Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4
Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4
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DOI：
10.1038/ni1431
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发表时间：
2007-03-01
影响因子：
30.5
通讯作者：
de Saint Basile, Genevieve
中科院分区：
文献类型：
--
作者：
Menager, Mickael M.;Menasche, Gael;de Saint Basile, Genevieve
细胞毒性T淋巴细胞和自然杀伤细胞通过免疫突触极化分泌细胞毒性颗粒发挥细胞毒性活性。Rab27a和hMunc13-4是细胞毒性颗粒胞吐的关键效应因子。在这里，我们表明淋巴细胞的细胞毒性功能需要两种细胞器的合作：溶酶体细胞毒性颗粒和内体胞外泡。独立于Rab27a， hMunc13-4介导Rab11（+）再循环和Rab27（+）内体晚期囊泡的组装，构成一个囊泡池，用于调节胞外分泌。它还可能通过与活性Rab27a相互作用引发细胞毒性颗粒融合。细胞毒性T淋巴细胞-靶细胞识别诱导两种细胞器的快速极化，它们在细胞-细胞接触区附近合并。我们的数据提供了对效应细胞毒性T淋巴细胞和自然杀伤细胞产生和释放细胞毒性颗粒的调控。
Cytotoxic T lymphocytes and natural killer cells exert their cytotoxic activity through the polarized secretion of cytotoxic granules at the immunological synapse. Rab27a and hMunc13-4 are critical effectors of the exocytosis of cytotoxic granules. Here we show that the cytotoxic function of lymphocytes requires the cooperation of two types of organelles: the lysosomal cytotoxic granule and the endosomal 'exocytic vesicle'. Independently of Rab27a, hMunc13-4 mediated the assembly of Rab11(+) recycling and Rab27(+) late endosomal vesicles, constituting a pool of vesicles destined for regulated exocytosis. It also primed cytotoxic granule fusion, possibly through interaction with active Rab27a. Cytotoxic T lymphocyte-target cell recognition induced rapid polarization of both types of organelles, which coalesced near the cell-cell contact area. Our data provide insight into the regulation of the generation and release of cytotoxic granules by effector cytotoxic T lymphocytes and natural killer cells.