NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing.
NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing.
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NAADP 激活 T 细胞溶细胞颗粒上的双孔通道，刺激胞吐作用和杀伤作用。
DOI：
10.1016/j.cub.2012.10.035
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发表时间：
2012-12-18
期刊：
影响因子：
9.2
通讯作者：
Galione, Antony
中科院分区：
文献类型：
--
作者：
Davis, Lianne C.;Morgan, Anthony J.;Chen, Ji-Li;Snead, Charlotte M.;Bloor-Young, Duncan;Shenderov, Eugene;Stanton-Humphreys, Megan N.;Conway, Stuart J.;Churchill, Grant C.;Parrington, John;Cerundolo, Vincenzo;Galione, Antony
细胞毒性T淋巴细胞（CTL）通过在两个细胞之间形成的免疫突触上的细胞溶解颗粒的Ca2+依赖性胞吐作用杀死被感染或致瘤细胞。虽然肌醇1,4,5-三磷酸（IP3）介导的Ca2+释放从内质网激活存储操作的Ca2+内流途径，这是胞外分泌所必需的，但它不是一个充分的刺激。在这里，我们确定Ca2+动员信使烟酸腺嘌呤二核苷酸磷酸（NAADP）及其最近发现的分子靶标，双孔通道（TPCs），在ctl中对T细胞受体信号传导很重要。我们证明，细胞溶解颗粒不仅是细胞溶解蛋白的储存库，也是NAADP通过颗粒上的TPC通道动员的酸性Ca2+储存库，因此TPC在CTL激活后迁移到免疫突触。此外，NAADP激活TPCs以一种IP3或离子霉素诱导的全局Ca2+信号无法模仿的方式驱动胞外分泌，这表明TPCs周围关键的局部Ca2+纳米结构域刺激颗粒胞外分泌。因此，通过NAADP/TPC途径，细胞溶解颗粒产生Ca2+信号，导致自身胞吐和细胞杀伤。这项研究强调了NAADP在刺激对免疫细胞功能至关重要的胞吐作用中的选择性作用，并可能在更广泛的细胞背景下影响刺激-分泌偶联。►T细胞受体通过NAADP/双孔通道（TPCs）动员酸性Ca2+储存►胞外颗粒本身就是由TPCs装饰的酸性Ca2+储存►TPCs在TCR激活时移动到免疫突触►NAADP刺激胞外分泌比单独的IP3/Ca2+内流更有效
A cytotoxic T lymphocyte (CTL) kills an infected or tumorigenic cell by Ca2+-dependent exocytosis of cytolytic granules at the immunological synapse formed between the two cells. Although inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release from the endoplasmic reticulum activates the store-operated Ca2+-influx pathway that is necessary for exocytosis, it is not a sufficient stimulus. Here we identify the Ca2+-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and its recently identified molecular target, two-pore channels (TPCs), as being important for T cell receptor signaling in CTLs. We demonstrate that cytolytic granules are not only reservoirs of cytolytic proteins but are also the acidic Ca2+ stores mobilized by NAADP via TPC channels on the granules themselves, so that TPCs migrate to the immunological synapse upon CTL activation. Moreover, NAADP activates TPCs to drive exocytosis in a way that is not mimicked by global Ca2+ signals induced by IP3 or ionomycin, suggesting that critical, local Ca2+ nanodomains around TPCs stimulate granule exocytosis. Hence, by virtue of the NAADP/TPC pathway, cytolytic granules generate Ca2+ signals that lead to their own exocytosis and to cell killing. This study highlights a selective role for NAADP in stimulating exocytosis crucial for immune cell function and may impact on stimulus-secretion coupling in wider cellular contexts. ► The T cell receptor mobilizes acidic Ca2+ stores via NAADP/two-pore channels (TPCs) ► Exocytotic granules are themselves acidic Ca2+ stores decorated with TPCs ► TPCs move to the immunological synapse upon TCR activation ► NAADP stimulates exocytosis more efficiently than does IP3/Ca2+ influx alone
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影响因子：
4.4
作者：
Chen, Ji-Li;Morgan, Anthony J.;Cerundolo, Vincenzo
通讯作者：
Cerundolo, Vincenzo
DOI：
10.1083/jcb.200904073
发表时间：
2009-07-27
期刊：
The Journal of cell biology
影响因子：
--
作者：
Brailoiu E;Churamani D;Cai X;Schrlau MG;Brailoiu GC;Gao X;Hooper R;Boulware MJ;Dun NJ;Marchant JS;Patel S
通讯作者：
Patel S
影响因子：
4.8
作者：
Dammermann, W;Guse, AH
通讯作者：
Guse, AH
影响因子：
4.8
作者：
Gasser, Andreas;Bruhn, Soren;Guse, Andreas H.
通讯作者：
Guse, Andreas H.
影响因子：
7
作者：
Casey, Tammy M.;Meade, Josephine L.;Hewitt, Eric W.
通讯作者：
Hewitt, Eric W.