Metabolic fitness of T cells is crucial for immune responses against infections and tumorigenesis. Both the T cell receptor (TCR) signal and environmental cues contribute to the induction of T cell metabolic reprogramming, but the underlying mechanism is incompletely understood. Here, we identified the E3 ubiquitin ligase Peli1 as an important regulator of T cell metabolism and antitumor immunity. Peli1 ablation profoundly promotes tumor rejection, associated with increased tumor‐infiltrating CD4 and CD8 T cells. The Peli1‐deficient T cells display markedly stronger metabolic activities, particularly glycolysis, than wild‐type T cells. Peli1 controls the activation of a metabolic kinase, mTORC1, stimulated by both the TCR signal and growth factors, and this function of Peli1 is mediated through regulation of the mTORC1‐inhibitory proteins, TSC1 and TSC2. Peli1 mediates non‐degradative ubiquitination of TSC1, thereby promoting TSC1‐TSC2 dimerization and TSC2 stabilization. These results establish Peli1 as a novel regulator of mTORC1 and downstream mTORC1‐mediated actions on T cell metabolism and antitumor immunity.

中文翻译：

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E3 泛素连接酶 Peli1 调节 mTORC1 的代谢作用以抑制抗肿瘤 T 细胞反应

T 细胞的代谢适应性对于针对感染和肿瘤发生的免疫反应至关重要。T 细胞受体 (TCR) 信号和环境信号都有助于诱导 T 细胞代谢重编程，但其潜在机制尚不完全清楚。在这里，我们将 E3 泛素连接酶 Peli1 鉴定为 T 细胞代谢和抗肿瘤免疫的重要调节剂。Peli1 消融显着促进肿瘤排斥，与肿瘤浸润性 CD4 和 CD8 T 细胞增加有关。与野生型 T 细胞相比，Peli1 缺陷型 T 细胞表现出明显更强的代谢活性，尤其是糖酵解。Peli1 控制由 TCR 信号和生长因子刺激的代谢激酶 mTORC1 的激活，而 Peli1 的这一功能是通过调节 mTORC1 抑制蛋白来介导的，TSC1 和 TSC2。Peli1 介导 TSC1 的非降解泛素化，从而促进 TSC1-TSC2 二聚化和 TSC2 稳定化。这些结果确立了 Peli1 作为 mTORC1 和下游 mTORC1 介导的 T 细胞代谢和抗肿瘤免疫作用的新型调节剂。