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

John W. Schoggins, Donna A. MacDuff, Naoko Imanaka, Maria D. Gainey, Bimmi Shrestha, Jennifer L. Eitson, Katrina B. Mar, R. Blake Richardson, Alexander V. Ratushny, Vladimir Litvak, Rea Dabelic, Balaji Manicassamy, John D. Aitchison, Alan Aderem, Richard M. Elliott, Adolfo García-Sastre, Vincent Racaniello, Eric J. Snijder, Wayne M. Yokoyama, Michael S. Diamond & 2 others Herbert W. Virgin, Charles M. Rice

Research output: Contribution to journalArticle

356 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)691-695
Number of pages5
JournalNature
Volume505
Issue number7485
DOIs
StatePublished - 2014

Fingerprint

Innate Immunity
Interferons
RNA Viruses
Antiviral Agents
Genes
Viruses
DNA Viruses
GMP synthase (glutamine-hydrolyzing)
Interferon Type I
Virus Diseases
Libraries
Cluster Analysis
Gene Expression
DNA

ASJC Scopus subject areas

  • General

Cite this

Schoggins, J. W., MacDuff, D. A., Imanaka, N., Gainey, M. D., Shrestha, B., Eitson, J. L., ... Rice, C. M. (2014). Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature, 505(7485), 691-695. https://doi.org/10.1038/nature12862

Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. / Schoggins, John W.; MacDuff, Donna A.; Imanaka, Naoko; Gainey, Maria D.; Shrestha, Bimmi; Eitson, Jennifer L.; Mar, Katrina B.; Richardson, R. Blake; Ratushny, Alexander V.; Litvak, Vladimir; Dabelic, Rea; Manicassamy, Balaji; Aitchison, John D.; Aderem, Alan; Elliott, Richard M.; García-Sastre, Adolfo; Racaniello, Vincent; Snijder, Eric J.; Yokoyama, Wayne M.; Diamond, Michael S.; Virgin, Herbert W.; Rice, Charles M.

In: Nature, Vol. 505, No. 7485, 2014, p. 691-695.

Research output: Contribution to journalArticle

Schoggins, JW, MacDuff, DA, Imanaka, N, Gainey, MD, Shrestha, B, Eitson, JL, Mar, KB, Richardson, RB, Ratushny, AV, Litvak, V, Dabelic, R, Manicassamy, B, Aitchison, JD, Aderem, A, Elliott, RM, García-Sastre, A, Racaniello, V, Snijder, EJ, Yokoyama, WM, Diamond, MS, Virgin, HW & Rice, CM 2014, 'Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity', Nature, vol. 505, no. 7485, pp. 691-695. https://doi.org/10.1038/nature12862
Schoggins, John W. ; MacDuff, Donna A. ; Imanaka, Naoko ; Gainey, Maria D. ; Shrestha, Bimmi ; Eitson, Jennifer L. ; Mar, Katrina B. ; Richardson, R. Blake ; Ratushny, Alexander V. ; Litvak, Vladimir ; Dabelic, Rea ; Manicassamy, Balaji ; Aitchison, John D. ; Aderem, Alan ; Elliott, Richard M. ; García-Sastre, Adolfo ; Racaniello, Vincent ; Snijder, Eric J. ; Yokoyama, Wayne M. ; Diamond, Michael S. ; Virgin, Herbert W. ; Rice, Charles M. / Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. In: Nature. 2014 ; Vol. 505, No. 7485. pp. 691-695.
@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.}",
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",

}

TY - JOUR

T1 - Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity

AU - Schoggins, John W.

AU - MacDuff, Donna A.

AU - Imanaka, Naoko

AU - Gainey, Maria D.

AU - Shrestha, Bimmi

AU - Eitson, Jennifer L.

AU - Mar, Katrina B.

AU - Richardson, R. Blake

AU - Ratushny, Alexander V.

AU - Litvak, Vladimir

AU - Dabelic, Rea

AU - Manicassamy, Balaji

AU - Aitchison, John D.

AU - Aderem, Alan

AU - Elliott, Richard M.

AU - García-Sastre, Adolfo

AU - Racaniello, Vincent

AU - Snijder, Eric J.

AU - Yokoyama, Wayne M.

AU - Diamond, Michael S.

AU - Virgin, Herbert W.

AU - Rice, Charles M.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84895904323&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84895904323&partnerID=8YFLogxK

U2 - 10.1038/nature12862

DO - 10.1038/nature12862

M3 - Article

VL - 505

SP - 691

EP - 695

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7485

ER -