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The E3 ubiquitin ligase Peli1 regulates the metabolic actions of mTORC1 to suppress antitumor T cell responses
Author(s) -
Ko ChunJung,
Zhang Lingyun,
Jie Zuliang,
Zhu Lele,
Zhou Xiaofei,
Xie Xiaoping,
Gao Tianxiao,
Yang JinYoung,
Cheng Xuhong,
Sun ShaoCong
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020104532
Subject(s) - ubiquitin ligase , biology , ubiquitin protein ligases , ubiquitin , dna ligase , mtorc1 , microbiology and biotechnology , dna ligases , cancer research , signal transduction , genetics , gene , pi3k/akt/mtor pathway
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.

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