A role for endobrevin/VAMP8 in CTL lytic granule exocytosis
A role for endobrevin/VAMP8 in CTL lytic granule exocytosis
复制标题
DOI：
10.1002/eji.200939378
复制
发表时间：
2009-12-01
影响因子：
5.4
通讯作者：
Hong, Wanjin
中科院分区：
文献类型：
--
作者：
Loo, Li Shen;Hwang, Le-Ann;Hong, Wanjin
CTL通过释放储存在预先形成的裂解颗粒中的有效细胞毒性酶来清除病毒感染的细胞和致瘤细胞。胞吐过程包括溶解颗粒朝向免疫突触的极化、溶解颗粒与质膜的束缚以及溶解颗粒与质膜的最终融合以释放细胞毒性酶。虽然很多是已知的溶解颗粒胞吐的早期步骤所需的分子机制，在融合过程中的最后一步的分子机制尚未确定。在这里，我们显示使用对照和VAMP 8 KO小鼠，VAMP 8定位于CTL裂解颗粒。尽管免疫突触和颗粒极化在VAMP 8 KO和对照CTL中均表现正常，但Vamp 8（-/-）CTL的CTL介导的杀伤减少。裂解酶分泌的分析表明，颗粒酶A和颗粒酶B分泌在VAMP 8（-/-）CTL中显著受损，而细胞中的裂解酶水平不受影响。我们的结果清楚地表明VAMP 8是通过影响溶解颗粒与质膜融合并释放其内容物的能力来调节CTL溶解能力的v-SNARE之一。
CTL clear virus-infected cells and tumorigenic cells by releasing potent cytotoxic enzymes stored in preformed lytic granules. The exocytosis process includes polarization of lytic granules toward the immunological synapse, tethering of lytic granules to the plasma membrane and finally fusion of lytic granules with the plasma membrane to release cytotoxic enzymes. Although much is known about the molecular machineries necessary for the earlier steps in lytic granule exocytosis, the molecular machinery governing the final step in the fusion process has not been identified. Here, we show using control and VAMP8 KO mice that VAMP8 is localized to the CTL lytic granules. While the immunological synapse and granule polarization appears normal in both VAMP8 KO and control CTL, CTL-mediated killing was reduced for the Vamp8(-/-) CTL. Analysis of lytic enzyme secretion demonstrated that granzyme A and granzyme B secretion is significantly compromised in VAMP8(-/-) CTL, while the levels of the lytic enzymes in the cells are unaffected. our results clearly show that VAMP8 is one of the v-SNARE that regulate the lytic ability of CTL by influencing the ability of the lytic granules to fuse with the plasma membrane and release its contents.