Journal Article

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

Schoggins, John W., Litvak, Vladimir, Aitchison, John D., García-Sastre, Adolfo, Yokoyama, Wayne M., MacDuff, Donna A., Ratushny, Alexander V., Shrestha, Bimmi, Imanaka, Naoko, Diamond, Michael S., Snijder, Eric J., Manicassamy, Balaji, Elliott, Richard M., Racaniello, Vincent, Virgin, Herbert W., Eitson, Jennifer L., Gainey, Maria D., Rice, Charles M., Dabelic, Rea, Richardson, R. Blake, Aderem, Alan, Mar, Katrina B.

2014

Overview

The specificity of interferon effectors across an expanded range of viruses is studied, with results indicating that positive-sense single-stranded RNA viruses are more susceptible to interferon-stimulated gene activity than negative-sense RNA or DNA viruses; in addition, the DNA sensor cGAS is shown to have an unappreciated role in RNA virus inhibition. cGAS crucial to innate immunity This study reports the use of cell culture models to scan an extensive interferon-stimulated gene (ISG) library for activity against a broad spectrum of viruses. The scan reveals that positive-sense single-stranded (ss)RNA viruses are more susceptible to ISG activities than negative-sense ssRNA viruses or a DNA virus. The DNA sensor cyclic GMP-AMP synthase (cGAS) is shown to inhibit several RNA viruses. The authors also generated cGAS knockout mice and showed an in vivo requirement for cGAS in antiviral responses. 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 1 , 2 , 3 . Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/31 / 38 / 38/39 / 38/47 / 38/61 / 42/35 / 631/326/596/2553 / 64/60 / Adenylic acid / Animals / Biological response modifiers / Cluster Analysis / Cyclic guanylic acid / Deoxyribonucleic acid / DNA / DNA Viruses - immunology / DNA Viruses - pathogenicity / Flow Cytometry / Gene expression / Gene Library / Genetic aspects / Genetic research / Humanities and Social Sciences / Immune response / Immunity / Immunity, Innate - genetics / Immunity, Innate - immunology / Immunosuppression / Infections / Interferon / Interferon Regulatory Factor-3 - immunology / Interferon Regulatory Factor-3 - metabolism / Interferons - immunology / Interferons - metabolism / letter / Membrane Proteins - metabolism / Mice / Mice, Knockout / multidisciplinary / Nucleotidyltransferases - deficiency / Nucleotidyltransferases - genetics / Nucleotidyltransferases - immunology / Nucleotidyltransferases - metabolism / Physiological aspects / Proteins / Regulation / RNA Viruses - immunology / RNA Viruses - pathogenicity / Rodents / Science / STAT1 Transcription Factor - metabolism / Studies / Substrate Specificity / Transferases / Viruses / Viruses - classification / Viruses - immunology / Viruses - pathogenicity