Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse
Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse
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DOI：
10.1038/ni1000
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发表时间：
2003-11-01
影响因子：
30.5
通讯作者：
Griffiths, GM
中科院分区：
文献类型：
--
作者：
Clark, RH;Stinchcombe, JC;Griffiths, GM
Hermansky-Pudlak综合征（HPS）是一种罕见的常染色体隐性遗传疾病，以血小板缺陷和眼皮肤白化病为特征。患有HPS 2型（HPS 2）的个体缺乏参与溶酶体分选的胞质衔接蛋白3（AP-3），并且也是免疫缺陷的。在这里，我们表征HPS 2突变，并证明AP-3缺陷导致细胞毒性T淋巴细胞（CTL）介导的细胞毒性的损失。虽然溶酶体蛋白CD 63错误定位于质膜，穿孔素和颗粒酶正确定位于AP-3缺陷型CTL的裂解颗粒。然而，AP-3缺陷型CTL的裂解颗粒增大，并且不能沿着微管移动并停靠在免疫突触的分泌结构域内。这些数据表明AP-3对于CTL的极化分泌是必需的。
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by platelet defects and oculocutaneous albinism. Individuals with HPS type 2 (HPS2) lack the cytosolic adaptor protein 3 (AP-3) involved in lysosomal sorting, and are also immunodeficient. Here we characterize an HPS2 mutation and demonstrate that AP-3 deficiency leads to a loss of cytotoxic T lymphocyte (CTL)- mediated cytotoxicity. Although the lysosomal protein CD63 was mislocalized to the plasma membrane, perforin and granzymes were correctly localized to the lytic granules in AP-3-deficient CTLs. However, the lytic granules of AP-3-deficient CTLs were enlarged and were unable to move along microtubules and dock within the secretory domain of the immunological synapse. These data show that AP-3 is essential for polarized secretion from CTLs.