Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins
Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins
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DOI：
10.1038/ni1047
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发表时间：
2004-03-01
影响因子：
30.5
通讯作者：
Rao, A
中科院分区：
文献类型：
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作者：
Heissmeyer, V;Macián, F;Rao, A
持续的钙信号传导通过钙调神经磷酸酶和转录因子NFAT介导诱导T细胞中的无反应性或抗原无反应性状态。我们在这里表明，钙离子诱导的无能是一个多步骤的程序，至少部分是通过特定的信号蛋白的蛋白水解降解来实现的。钙调磷酸酶增加E3泛素连接酶Itch、Cbl-b和GRAIL的mRNA和蛋白质，并诱导Tsg 101的表达，Tsg 101是ESCRT-1内体分选复合物的泛素结合组分。随后的刺激或同型细胞粘附促进了Itch和相关蛋白Nedd 4的膜转位，导致两个关键信号蛋白PKC-θ和PLC-γ 1的降解。来自Itch和Cbl-b缺陷小鼠的T细胞对无反应性诱导具有抗性。无反应性T细胞在TCR触发后表现出受损的钙动员，并且不能维持成熟的免疫突触，而是表现出含有淋巴细胞功能相关抗原1的外环的晚期解体。我们的研究结果定义了一个复杂的分子程序，链接基因转录诱导的钙和钙调神经磷酸酶的一个矛盾的损伤的信号转导在无能的T细胞。
Sustained calcium signaling induces a state of anergy or antigen unresponsiveness in T cells, mediated through calcineurin and the transcription factor NFAT. We show here that Ca2+-induced anergy is a multistep program that is implemented at least partly through proteolytic degradation of specific signaling proteins. Calcineurin increased mRNA and protein of the E3 ubiquitin ligases Itch, Cbl-b and GRAIL and induced expression of Tsg101, the ubiquitin-binding component of the ESCRT-1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promoted membrane translocation of Itch and the related protein Nedd4, resulting in degradation of two key signaling proteins, PKC-theta and PLC-gamma1. T cells from Itch- and Cbl-b-deficient mice were resistant to anergy induction. Anergic T cells showed impaired calcium mobilization after TCR triggering and were unable to maintain a mature immunological synapse, instead showing late disorganization of the outer ring containing lymphocyte function-associated antigen 1. Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells.