The E3 ubiquitin ligase Peli1 regulates the metabolic actions of mTORC1 to suppress antitumor T cell responses

• Published in: The EMBO journal Vol. 40; no. 2; pp. e104532 - n/a
• Main Authors: Ko, Chun‐Jung, Zhang, Lingyun, Jie, Zuliang, Zhu, Lele, Zhou, Xiaofei, Xie, Xiaoping, Gao, Tianxiao, Yang, Jin‐Young, Cheng, Xuhong, Sun, Shao‐Cong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.01.2021; Springer Nature B.V; John Wiley and Sons Inc
• Subjects: Ablation; Animals; Antitumor activity; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Cell Line; Cell Line, Tumor; Dimerization; Effector cells; EMBO19; EMBO21; EMBO31; Glycolysis; Glycolysis - physiology; Growth factors; HEK293 Cells; Humans; Immunity; Kinases; Lymphocytes; Lymphocytes T; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolic rate; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; mTORC1; Nuclear Proteins - metabolism; Peli1; Proteins; Receptors, Antigen, T-Cell - metabolism; Signal transduction; T cell metabolism; antitumor immunity; T cell receptors; Tuberous Sclerosis Complex 1; Tuberous Sclerosis Complex 1 Protein - metabolism; Tuberous Sclerosis Complex 2; Tuberous Sclerosis Complex 2 Protein - metabolism; Tumorigenesis; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Peli1; T cell metabolism; antitumor immunity; ubiquitination; mTORC1
• DOI: 10.15252/embj.2020104532
• ISSN: 0261-4189; 1460-2075

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. Synopsis The mTORC1 signaling pathway mediates metabolic reprograming and effector function of activated T cells, which is important for antitumor immunity. TSC1 ubiquitination by E3 ubiquitin ligase Peli1 negatively regulates mTORC1 activation and controls glycolytic metabolism and antitumor effector function of T cells. Peli1 negatively regulates activation of the metabolic kinase mTORC1. Peli1 mediates K63 ubiquitination of mTORC1‐inhibitory protein TSC1 and promotes TSC1/TSC2 complex stability. Peli1 deletion promotes the metabolic activities of T cells. Peli1 deficiency in mice promotes antitumor immunity. Graphical Abstract K63‐linked ubiquitination of TSC1 by the Peli E3 inhibits mTORC1 signaling and metabolic reprogramming of T cells.