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Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity
Open accessAbstract
The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors. Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS, also known as MB21D1) as a gene whose expression also broadly inhibits several RNA viruses. In vitro, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.
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“For example, RNA viruses can activate the cGAS-STING pathway despite the specificity of cGAS for cytoplasmic DNA over RNA (Gao et al., 2013b; Schoggins et al., 2014).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Schoggins et al., 2014
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Metadata
- Authors
- Schoggins, J. W., MacDuff, D. A., Imanaka, N., Gainey, M. D., Shrestha, B., Eitson, J. L., Mar, K. B., Richardson, R. B., Ratushny, A. V., Litvak, V., Dabelic, R., Manicassamy, B., Aitchison, J. D., Aderem, A., Elliott, R. M., García-Sastre, A., Racaniello, V., Snijder, E. J., Yokoyama, W. M., Diamond, M. S., Virgin, H. W., & Rice, C. M.
- Affiliations
- MRC University of Glasgow Centre for Virus Research (GB)
- Washington University in St. Louis (US)
- Rockefeller University (US)
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Center for Infectious Disease Research (US)
- Columbia University (US)
- University of Chicago (US)
- University of St Andrews (GB)
- Leiden University Medical Center (NL)
- Corresponding author
- Schoggins, John W.
- Rice, Charles M.
- ORCID
- Venue
- Nature
- Published
- 2013-11-27
- Volume
- 505
- Issue
- 7485
- Pages
- 691-695
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4077721
- OpenAlex
- W2058277625
- Cited by
- 896
- References
- 39
- Citations by year
- 2026: 41 · 2025: 49 · 2024: 51 · 2023: 80 · 2022: 76 · 2021: 79 · 2020: 92 · 2019: 74 · 2018: 82 · 2017: 58 · 2016: 74 · 2015: 87 · 2014: 52
- FWCI
- 39.24
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-07-08)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Veterans Affairs (HHSN272200900041CU19)
- Wellcome Trust (099220)
- National Institutes of Health (5t32ai005284-45)
- National Institute of General Medical Sciences (U54GM103511, GM103511, GM 076547, P50GM076547)
- National Institute of Allergy and Infectious Diseases (T32-AI005284, AI 057160, AI091707, U01AI095611, HHSN266200700010C, AI057158, R01AI091707, AI104972, U19AI083025, R01AI032972, AI095611, U54AI057160, R01AI025032, R00AI095320, AI083025, U54AI057158, R01AI102597, R01AI104972, HHSN272200900041C)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK095031, DK095031)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR007279)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Keywords
- cGAS, interferon-stimulated genes, antiviral innate immunity, positive-sense single-stranded RNA viruses, negative-sense RNA viruses, DNA viruses, STING, IRF3, type I interferon
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, DNA Viruses, Flow Cytometry, Immunity, Innate, Interferons, Membrane Proteins, Nucleotidyltransferases, RNA Viruses, Substrate Specificity, Viruses, Gene Library, Cluster Analysis, Mice, Knockout, STAT1 Transcription Factor, Interferon Regulatory Factor-3, Mice
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