Diacylglycerol kinases (DGKs) play important roles in restraining diacylglycerol (DAG)‐mediated signaling. Within the DGK family, the ζ isoform appears to be the most important isoform in T cells for controlling their development and function. DGKζ has been demonstrated to regulate T cell maturation, activation, anergy, effector/memory differentiation, defense against microbial infection, and antitumor immunity. Given its critical functions, DGKζ function should be tightly regulated to ensure proper signal transduction; however, mechanisms that control DGKζ function are still poorly understood. We report here that DGKζ dynamically translocates from the cytosol into the nuclei in T cells after TCR stimulation. In mice, DGKζ mutant defective in nuclear localization displayed enhanced ability to inhibit TCR‐induced DAG‐mediated signaling in primary T cells, maturation of conventional αβT and iNKT cells, and activation of peripheral T cells compared with WT DGKζ. Our study reveals for the first time nuclear sequestration of DGKζ as a negative control mechanism to spatially restrain it from terminating DAG mediated signaling in T cells. Our data suggest that manipulation of DGKζ nucleus‐cytosol shuttling as a novel strategy to modulate DGKζ activity and immune responses for treatment of autoimmune diseases and cancer.

中文翻译：

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二酰基甘油激酶 ζ 介导的小鼠核隔离对 T 细胞受体信号传导的抑制作用的负控制。

二酰基甘油激酶 (DGKs) 在抑制二酰基甘油 (DAG) 介导的信号传导中起重要作用。在 DGK 家族中，ζ 异构体似乎是 T 细胞中用于控制其发育和功能的最重要的异构体。DGKζ 已被证明可调节 T 细胞成熟、活化、无反应、效应器/记忆分化、防御微生物感染和抗肿瘤免疫。鉴于其关键功能，应严格调节 DGKζ 功能以确保正确的信号转导；然而，控制 DGKζ 功能的机制仍然知之甚少。我们在此报告 DGKζ 在 TCR 刺激后动态地从胞质溶胶转移到 T 细胞的细胞核中。在老鼠身上，与 WT DGKζ 相比，核定位缺陷的 DGKζ 突变体在抑制 TCR 诱导的原代 T 细胞中 DAG 介导的信号传导、常规 αβT 和 iNKT 细胞的成熟以及外周 T 细胞的活化方面表现出增强的能力。我们的研究首次揭示了 DGKζ 的核隔离作为一种负控制机制，以在空间上抑制它终止 T 细胞中 DAG 介导的信号传导。我们的数据表明，操纵 DGKζ 核-胞质溶胶穿梭是一种调节 DGKζ 活性和免疫反应治疗自身免疫性疾病和癌症的新策略。我们的研究首次揭示了 DGKζ 的核隔离作为一种负控制机制，以在空间上抑制它终止 T 细胞中 DAG 介导的信号传导。我们的数据表明，操纵 DGKζ 核-胞质溶胶穿梭是一种调节 DGKζ 活性和免疫反应治疗自身免疫性疾病和癌症的新策略。我们的研究首次揭示了 DGKζ 的核隔离作为一种负控制机制，以在空间上抑制它终止 T 细胞中 DAG 介导的信号传导。我们的数据表明，操纵 DGKζ 核-胞质溶胶穿梭是一种调节 DGKζ 活性和免疫反应治疗自身免疫性疾病和癌症的新策略。