ArticlePLoS pathogens2021
RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.
Article in PLoS pathogens, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 53 citations in OpenAlex.
- The cGAS-STING/MITA pathway in innate antiviral immunity and beyond.Cell insight · 2026Review
- Cancer-Intrinsic Protein Neddylation Modulates the Intratumoral Immune Landscape to Constrain Immune Checkpoint Blockade Therapy.Cancer immunology research · 2026Article
- UBE2M deficiency in alveolar macrophages promotes emphysema through HIF-2α/MMP12 axis.Chinese medical journal pulmonary and critical care medicine · 2026Article
- Viral subversion of neddylation: dual roles in replication efficiency and evasion of antiviral immunity.Archives of virology · 2026Review
- Opportunities and challenges of targeting cGAS-STING in cancer.Nature reviews. Cancer · 2026Review
- HSV-2 genome recognition by nuclear cGAS instigates IFN-β production and influences inflammasome activation duringFrontiers in immunology · 2026Article
- Neddylation related gene signature for prognostic biomarkers in colorectal cancer with integrated bioinformatics and experimental analysis.Discover oncology · 2025Article
- PRMT1-mediated methylation of UBE2m promoting calcium oxalate crystal-induced kidney injury by inhibiting fatty acid metabolism.Cell death & disease · 2025Article
- cGAS, an innate dsDNA sensor with multifaceted functions.Cell insight · 2025Review
- Inhibition of the neddylation E2 enzyme UBE2M in macrophages protects against E. coli-induced sepsis.The Journal of biological chemistry · 2025Article
- E3 Ligase Rbx1 Orchestrates Thymus Development and Fate Determination of αβ-γδ T Cells.Research (Washington, D.C.) · 2025Article
- The RNA-binding proteins regulate innate antiviral immune signaling by modulating pattern recognition receptors.Virology journal · 2024Review
- Unconventional posttranslational modification in innate immunity.Cellular and molecular life sciences : CMLS · 2024Review
- Protein neddylation and its role in health and diseases.Signal transduction and targeted therapy · 2024Review
- Review
- The UAS thioredoxin-like domain of UBXN7 regulates E3 ubiquitin ligase activity of RNF111/Arkadia.BMC biology · 2023Article
- SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis.The Journal of clinical investigation · 2023Article
- Waking immune-resistant tumors with neddylation.The Journal of clinical investigation · 2023Article
- UXT attenuates the CGAS-STING1 signaling by targeting STING1 for autophagic degradation.Autophagy · 2023Article
- Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases.Zoological research · 2023Review
Corrections and comments
- Erratum issued
Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. By performing mass spectrometry, we identified Lys231 and Lys421 as essential neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense.
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