Findings demonstrate impaired activation and survival in CD8+ T cells lacking NAE1, suggesting neddylation's role in immunity.
Description Optimal activation of CD8+ T cells is crucial for immunity-mediated destruction of cancer, requiring a substantial amount of proteins. Despite extensive studies emphasizing the role of transcriptional regulation in this process, 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. We identify that neddylation, a recently discovered PTM, is activated upon TCR stimulation. Mechanistically, we found the rate-limiting enzyme of neddylation, NAE1, is induced by the NFATc1, a critical transcription factor downstream of TCR signaling. Our observation revealed that ablation of NAE1 significantly disturbed the proteomic landscape related to activation and mitochondrial function with minimal impact on the transcriptome. 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 anti-tumor function and promoted tumor progression. By contrast, the overexpression of NAE1 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 anti-tumor CD8+ T cell responses. Funding Sources This work was supported by 1R01CA269984 (GX) from the National Institute of Health, CCR231013713 from Susan G. Komen (G.X.) and RSG-23-1036499-01 (G.X.) from the American Cancer Society. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
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Jin et al. (2025) studied this question.