Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells
Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells
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DOI：
10.1172/jci40732
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发表时间：
2009-12-01
影响因子：
15.9
通讯作者：
de Saint Basile, Genevieve
中科院分区：
文献类型：
--
作者：
Cote, Marjorie;Menager, Mickael M.;de Saint Basile, Genevieve
家族性噬血细胞性淋巴组织细胞增生症（FHL）是一种遗传异质性常染色体隐性免疫疾病，其特征是发生不受控制的淋巴细胞和巨噬细胞活化浸润多个器官。已在FHL患者中鉴定出穿孔素（PRF 1;也称为FHL 2）、Munc 13 -4（UNC 13 D;也称为FHL 3）和突触融合蛋白-11（STX 11;也称为FHL 4）基因的致病突变。这些基因都编码参与淋巴细胞细胞毒活性的蛋白质。在这里，我们发现编码突触融合蛋白结合蛋白2（Munc 18 -2;官方基因符号STXBP 2）的基因在另一个FHL患者亚组（我们命名为“FHL 5”）中发生突变。从这些患者中分离的淋巴母细胞具有强烈降低的STXBP 2蛋白表达，并且NK细胞表现出受损的细胞毒性颗粒胞吐作用，这一缺陷可以通过野生型STXBP 2的异位表达来克服。此外，我们提供的证据表明，syntaxin-11是淋巴细胞中STXBP 2的主要伴侣，因为它的表达需要STXBP 2的存在。我们的工作表明STXBP 2缺陷导致FHL 5。这些数据表明，STXBP 2是需要在分泌途径的后期步骤通过结合突触融合蛋白11释放细胞毒性颗粒，突触融合蛋白11是细胞内膜融合机制的另一个组成部分。
Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous autosomal recessive immune disorder characterized by the occurrence of uncontrolled activation of lymphocytes and macrophages infiltrating multiple organs. Disease-causing mutations in the perforin (PRF1; also known as FHL2), Munc13-4 (UNC13D; also known as FHL3), and syntaxin-11 (STX11; also known as FHL4) genes have been identified in individuals with FHL. These genes all encode proteins involved in the cytotoxic activity of lymphocytes. Here, we show that the gene encoding syntaxin-binding protein 2 (Munc18-2; official gene symbol STXBP2) is mutated in another subset of patients with FHL (designated by us as "FHL5"). Lymphoblasts isolated from these patients had strongly decreased STXBP2 protein expression, and NK cells exhibited impaired cytotoxic granule exocytosis, a defect that could be overcome by ectopic expression of wild-type STXBP2. Furthermore, we provide evidence that syntaxin-11 is the main partner of STXBP2 in lymphocytes, as its expression required the presence of STXBP2. Our work shows that STXBP2 deficiency causes FHL5. These data indicate that STXBP2 is required at a late step of the secretory pathway for the release of cytotoxic granules by binding syntaxin 11, another component of the intracellular membrane fusion machinery.