The NAE1-mediated neddylation operates as an essential post-translational modification checkpoint for effector CD8+ T cells

• 成果类型: Article
• 署名作者: Jin, Jiacheng; Zhang, Ruohan; Li, Jianying; Gao, Fengxia; Liao, Zhiwei; Yu, Yanbao; Wang, Yi; Bucci, Donna; Xiao, Min; Ma, Ruilin; Ma, Qin; Gao, Shuaixin; Lio, Jerry; Novais, Fernanda; Huang, Stanley Ching- Cheng; Zhu, Jiangjiang; Ghoneim, Hazem; Wen, Haitao; Li, Zihai; Sun, Nuo; Xin, Gang
• 署名单位: University System of Ohio; Ohio State University; James Cancer Hospital & Solove Research Institute; James Cancer Hospital & Solove Research Institute; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; University of Delaware; New York University; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9669
• DOI: 10.1073/pnas.2424061122
• 发表日期: 2025-03-11
• 关键词: mitochondrial outer-membrane; metabolism; expression; proteins; proteome

摘要

Optimal activation of CD8+ T cells is crucial for immunity-mediated destruction of cancer, requiring a substantial amount of proteins involved in metabolism, proliferation, and effector function. Despite extensive studies emphasizing the role of transcriptional regulation in this process, paired transcriptomic and proteomic analyses reveal that the RNA profile is poorly correlated with protein levels. This discrepancy underscores the importance of post-translational modifications (PTMs) in controlling protein abundance during activation. However, the impact of PTMs on the CD8+ T cell protein dynamic remains underexplored. We identify that neddylation, a recently discovered PTM, is activated in response to T cell receptor (TCR) stimulation and enriched in effector CD8+ T cells from colon cancer patients. Mechanistically, we found the rate-limiting enzyme of neddylation, neural precursor cell expressed developmentally down-regulated protein 8 activating enzyme E1 (NAE1), is induced by the NFATc1, a critical transcription factor downstream of TCR signaling. Our observation revealed that genetic ablation of NAE1 significantly disturbed the proteomic landscape related to activation and mitochondrial function. As a result, CD8+ T cells lacking NAE1 exhibited severely compromised activation, proliferation, and survival, which was accompanied by impaired mitochondrial function. Consistently, deletion of NAE1 in CD8+ T cells abolished their antitumor function and promoted tumor progression. By contrast, the overexpression of NAE1 significantly improved the function of tumor-infiltrating CD8+ T cells. Overall, we uncovered neddylation, a previously underappreciated PTM, as a proteomic checkpoint for CD8+ T cell activation. Enforced expression of NAE1 offers promising therapeutic potential for boosting the antitumor CD8+ T cell responses.