ArticlemBio2025
Targeting CTP synthetase 1 to restore interferon induction and impede nucleotide synthesis in SARS-CoV-2 infection.
Article in mBio, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- A pan-viral map of host dependency factors from multi-omics integration and machine learning across influenza A, SARS-CoV-2, Zika, and dengue viruses.Journal of translational medicine · 2026Article
- SARS-CoV-2 ORF8: an accessory protein at the interface of immune evasion and inflammation.Frontiers in immunology · 2026Review
- CTPS2 regulates CTP synthetase activity by interacting with CTPS1.Life science alliance · 2025Article
- Viral pseudo-enzyme facilitates KSHV lytic replication via suppressing PFAS-mediated RTA deamidation.Virologica Sinica · 2025Article
- An automated network-based tool to search for metabolic vulnerabilities in cancer.Nature communications · 2024Article
- SARS-CoV-2 ORF8 as a Modulator of Cytokine Induction: Evidence and Search for Molecular Mechanisms.Viruses · 2024Review
- Multi-omics analysis reveals the impact of influenza a virus host adaptation on immune signatures in pig tracheal tissue.Frontiers in immunology · 2024Article
- The emerging roles of glutamine amidotransferases in metabolism and immune defense.Nucleosides, nucleotides & nucleic acids · 2024Review
- Review
- Review
- CTP synthase: the hissing of the cellular serpent.Histochemistry and cell biology · 2022Review
- SARS-CoV-2 couples evasion of inflammatory response to activated nucleotide synthesis.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- The Roles of APOBEC-mediated RNA Editing in SARS-CoV-2 Mutations, Replication and Fitness.Research square · 2022Article
- The Roles of APOBEC-mediated RNA Editing in SARS-CoV-2 Mutations, Replication and Fitness.bioRxiv : the preprint server for biology · 2022Article
- Severe Acute Respiratory Syndrome Coronavirus 2 ORF8 Protein Inhibits Type I Interferon Production by Targeting HSP90B1 Signaling.Frontiers in cellular and infection microbiology · 2022Article
- Structural basis for isoform-specific inhibition of human CTPS1.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway.iScience · 2021Article
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10 authors.
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Abstract
Despite the global impact caused by the most recent SARS-CoV-2 pandemic, our knowledge of the molecular underpinnings of its highly infectious nature remains incomplete. We report here that SARS-CoV-2 exploits cellular CTP synthetase 1 (CTPS1) to promote CTP synthesis and suppress interferon (IFN) induction. In addition to catalyzing CTP synthesis, CTPS1 also deamidates interferon regulatory factor 3 (IRF3) to dampen interferon induction. Screening a SARS-CoV-2 expression library, we identified several viral proteins that interact with CTPS1. Functional analyses demonstrate that ORF8 and Nsp8 activate CTPS1 to deamidate IRF3 and negate IFN induction, whereas ORF7b and ORF8 activate CTPS1 to promote CTP synthesis. These results highlight CTPS1 as a signaling node that integrates cellular metabolism and innate immune response. Indeed, small-molecule inhibitors of CTPS1 deplete CTP and boost IFN induction in SARS-CoV-2-infected cells, thus effectively impeding SARS-CoV-2 replication and pathogenesis in mouse models. Our work uncovers an intricate mechanism by which a viral pathogen couples immune evasion to metabolic activation to fuel viral replication. Inhibition of the cellular CTPS1 offers an attractive means to develop antiviral therapy against highly mutagenic viruses.IMPORTANCEOur understanding of the underpinnings of highly infectious SARS-CoV-2 is rudimentary at best. We report here that SARS-CoV-2 activates CTPS1 to promote CTP synthesis and suppress IFN induction, thus coupling immune evasion to activated nucleotide synthesis. Inhibition of the key metabolic enzyme not only depletes the nucleotide pool but also boosts host antiviral defense, thereby impeding SARS-CoV-2 replication. Targeting cellular enzymes presents a strategy to counter the rapidly evolving SARS-CoV-2 variants.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.