@article{15552d43045c451cac2d2c330a46d6bd,
title = "Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity",
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.",
author = "Schoggins, {John W.} and MacDuff, {Donna A.} and Naoko Imanaka and Gainey, {Maria D.} and Bimmi Shrestha and Eitson, {Jennifer L.} and Mar, {Katrina B.} and Richardson, {R. Blake} and Ratushny, {Alexander V.} and Vladimir Litvak and Rea Dabelic and Balaji Manicassamy and Aitchison, {John D.} and Alan Aderem and Elliott, {Richard M.} and Adolfo Garc{\'i}a-Sastre and Vincent Racaniello and Snijder, {Eric J.} and Yokoyama, {Wayne M.} and Diamond, {Michael S.} and Virgin, {Herbert W.} and Rice, {Charles M.}",
note = "Funding Information: Acknowledgements We thank the following investigators for contributing viral molecular clones or viral stocks: R. Cattaneo (MV), P. Collins (PIV3, HMPV, RSV), I Frolov (VEEV), M. Heise (SINV), S. Higgs (ONNV), P. Traktman (VV), J. L. Whitton (CVB). We thank E. Jouanguy and J.-L. Casanova for STAT12/2 fibroblasts. We acknowledge the support of C. Zhao, X. Wang and W. Zhang at The Rockefeller University Genomics Resource Center. We thank E. Castillo, B. Flatley, A. Webson, E. Duan and A. McLees for laboratory support,andD. Kraemalmeyer for managing mouse colonies. This work was supported in part byNationalInstitutes of Health grants AI091707 to C.M.R., AI057158 to I. Lipkin (Northeast Biodefense Center, subcontract to C.M.R.), DK095031 to J.W.S., AI057160 to H.W.V., HHSN272200900041CU19 to M.S.D. and H.W.V., AI104972 to M.S.D., AI083025, AI095611 and CEIRS contract HHSN266200700010C to A.G-S., GM076547 and GM103511 to J.D.A. and AI057160 to W.M.Y., an investigator of the Howard Hughes Medical Institute. M.D.G. is supported by T32 AR007279. Additional funding was provided by the Greenberg Medical Research Institute, the Starr Foundation and the Ronald A. Shellow, M.D. Memorial Fund (C.M.R.).",
year = "2014",
doi = "10.1038/nature12862",
language = "English (US)",
volume = "505",
pages = "691--695",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7485",
}