Journal article
Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity
Nature (London), Vol.505(7485), pp.691-695
01/30/2014
DOI: 10.1038/nature12862
PMCID: PMC4077721
PMID: 24284630
Abstract
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.
Details
- Title: Subtitle
- Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity
- Creators
- John W Schoggins - 1] Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065, USA Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA (J.W.S.); MRC-University of Glasgow Centre for Virus Research, Glasgow, Scotland G61 1QH, UK (R.M.E.)Donna A MacDuff - Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USANaoko Imanaka - Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065, USAMaria D Gainey - Rheumatology Division, Department of Medicine, and Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, Missouri 63110, USABimmi Shrestha - Infectious Diseases Division, Department of Medicine and Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USAJennifer L Eitson - Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAKatrina B Mar - Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAR Blake Richardson - Southwestern Medical CenterAlexander V Ratushny - 1] Seattle Biomedical Research Institute, Seattle, Washington 98109, USA Institute for Systems Biology, Seattle, Washington 98109, USAVladimir Litvak - Seattle Biomedical Research Institute, Seattle, Washington 98109, USARea Dabelic - Department of Microbiology and Immunology, Columbia University, New York, New York 10032, USABalaji Manicassamy - University of Iowa, Microbiology and ImmunologyJohn D Aitchison - 1] Seattle Biomedical Research Institute, Seattle, Washington 98109, USA Institute for Systems Biology, Seattle, Washington 98109, USAAlan Aderem - Seattle Biomedical Research Institute, Seattle, Washington 98109, USARichard M Elliott - 1] School of Biology, University of St Andrews, St Andrews, Scotland KY16 9ST, UK Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA (J.W.S.); MRC-University of Glasgow Centre for Virus Research, Glasgow, Scotland G61 1QH, UK (R.M.E.)Adolfo García-Sastre - 1] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USAVincent Racaniello - Department of Microbiology and Immunology, Columbia University, New York, New York 10032, USAEric J Snijder - Leiden University Medical CenterWayne M Yokoyama - Rheumatology Division, Department of Medicine, and Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, Missouri 63110, USAMichael S Diamond - 1] Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA Infectious Diseases Division, Department of Medicine and Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USAHerbert W Virgin - Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USACharles M Rice - Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065, USA
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.505(7485), pp.691-695
- DOI
- 10.1038/nature12862
- PMID
- 24284630
- PMCID
- PMC4077721
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Grant note
- K01 DK095031 / NIDDK NIH HHS HHSN266200700010C / PHS HHS Howard Hughes Medical Institute GM103511 / NIGMS NIH HHS U54 GM103511 / NIGMS NIH HHS U01 AI095611 / NIAID NIH HHS HHSN272200900041CU19 / CSP VA AI083025 / NIAID NIH HHS AI104972 / NIAID NIH HHS U54 AI057160 / NIAID NIH HHS T32 AR007279 / NIAMS NIH HHS R01 AI104972 / NIAID NIH HHS G0801822 / Medical Research Council GM076547 / NIGMS NIH HHS P50 GM076547 / NIGMS NIH HHS R01 AI025032 / NIAID NIH HHS HHSN266200700010C / NIAID NIH HHS R01 AI032972 / NIAID NIH HHS HHSN272200900041C / NIAID NIH HHS R01 AI091707 / NIAID NIH HHS DK095031 / NIDDK NIH HHS T32 AI005284 / NIAID NIH HHS U54 AI057158 / NIAID NIH HHS AI091707 / NIAID NIH HHS AI057160 / NIAID NIH HHS AI095611 / NIAID NIH HHS U19 AI083025 / NIAID NIH HHS R00 AI095320 / NIAID NIH HHS 099220 / Wellcome Trust AI057158 / NIAID NIH HHS R01 AI102597 / NIAID NIH HHS
- Language
- English
- Date published
- 01/30/2014
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984083289402771
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