The NAE1-mediated neddylation operates as an essential post-translational modification checkpoint for effector CD8 <sup>+</sup> T cells
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (21)
Jiacheng Jin
Pelotonia Institute for Immuno-oncology, Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, College of Medicine, The Ohio State University
Ruohan Zhang
Department of Physiology and Cell Biology, College of Medicine, The Ohio State University Wexner Medical Center
Jianying Li
Pelotonia Institute for Immuno-oncology, Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, College of Medicine, The Ohio State University
Fengxia Gao
Pelotonia Institute for Immuno-oncology, Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, College of Medicine, The Ohio State University
Zhiwei Liao
Pelotonia Institute for Immuno-oncology, Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, College of Medicine, The Ohio State University
Yanbao Yu
Yi Wang
Donna Bucci
Pelotonia Institute for Immuno-oncology, Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, College of Medicine, The Ohio State University
Min Xiao
School of Chemistry and Chemical Engineering
Ruilin Ma
Department of Chemistry, New York University
Qin Ma
School of Chemistry and Molecular Engineering, State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing 211816, China
Shuaixin Gao
Human Nutrition Program and James Comprehensive Cancer Center, Ohio State University
Jerry Lio
Department of Microbial Infection and Immunity, The Ohio State University College of Medicine
Fernanda Novais
Department of Microbial Infection and Immunity, The Ohio State University College of Medicine
Stanley Ching-Cheng Huang
Jiangjiang Zhu
Department of Human Sciences, College of Education and Human Ecology, The Ohio State University
Hazem Ghoneim
Pelotonia Institute for Immuno-oncology, Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, College of Medicine, The Ohio State University
Haitao Wen
Zihai Li
Nuo Sun
Gang Xin