期刊
CURRENT BIOLOGY
卷 22, 期 24, 页码 2331-2337出版社
CELL PRESS
DOI: 10.1016/j.cub.2012.10.035
关键词
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资金
- Wellcome Trust
- Medical Research Council
- Cancer Research UK [C399/A2291]
- BBSRC [BB/G008523/1] Funding Source: UKRI
- MRC [MC_UU_12010/1, G1000800] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G008523/1] Funding Source: researchfish
- Cancer Research UK [11331] Funding Source: researchfish
- Medical Research Council [MC_UU_12010/1, G1000800e, G1000800] Funding Source: researchfish
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 (1P3)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 [1-4]. Here we identify the Ca2+-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and its recently identified molecular target, two-pore channels (TPCs) [5-7], 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.
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