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* Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo,
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka,
Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Osaka,
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo,
¶ National Institute of Advanced Industrial Science and Technology, Gene Function Research Center, Tsukuba Science City,
|| Department of Biochemistry, Graduate School of Medicine, Nagoya City University, Nagoya, Aichi, and
# Department of Tumor Cell Biology, The Tokyo Metropolitan Institute for Medical Science, Tokyo, Japan
IFN regulatory factor 3 (IRF-3) is a critical transcription factor that regulates an establishment of innate immune status following detection of viral pathogens. Recent studies have revealed that two I
B kinase (IKK)-like kinases, NF-B-activating kinase/Traf family member-associated NF-B activator-binding kinase 1 and IKK-i/IKK
, are responsible for activation of IRF-3, but the regulatory mechanism of the IRF-3 signaling pathway has not been fully understood. In this study, we report that IRF-3 activation is suppressed by A20, which was initially identified as an inhibitor of apoptosis and inducibly expressed by dsRNA. A20 physically interacts with NF-B-activating kinase/Traf family member-associated NF-B activator-binding kinase 1 and IKK-i/IKK, and inhibits dimerization of IRF-3 following engagement of TLR3 by dsRNA or Newcastle disease virus infection, leading to suppression of the IFN stimulation response element- and IFN-
promoter-dependent transcription. Importantly, knocking down of A20 expression by RNA interference results in enhanced IRF-3-dependent transcription triggered by the stimulation of TLR3 or virus infection. Our study thus demonstrates that A20 is a candidate negative regulator of the signaling cascade to IRF-3 activation in the innate antiviral response.
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