VAMP8-dependent fusion of recycling endosomes with the plasma membrane facilitates T lymphocyte cytotoxicity.
VAMP8-dependent fusion of recycling endosomes with the plasma membrane facilitates T lymphocyte cytotoxicity.
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DOI：
10.1083/jcb.201411093
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发表时间：
2015-07-06
期刊：
影响因子：
--
通讯作者：
Rettig J
中科院分区：
文献类型：
--
作者：
Marshall MR;Pattu V;Halimani M;Maier-Peuschel M;Müller ML;Becherer U;Hong W;Hoth M;Tschernig T;Bryceson YT;Rettig J
VAMP8 与回收内体区室相关，而不是与细胞毒性颗粒相关，并且是回收内体和质膜之间融合步骤所必需的，该融合步骤将 Syntaxin-11 带到免疫突触以进行细胞毒性颗粒胞吐作用。细胞毒性 T 淋巴细胞 (CTL) 通过直接释放细胞毒性颗粒内容物消除感染细胞和肿瘤细胞。尽管多种 SNARE 蛋白与细胞毒性颗粒胞吐作用有关，但囊泡 SNARE 蛋白（即囊泡相关膜蛋白 (VAMP)）的作用仍然是个谜。 VAMP8 被认为代表介导小鼠胞吐作用的细胞毒性颗粒囊泡 SNARE 蛋白。然而，在原代人类 CTL 中，VAMP8 与 Rab11a 阳性回收内体共定位。受到刺激后，这些内体迅速运输到质膜并与质膜融合，然后发生细胞毒性颗粒的融合。 VAMP8 的敲低阻断了免疫突触处的循环内体和细胞毒性颗粒融合，而不影响激活信号传导。从机制上讲，VAMP8依赖性回收内体将syntaxin-11沉积在免疫突触处，促进质膜SNARE复合物的组装以进行细胞毒性颗粒融合。因此，细胞毒性颗粒胞吐作用是一个连续的多囊泡融合过程，在细胞毒性颗粒融合之前需要 VAMP8 介导的再循环内体融合。我们的研究结果表明，其他细胞类型中的分泌颗粒胞吐途径也可能比之前认识的更复杂。
VAMP8 is associated with the recycling endosome compartment rather than with cytotoxic granules and is required for a fusion step between recycling endosomes and the plasma membrane that brings syntaxin-11 to the immune synapse for cytotoxic granule exocytosis. Cytotoxic T lymphocytes (CTLs) eliminate infected and neoplastic cells through directed release of cytotoxic granule contents. Although multiple SNARE proteins have been implicated in cytotoxic granule exocytosis, the role of vesicular SNARE proteins, i.e., vesicle-associated membrane proteins (VAMPs), remains enigmatic. VAMP8 was posited to represent the cytotoxic granule vesicular SNARE protein mediating exocytosis in mice. In primary human CTLs, however, VAMP8 colocalized with Rab11a-positive recycling endosomes. Upon stimulation, these endosomes rapidly trafficked to and fused with the plasma membrane, preceding fusion of cytotoxic granules. Knockdown of VAMP8 blocked both recycling endosome and cytotoxic granule fusion at immune synapses, without affecting activating signaling. Mechanistically, VAMP8-dependent recycling endosomes deposited syntaxin-11 at immune synapses, facilitating assembly of plasma membrane SNARE complexes for cytotoxic granule fusion. Hence, cytotoxic granule exocytosis is a sequential, multivesicle fusion process requiring VAMP8-mediated recycling endosome fusion before cytotoxic granule fusion. Our findings imply that secretory granule exocytosis pathways in other cell types may also be more complex than previously appreciated.
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影响因子：
15.9
作者：
Cote, Marjorie;Menager, Mickael M.;de Saint Basile, Genevieve
通讯作者：
de Saint Basile, Genevieve
影响因子：
20.3
作者：
Bryceson, Yenan T.;Rudd, Eva;Ljunggren, Hans-Gustaf
通讯作者：
Ljunggren, Hans-Gustaf
影响因子：
64.8
作者：
KAGI, D;LEDERMANN, B;HENGARTNER, H
通讯作者：
HENGARTNER, H
影响因子：
20.3
作者：
Chiang, Samuel C. C.;Theorell, Jakob;Bryceson, Yenan T.
通讯作者：
Bryceson, Yenan T.
影响因子：
20.3
作者：
Bryceson, YT;March, ME;Long, EO
通讯作者：
Long, EO