The Journal of Experimental Medicine
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Published online 19 June 2006 doi:10.1084/jem.20060792
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 7, 1795-1803
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ARTICLE

 Essential role of IPS-1 in innate immune responses against RNA viruses

Himanshu Kumar1, Taro Kawai2, Hiroki Kato1, Shintaro Sato2, Ken Takahashi1, Cevayir Coban1,3, Masahiro Yamamoto1, Satoshi Uematsu1, Ken J. Ishii2, Osamu Takeuchi1,2, and Shizuo Akira1,2,3

1 Department of Host Defense, 2 Exploratory Research for Advanced Technology, Japan Science and Technology Agency, 3 The 21st Century COE, Combined Program on Microbiology and Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan

CORRESPONDENCE Shizuo Akira: sakira{at}biken.osaka-u.ac.jp

IFN-ß promoter stimulator (IPS)-1 was recently identified as an adapter for retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda5), which recognize distinct RNA viruses. Here we show the critical role of IPS-1 in antiviral responses in vivo. IPS-1–deficient mice showed severe defects in both RIG-I– and Mda5-mediated induction of type I interferon and inflammatory cytokines and were susceptible to RNA virus infection. RNA virus–induced interferon regulatory factor-3 and nuclear factor {kappa}B activation was also impaired in IPS-1–deficient cells. IPS-1, however, was not essential for the responses to either DNA virus or double-stranded B-DNA. Thus, IPS-1 is the sole adapter in both RIG-I and Mda5 signaling that mediates effective responses against a variety of RNA viruses.

Abbreviations used: CARD, Caspase-recruiting domains; ds, double-stranded; EMCV, encephalomyocarditis virus; ERK, extracellular signal-regulated kinase; GM-CSF, granulocyte/macrophage colony-stimulating factor; GM-DC, GM-CSF–generated bone marrow–derived dendritic cell; IRF, interferon regulatory factor; IPS, IFN-ß promoter stimulator; Mda5, melanoma differentiation-associated gene 5; MEF, mouse embryonic fibroblast cell; MOI, multiplicity of infection; MVA, modified vaccinia virus Ankara; NDV, Newcastle disease virus; PEC, peritoneal macrophage; poly I:C, polyinosinic-polycytidylic acid; PRR, pattern recognition receptor; RIG-I, retinoic acid–inducible gene I; SeV, Sendai virus; TLR, Toll-like receptor; VSV, vesicular stomatitis virus; TRIF, TIR domain–containing adaptor inducing IFN-ß.

H. Kumar and T. Kawai contributed equally to this work.


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