Signalling to transcription: Store-operated Ca2+ entry and NFAT activation in lymphocytes
Signalling to transcription: Store-operated Ca2+ entry and NFAT activation in lymphocytes
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DOI：
10.1016/j.ceca.2007.03.007
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发表时间：
2007-08-01
期刊：
影响因子：
4
通讯作者：
Rao, Anjana
中科院分区：
文献类型：
--
作者：
Gwack, Yousang;Feske, Stefan;Rao, Anjana
在由抗原或抗原-抗体复合物刺激的免疫系统细胞中，来自细胞外介质的Ca 2+进入由内质网Ca 2+储存的消耗驱动，并且通过被称为Ca 2+释放激活的Ca 2+（CRAC）通道的专门的储存操作的Ca 2+通道发生。钙池操作的钙内流过程对于免疫系统细胞的短期和长期反应至关重要。短期应答包括肥大细胞脱粒和效应细胞溶解性T细胞杀死靶细胞，而长期应答通常涉及基因转录的变化，包括T和B细胞增殖和分化。Ca 2+内流的下游转录大部分通过活化T细胞的转录因子核因子（NFAT）成漏斗状，NFAT是静息细胞中的细胞质中的高度磷酸化的蛋白质，但是当被钙调蛋白依赖性丝氨酸/苏氨酸磷酸酶钙调磷酸酶去磷酸化时进入细胞核。Ca 2 +/钙调神经磷酸酶/NFAT信号通路对淋巴细胞活化的重要性通过以下发现而得到强调：患有遗传性严重联合免疫缺陷（SCID）综合征的家族中的潜在缺陷是CRAC通道功能、钙库操作的Ca 2+进入、NFAT活化和细胞因子、趋化因子和许多其他NFAT靶基因的转录的缺陷，所述靶基因的转录对于生产性免疫防御是必需的。我们最近使用了一种双管齐下的遗传方法来确定奥赖I作为CRAC通道的孔亚基。一方面，我们启动了一种定位克隆方法，其中我们利用全基因组单核苷酸多态性（SNP）定位来鉴定与上述SCID家族中突变基因相关的基因组区域。与此同时，我们在果蝇中使用全基因组RNAi筛选来鉴定NFAT核转位和钙库操作的Ca 2+进入的关键调节因子。这些方法，连同随后的突变和电生理学分析，共同确定人奥赖I作为CRAC通道的孔亚基和作为在SCID患者中突变的基因产物。(C)2007爱思唯尔有限公司保留所有权利。
In cells of the immune system that are stimulated by antigen or antigen-antibody complexes, Ca2+ entry from the extracellular medium is driven by depletion of endoplasmic reticulum Ca2+ stores and occurs through specialized store-operated Ca2+ channels known as Ca2+- release-activated Ca2+ (CRAC) channels. The process of store-operated Ca2+ influx is essential for short-term as well as long-term responses by immune-system cells. Short-term responses include mast cell degranulation and killing of target cells by effector cytolytic T cells, whereas long-term responses typically involve changes in gene transcription and include T and B cell proliferation and differentiation. Transcription downstream of Ca2+ influx is in large part funneled through the transcription factor nuclear factor of activated T cells (NFAT), a heavily phosphorylated protein that is cytoplasmic in resting cells, but that enters the nucleus when dephosphorylated by the calmodulin-dependent serine/threonine phosphatase calcineurin. The importance of the Ca2+/calcineurin/NFAT signalling pathway for lymphocyte activation is underscored by the finding that the underlying defect in a family with a hereditary severe combined immune deficiency (SCID) syndrome is a defect in CRAC channel function, store-operated Ca2+ entry, NFAT activation and transcription of cytokines, chemokines and many other NFAT target genes whose transcription is essential for productive immune defence. We recently used a two-pronged genetic approach to identify Orai I as the pore subunit of the CRAC channel. On the one hand, we initiated a positional cloning approach in which we utilised genome-wide single nucleotide polymorphism (SNP) mapping to identify the genomic region linked to the mutant gene in the SCID family described above. In parallel, we used a genome-wide RNAi screen in Drosophila to identify critical regulators of NFAT nuclear translocation and store-operated Ca2+ entry. These approaches, together with subsequent mutational and electrophysiological analyses, converged to identify human Orai I as a pore subunit of the CRAC channel and as the gene product mutated in the SCID patients. (C) 2007 Elsevier Ltd. All rights reserved.