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Nature. 2014 Jan 30;505(7485):691-5. doi: 10.1038/nature12862. Epub 2013 Nov 27.

Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity.

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  • 11] Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065, USA [2] 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.).
  • 2Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
  • 3Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065, USA.
  • 4Rheumatology Division, Department of Medicine, and Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, Missouri 63110, USA.
  • 5Infectious Diseases Division, Department of Medicine and Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
  • 6Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 71] Seattle Biomedical Research Institute, Seattle, Washington 98109, USA [2] Institute for Systems Biology, Seattle, Washington 98109, USA.
  • 8Seattle Biomedical Research Institute, Seattle, Washington 98109, USA.
  • 9Department of Microbiology and Immunology, Columbia University, New York, New York 10032, USA.
  • 10Department of Microbiology, University of Chicago, Chicago, Illinois 60637, USA.
  • 111] School of Biology, University of St Andrews, St Andrews, Scotland KY16 9ST, UK [2] 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.).
  • 121] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
  • 13Department of Medical Microbiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
  • 141] Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA [2] Infectious Diseases Division, Department of Medicine and Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.

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.

PMID:
24284630
[PubMed - indexed for MEDLINE]
PMCID:
PMC4077721
Free PMC Article

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