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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells
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Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells

机译：内皮一氧化氮合酶调节抗原刺激的T细胞的高尔基复合体上的N-Ras活化

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摘要

Ras/ERK signaling plays an important role in T cell activation and development. We recently reported that endothelial nitric oxide synthase (eNOS)-derived NO regulates T cell receptor (TCR)-dependent ERK activation by a cGMP-independent mechanism. Here, we explore the mechanisms through which eNOS exerts this regulation. We have found that eNOS-derived NO positively regulates Ras/ERK activation in T cells stimulated with antigen on antigen-presenting cells (APCs). Intracellular activation of N-, H-, and K-Ras was monitored with fluorescent probes in T cells stably transfected with eNOS-GFP or its G2A point mutant, which is defective in activity and cellular localization. Using this system, we demonstrate that eNOS selectively activates N-Ras but not K-Ras on the Golgi complex of T cells engaged with APC, even though Ras isoforms are activated in response to NO from donors. We further show that activation of N-Ras involves eNOS-dependent S-nitrosylation on Cys~(118), suggesting that upon TCR engagement, eNOS-derived NO directly activates N-Ras on the Golgi. Moreover, wild-type but not C118S N-Ras increased TCR-dependent apoptosis, suggesting that S-nitrosylation of Cys~(118) contributes to activation-induced T cell death. Our data define a signaling mechanism for the regulation of the Ras/ERK pathway based on the eNOS-dependent differential activation of N-Ras and K-Ras at specific cell compartments.
机译：Ras / ERK信号传导在T细胞活化和发育中起重要作用。我们最近报道，内皮一氧化氮合酶（eNOS）衍生的NO通过cGMP独立机制调节T细胞受体（TCR）依赖的ERK激活。在这里，我们探讨了eNOS施加此调控的机制。我们已经发现，eNOS衍生的NO在抗原呈递细胞（APC）上被抗原刺激的T细胞中正调控Ras / ERK活化。用荧光探针监测被eNOS-GFP或其G2A点突变体稳定转染的T细胞中N-，H-和K-Ras的细胞内激活，这在活性和细胞定位方面均存在缺陷。使用该系统，我们证明eNOS选择性激活与APC结合的T细胞的高尔基复合体上的N-Ras，而不激活K-Ras，即使Ras亚型是响应供体的NO而被激活的。我们进一步表明，N-Ras的激活涉及Cys〜（118）上依赖eNOS的S-亚硝基化，这表明在TCR参与后，eNOS衍生的NO直接激活了高尔基体上的N-Ras。此外，野生型而非C118S N-Ras会增加TCR依赖性细胞凋亡，提示Cys〜（118）的S-亚硝基化有助于激活诱导的T细胞死亡。我们的数据基于特定细胞区室中N-Ras和K-Ras的依赖eNOS的差异激活作用，定义了Ras / ERK途径调控的信号传导机制。

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