Targeted cleavage of signaling proteins by caspase 3 inhibits T cell receptor signaling in anergic T cells
Targeted cleavage of signaling proteins by caspase 3 inhibits T cell receptor signaling in anergic T cells
复制标题
DOI：
10.1016/j.immuni.2008.06.010
复制
发表时间：
2008-08-15
期刊：
影响因子：
32.4
通讯作者：
Macian, Fernando
中科院分区：
文献类型：
--
作者：
Puga, Irene;Rao, Anjana;Macian, Fernando
T细胞受体（TCR）在缺乏共刺激的情况下参与诱导基因表达程序的钙依赖性上调，这导致T细胞无反应性的建立。Casp3是在无反应诱导过程中被激活的基因之一。在这里，我们表明，caspase 3是诱导T细胞无反应性所必需的。次优的T细胞刺激诱导半胱天冬酶3激活，这并不导致细胞死亡。此外，半胱天冬酶3缺陷型T细胞对无能量刺激的反应受损。在无反应性T细胞中，活化的半胱天冬酶3与质膜相关，在那里它切割并灭活蛋白质，如Grb 2相关的shc下游衔接子（GADS）和鸟嘌呤核苷酸交换因子Vav 1，导致TCR信号传导阻断。我们的研究结果确定了caspase 3在非凋亡T细胞中的作用，并支持caspase 3依赖的信号蛋白的蛋白水解失活对维持T细胞耐受性至关重要。
T cell receptor (TCR) engagement in the absence of costimulation induces the calcium-dependent upregulation of a program of gene expression that leads to the establishment of T cell anergy. Casp3 is one of the genes activated during anergy induction. Here we show that caspase 3 is required for the induction of T cell unresponsiveness. Suboptimal T cell stimulation induced caspase 3 actvation, which did not result in cell death. Furthermore, caspase 3-deficient T cells showed impaired responses to anergizing stimuli. In anergic T cells, activated caspase 3 associated to the plasma membrane, where it cleaved and inactivated proteins such as the Grb2-related adaptor downstream of shc (GADS) and the guanine-nucleotide exchange factor Vav1, causing a blockade in TCR signaling. Our results identify a role for caspase 3 in nonapoptotic T cells and support that caspase 3-dependent proteolytic inactivation of signaling proteins is essential to maintain T cell tolerance.