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J. Biol. Chem., Vol. 282, Issue 10, 7576-7581, March 9, 2007

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Viral Infections Activate Types I and III Interferon Genes through a Common Mechanism^*

Kazuhide Onoguchi^¶, Mitsutoshi Yoneyama, Azumi Takemura, Shizuo Akira^||, Tadatsugu Taniguchi^**, Hideo Namiki^¶, and Takashi Fujita¹

From the Laboratory of Molecular Genetics, Institute for Virus Research and Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan, ^¶Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan, ^||Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan, and ^**Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan

Viral infections trigger innate immune responses, including the production of type I interferons (IFN- and -) and other proinflammatory cytokines. Novel antiviral cytokines IFN-1, IFN-2, and IFN-3 are classified as type III IFNs and have evolved independently of type I IFNs. Type III IFN genes are regulated at the level of transcription and induced by viral infection. Although the regulatory mechanism of type I IFNs is well elucidated, the expression mechanism of IFN-s is not well understood. Here, we analyzed the mechanism by which IFN- gene expression is induced by viral infections. Loss- and gain-of-function experiments revealed the involvement of RIG-I (retinoic acid-inducible gene I), IPS-1, TBK1, and interferon regulatory factor-3, key regulators of the virus-induced activation of type I IFN genes. Consistent with this, a search for the cis-regulatory element of the human ifn1 revealed a cluster of interferon regulatory factor-binding sites and a NF-B-binding site. Functional analysis demonstrated that all of these sites are essential for gene activation by the virus. These results strongly suggest that types I and III IFN genes are regulated by a common mechanism.

Received for publication, September 6, 2006 , and in revised form, January 2, 2007.

^* This work is supported by the Japan Society for the Promotion of Science, Ministry of Education, Culture, Sports, Science, and Technology of Japan, Uehara Memorial Foundation, and Nippon Boehringer Ingelheim. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan. Tel.: 81-75-751-4031; Fax: 81-75-751-4031; E-mail: tfujita{at}virus.kyoto-u.ac.jp.

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