Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity
By John W. Schoggins, Donna A. MacDuff, N. Imanaka, Maria D. Gainey, Bimmi Shrestha, Jennifer L. Eitson, K. Mar, R. B. Richardson, A. Ratushny, V. Litvak and 12 more. Nature, 2013
910 citations recorded by the source corpus.
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.
Subfields: Immunology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/12fcbcb4e2b74cc788fe4e0256c93ab9deeeded2
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Citations in the corpus
- Mitochondrial DNA in inflammation and immunity (2020, neutral): “Curiously, infection with RNA viruses, such as dengue virus, also elicits a cGAS-STING response, despite cGAS being a DNA-specific PRR [44].”
- Host cell-intrinsic innate immune recognition of SARS-CoV-2 (2021, neutral): “ISGs can modulate the infection of many viruses, although the mechanism of action for many of these proteins remains undefined [53,60].”
- cGAS in action: Expanding roles in immunity and inflammation (2019, background): “IRF3 then dimerizes and translocates to the nucleus to drive the expression of type I IFNs and ISGs.”
- A Mouse Model of Zika Virus Pathogenesis (2016, neutral): “…Broek et al., 1995), Ifnlr1−/− (Ank et al., 2008), Ifit1−/− (Szretter et al., 2012), Ifit2−/− (Fensterl et al., 2012), Ifitm3−/− (Lange et al., 2008), Isg15−/− (Osiak et al., 2005), Ube1l−/− (Kim et al., 2006), Mb21d−/− (cGas) (Schoggins et al., 2014), and Tmem173−/− (STING) (Sauer et al., 2011).”
- Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases (2015, background): “However, so far, only cGAS has been demonstrated by genetic experiments to function as a nonredundant and essential cytosolic DNA sensor that activates the type-I IFN pathway in vivo (13, 41).”
- Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes (2020, neutral): “, 2010), cGas (Schoggins et al., 2014), Sting (Sauer et al.”
- Interferon-Stimulated Genes: A Complex Web of Host Defenses (2014, background): “Recently, a comprehensive large-scale screen for antiviral ISGs was performed with a library of over 380 ISGs against a diverse panel of viruses (89, 221).”