TY - JOUR
T1 - A diverse range of gene products are effectors of the type i interferon antiviral response
AU - Schoggins, John W.
AU - Wilson, Sam J.
AU - Panis, Maryline
AU - Murphy, Mary Y.
AU - Jones, Christopher T.
AU - Bieniasz, Paul
AU - Rice, Charles M.
N1 - Funding Information:
Acknowledgements We thank the following investigators for contributing viral molecular clones: C. Stoyanov (YFV), S. Higgs (CHIKV), I. Frolov (WNV and VEEV), M.MacDonald andJ.Law(SINV(ts6) and SINV-Fluc),M.Heise (SINV andSINV-GFP).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. For technical advice, we thank S. Mazel and C. Bare at The Rockefeller University Flow Cytometry Resource Center, supported by the Empire State Stem Cell Fund through the New York State Department of Health (NYSDOH) contract no. C023046; the opinions expressed here are solely those of the authors and do not necessarily reflect those of the Empire State Stem Cell Fund, the NYSDOH or the State of New York. We thank M. Holz, E. Castillo and A. Webson for laboratory support; C. Murray for critical reading and editing of the manuscript; and A. Ploss, M. Scull, M. T. Catanese and S. You for discussions. This work was supported in part by National Institutes of Health grants AI057158 (Northeast Biodefense Center-Lipkin) to C.M.R. and AI064003 to P.B. 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.). J.W.S. and C.T.J. were supported by National Research Service Awards DK082155 and DK081193, respectively, from the National Institute of Diabetes and Digestive and Kidney Diseases.
PY - 2011/4/28
Y1 - 2011/4/28
N2 - The type I interferon response protects cells against invading viral pathogens. The cellular factors that mediate this defence are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery more than 25 years ago, only a few have been characterized with respect to antiviral activity. For most ISG products, little is known about their antiviral potential, their target specificity and their mechanisms of action. Using an overexpression screening approach, here we show that different viruses are targeted by unique sets of ISGs. We find that each viral species is susceptible to multiple antiviral genes, which together encompass a range of inhibitory activities. To conduct the screen, more than 380 human ISGs were tested for their ability to inhibit the replication of several important human and animal viruses, including hepatitis C virus, yellow fever virus, West Nile virus, chikungunya virus, Venezuelan equine encephalitis virus and human immunodeficiency virus type-1. Broadly acting effectors included IRF1, C6orf150 (also known as MB21D1), HPSE, RIG-I (also known as DDX58), MDA5 (also known as IFIH1) and IFITM3, whereas more targeted antiviral specificity was observed with DDX60, IFI44L, IFI6, IFITM2, MAP3K14, MOV10, NAMPT (also known as PBEF1), OASL, RTP4, TREX1 and UNC84B (also known as SUN2). Combined expression of pairs of ISGs showed additive antiviral effects similar to those of moderate type I interferon doses. Mechanistic studies uncovered a common theme of translational inhibition for numerous effectors. Several ISGs, including ADAR, FAM46C, LY6E and MCOLN2, enhanced the replication of certain viruses, highlighting another layer of complexity in the highly pleiotropic type I interferon system.
AB - The type I interferon response protects cells against invading viral pathogens. The cellular factors that mediate this defence are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery more than 25 years ago, only a few have been characterized with respect to antiviral activity. For most ISG products, little is known about their antiviral potential, their target specificity and their mechanisms of action. Using an overexpression screening approach, here we show that different viruses are targeted by unique sets of ISGs. We find that each viral species is susceptible to multiple antiviral genes, which together encompass a range of inhibitory activities. To conduct the screen, more than 380 human ISGs were tested for their ability to inhibit the replication of several important human and animal viruses, including hepatitis C virus, yellow fever virus, West Nile virus, chikungunya virus, Venezuelan equine encephalitis virus and human immunodeficiency virus type-1. Broadly acting effectors included IRF1, C6orf150 (also known as MB21D1), HPSE, RIG-I (also known as DDX58), MDA5 (also known as IFIH1) and IFITM3, whereas more targeted antiviral specificity was observed with DDX60, IFI44L, IFI6, IFITM2, MAP3K14, MOV10, NAMPT (also known as PBEF1), OASL, RTP4, TREX1 and UNC84B (also known as SUN2). Combined expression of pairs of ISGs showed additive antiviral effects similar to those of moderate type I interferon doses. Mechanistic studies uncovered a common theme of translational inhibition for numerous effectors. Several ISGs, including ADAR, FAM46C, LY6E and MCOLN2, enhanced the replication of certain viruses, highlighting another layer of complexity in the highly pleiotropic type I interferon system.
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U2 - 10.1038/nature09907
DO - 10.1038/nature09907
M3 - Article
C2 - 21478870
AN - SCOPUS:79955542915
VL - 472
SP - 481
EP - 485
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7344
ER -