The NAE1-mediated neddylation operates as an essential posttranslational modification checkpoint for effector CD8+ T cells
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ABSTRACT:
PROVIDER: PRJNA1221917 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32299968_1.fastq.gz | Fastqsanger.gz | |||
| SRR32299968_2.fastq.gz | Fastqsanger.gz | |||
| SRR32299969_1.fastq.gz | Fastqsanger.gz | |||
| SRR32299969_2.fastq.gz | Fastqsanger.gz | |||
| SRR32299970_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
2025-02-11 | GSE289216 | GEO
Project description:Type II testicular germ cell tumors (TGCT) are the most prevalent tumors in young men. Patients suffering from cisplatin resistant TGCTs are facing very poor prognosis demanding novel therapeutic options. Neddylation is a known posttranslational modification mediating many important biological processes including tumorigenesis. Overactivation of neddylation pathway promotes carcinogenesis and tumor progression in various entities by inducing proteasomal degradation of tumor suppressors (e.g., p21, p27). We used a genome-scale CRISPR/Cas9 activation screen to identify cisplatin resistance factors. TGCT cell lines were treated with the neddylation inhibitor (MLN4924)/cisplatin/combination and investigated for changes in viability (XTT assay), apoptosis/cell cycle (flow cytometry) as well as in the transcriptome (3’mRNA sequencing). NAE1 overexpression was detected in cisplatin resistant colonies from the CRISPR screen. Inhibition of neddylation using MLN4924 increased cisplatin cytotoxicity in TGCT cell lines and sensitized cisplatin resistant cells towards cisplatin. Apoptosis, G2/M-phase cell cycle arrest, gH2A.X/P27 accumulation and mesoderm/endoderm differentiation was observed in TGCT cells while fibroblast cells were unaffected. We identified overactivation of neddylation as a factor for cisplatin resistance in TGCTs and highlighted the additive effect of NAE1 inhibition by MLN4924 in combination with cisplatin as a novel treatment option for TGCTs.
2023-03-20 | GSE216043 | GEO
Project description:Type II testicular germ cell tumors (TGCT) are the most prevalent tumors in young men. Patients suffering from cisplatin resistant TGCTs are facing very poor prognosis demanding novel therapeutic options. Neddylation is a known posttranslational modification mediating many important biological processes including tumorigenesis. Overactivation of neddylation pathway promotes carcinogenesis and tumor progression in various entities by inducing proteasomal degradation of tumor suppressors (e.g., p21, p27). We used a genome-scale CRISPR/Cas9 activation screen to identify cisplatin resistance factors. TGCT cell lines were treated with the neddylation inhibitor (MLN4924)/cisplatin/combination and investigated for changes in viability (XTT assay), apoptosis/cell cycle (flow cytometry) as well as in the transcriptome (3’mRNA sequencing). NAE1 overexpression was detected in cisplatin resistant colonies from the CRISPR screen. Inhibition of neddylation using MLN4924 increased cisplatin cytotoxicity in TGCT cell lines and sensitized cisplatin resistant cells towards cisplatin. Apoptosis, G2/M-phase cell cycle arrest, gH2A.X/P27 accumulation and mesoderm/endoderm differentiation was observed in TGCT cells while fibroblast cells were unaffected. We identified overactivation of neddylation as a factor for cisplatin resistance in TGCTs and highlighted the additive effect of NAE1 inhibition by MLN4924 in combination with cisplatin as a novel treatment option for TGCTs.
2023-03-20 | GSE225852 | GEO
Project description: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.
| S-EPMC11912420 | biostudies-literature
Project description:Background: Polycystic liver diseases (PLD) are genetic disorders characterized by progressive growth of numerous liver cysts, causing significant morbidity. Previous studies revealed genes affecting protein biogenesis and more recently, protein SUMOylation, a posttranslational modification (PTM), has been implicated in PLD pathobiology. On the other hand, protein NEDDylation is a newly-characterized PTM, modulating a plethora of biological processes and its dysregulation is associated with development and progression of several human diseases. In this regard, the role of NEDDylation in PLD remains elusive and unraveling its role in the pathogenesis of these genetic disorders could open new avenues for the development of novel treatments in the future. Objective: To explore the role of protein NEDDylation in PLD and its potential therapeutic regulatory value. Methods: Expression and function of NEDDylation, including response to Pevonedistat (first-in-class selective inhibitor of the NEDDylation E1 enzyme NAE1), were assessed in vitro. Proteomic analyses of immunoprecipitated NEDDylated proteins were performed by mass spectrometry.
2022-02-16 | PXD022571 | Pride
Project description:Myelination is essential for neuronal function and health. In peripheral nerves, >100 causative mutations have been identified that cause Charcot-Marie-Tooth disease, a disorder that can affect myelin sheaths. Among these, a number of mutations are related to essential targets of the post-translation modification neddylation, although how these lead to myelin defects is unclear. Here, we demonstrate that inhibiting neddylation leads to a striking absence of peripheral myelin and axonal loss both in developing and regenerating mouse nerves. Importantly, our data indicate that neddylation exerts a global influence on the complex transcriptional and post-transcriptional program by simultaneously regulating the expression and function of multiple essential myelination signals, including the master transcription factor EGR2 and the negative regulators c-Jun and Sox2, and inducing global secondary changes in downstream pathways, including the mTOR and YAP/TAZ signalling pathways. This places neddylation as a critical regulator of myelination and delineates the potential pathogenic mechanisms involved in CMT mutations related to neddylation.
2024-03-06 | GSE241269 | GEO
Project description:BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR-ABL1-targeting TKIs in CML. Unlike their function in reducing drug resistance in many solid tumors, we revealed that neddylation inhibitors counteracted the cytotoxicity of TKIs against CML cells, both in cellular experiments and in animal model. Conversely, neddylation agonist sensitized the function of TKIs. RNA sequencing data revealed that neddylation inhibitor reversed the transcriptomic changes induced by TKI. Co-immunoprecipitation (co-IP) assay identified ABL1 kinase domain as a novel substrate for neddylation. Furthermore, an artificial intelligence (AI) 3-Dimensional spatial structure binding technology was employed to predict the impact of neddylation on the structure of ABL1 kinase domain. Finally, we provided potential evidence showing that TKI therapy decreased the expression of neddylation enzymes in the bone marrow of CML patients. Hence, our study offers new insights into the post-translational modification (PTM)-mediated drug resistance, and highlights the potential clinical benefits of neddylation agonists in improving the responsiveness of BCR-ABL1 TKIs in CML.
2024-09-15 | GSE275701 | GEO
Project description:We used microarrays to detail the global program of gene expression underlying SAG-dependent neddylation and identified distinct classes of disparate genes during this process.
2020-03-31 | GSE83593 | GEO
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.
2022-11-19 | GSE217964 | GEO
Project description:Hypoxia, an inadequate supply of tissue oxygen tension, has been reported to induce apoptosis of spermatogenic cells and is associated with male infertility. Neddylation, a post-translational modification similar to ubiquitination, has been shown to be involved in the hypoxia stress response. However, the functions of neddylation in hypoxia-induced apoptosis of spermatogenic cells and its association with male infertility remain largely unexplored. In this study, aiming to explore the role of neddylation in male infertility, we used the specific neddylation inhibitor MLN4924 for treatment in mouse type B spermatogonia GC-2 cells. Our results showed that MLN4924 had no apparent effect on GC-2 cell apoptosis under normoxia, but significantly increased apoptotic cells under hypoxia. Transcriptomic analysis and qPCR assay confirmed that MLN4924 could suppress the expression of hypoxia target genes in GC-2 cells under hypoxia. In addition, MLN4924 could enhance the induction of intracellular and mitochondrial reactive oxygen species (ROS) under hypoxia. These results indicate that the neddylation inhibitor MLN4924 potentiates hypoxia-induced apoptosis of mouse type B spermatogonia GC-2 cells, and neddylation may play an important role in promoting spermatogenic cells to adapt to hypoxia stress.
2023-11-02 | GSE245989 | GEO