Munc18b/STXBP2 is required for platelet secretion
Munc18b/STXBP2 is required for platelet secretion
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DOI：
10.1182/blood-2012-05-430629
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发表时间：
2012-09-20
期刊：
影响因子：
20.3
通讯作者：
Whiteheart, Sidney W.
中科院分区：
文献类型：
--
作者：
Al Hawas, Rania;Ren, Qiansheng;Whiteheart, Sidney W.
血小板对于止血至关重要，因为它们会在血管损伤时释放颗粒内容物。血小板胞吐作用由可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体 (SNARE) 介导，其相互作用受调节因子（例如 Sec/Munc18 蛋白）控制。这些蛋白是突触蛋白伴侣 t-SNARE，是胞吐作用所必需的。血小板包含 3 种 Munc18 亚型：Munc18a、Munc18b 和 Munc18c。我们报告 Munc18b 是主要的亚型，是血小板分泌所必需的。家族性噬血细胞性淋巴组织细胞增多症 5 型 (FHL5) 是由 Munc18b/STXBP2 基因缺陷引起的。我们证实了之前的一份报告，显示 FHL5 患者的血小板分泌有缺陷。血清素、ADP/ATP 和血小板因子 4 的释放在 2 名双等位基因患者和部分杂合子患者中受到严重影响。溶酶体内容物的释放仅在双等位血小板中受到影响。 FHL5 双等位基因患者的血小板显示 Munc18b 降低，并且 Syntaxin-11 水平显着降低；其他语法蛋白不受影响。 Munc18b 与人血小板中突触蛋白 11、SNAP-23 和囊泡相关膜蛋白 8 形成复合物。其他潜在的分泌调节因子 Munc13-4 和 Rab27 也被发现与之相关。这些数据证明了 Munc18b 在血小板胞吐作用中的关键作用，可能是作为限制因素，并表明它调节突触蛋白 11。 （血。2012；120(12):2493-2500）
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. (Blood. 2012;120(12):2493-2500)