP23 regulates fusion of granules with the extracellular membrane, rather than granule loading or formation. A macrothrombocytopenia was also observed, which, combined with ablation of secretion, resulted in a pronounced bleeding defect in a tail bleed assay and almost complete ablation of arterial and venous thrombosis. The macrothrombocytopenia was not due to reduced megakaryopoiesis but instead likely was due to the increased loss of platelets through bleeding, consistent with an increase in platelet total RNA content indicating a greater number of reticulated platelets. The data definitively show SNAP23 to be critical for granule release of any kind from platelets, irrespective of stimulus, and this is the first single gene to be shown to be universally essential for exocytosis in platelets.
血小板分泌是生理和病理生理血小板功能的核心。SNAP23 长期以来一直被认为是调节血小板颗粒分泌的主要 SNARE 蛋白，尽管在遗传模型中尚未得到明确证明。在这里，我们使用血小板特异性条件性 SNAP23 敲除小鼠，表明 SNAP23 的缺失导致致密颗粒、α 颗粒和溶酶体分泌完全缺失。测量的颗粒货物含量和颗粒数量正常，表明 SNAP23 调节颗粒与细胞外膜融合，而不是颗粒装载或形成。还观察到巨血小板增多症，与分泌缺失相结合，导致尾巴出血试验中明显的出血缺陷，以及动脉和静脉血栓形成几乎完全缺失。巨血小板增多症不是由于巨核细胞生成减少，而是由于出血导致血小板的丢失增加，这与血小板总 RNA 含量的增加一致，表明存在更多的网织血小板。这些数据明确表明，SNAP23 对血小板中任何类型的颗粒释放都是至关重要的，无论刺激如何，这是第一个被证明对血小板胞吐作用普遍必需的单一基因。
