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The NAE1-mediated neddylation operates as an essential posttranslational modification checkpoint for effector CD8+ 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 posttranslational 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE289216 | GEO | 2025/02/11

REPOSITORIES: GEO

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Project description:The heart undergoes significant structural, metabolic, gene expression and functional alterations during the perinatal to postnatal transition. While recent studies have identified multiple epigenetic and transcriptional regulators of cardiac maturation, post-transcriptional mechanisms regulating this process remain poorly understood. Neddylation is a post-translational modification that conjugates a small ubiquitin-like protein, NEDD8, to protein substrates via an E1-E2-E3 enzymatic cascade. The goal of this study was to define the role of neddylation in perinatal cardiac development and cardiac maturation. Neddylation was inhibited in adult mouse hearts by cardiac-specific deletion of NAE1 gene, a regulatory subunit of NEDD8 E1 enzyme, or in neonatal cardiomyocytes (CMs) with a pharmacological neddylation inhibitor, MLN4924. The impact on cardiac transcriptome, metabolism, maturation and function was assessed. Mosaic deletion of NAE1 in ~40% neonatal CMs disrupted aspects of maturation, including transverse-tubule formation, cellular hypertrophy and fetal/adult isoform switching, whereas deletion of NAE1 in over 80% CMs led to rapid development of cardiomyopathy and heart failure. Transcriptome analysis demonstrated an association of metabolic derangement with immature cardiomyocyte signature. Biochemical, ultrastructural and metabolomics analyses confirmed downregulation of fatty acid and oxidative phosphorylation genes, deficits in fatty acid utilization, mitochondrial dysfunction, and significantly altered metabolic profiles in NAE1-deficient hearts or MLN4924-treated neonatal CMs. Mechanistically, we found that HIF1α, a transcription factor known to promote glycolysis and suppress oxidative metabolism, is a putative NEDD8 target. Inhibition of neddylation resulted in HIF1α accumulation and activation, which contributed to diminished fatty acid utilization. Taken together, we conclude that neddylation plays a crucial role in CM maturation and postnatal cardiac development through sustaining the glycolytic to oxidative metabolic switch in perinatal hearts.

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

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