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* Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan;
Department of Molecular Immunology, Nara Institute for Science and Technology, Ikoma, Nara, Japan;
Department of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan; and
Department of Immunology, Osaka Medical Center for Cancer, Higashinari-ku, Osaka, Japan
TLR3 and the cytoplasmic helicase family proteins (retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5)) serve as dsRNA pattern-recognition receptors. In response to poly(I:C), a representative of dsRNA, and viral infection, they have been shown to activate the transcription factor IFN regulatory factor (IRF)-3, which in turn induces activation of the IFN-
promoter. RIG-I/MDA5 recognizes dsRNA in the cytoplasm, whereas TLR3 resides in the cell surface membrane or endosomes to engage in extracytoplasmic recognition of dsRNA. Recent reports suggest that TLR3 induces cellular responses in epithelial cells in response to respiratory syncytial virus (RSV). The modus for TLR3 activation by RSV, however, remains unresolved. By small interference RNA gene-silencing technology and human cell transfectants, we have revealed that knockdown of NAK-associated protein 1 (NAP1) leads to the down-regulation of IFN- promoter activation >24 h after poly(I:C) or virus (RSV and vesicular stomatitis virus) treatment. NAP1 is located downstream of the adapter Toll-IL-1R homology domain-containing adapter molecule (TICAM)-1 (Toll/IL-1R domain-containing adapter-inducing IFN-) in the TLR3 pathway, but TICAM-1 and TLR3 did not participate in the IRF-3 and IFN- promoter activation by RSV infection. Virus-mediated activation of the IFN- promoter was largely abrogated by the gene silencing of IFN- promoter stimulator-1 (mitochondria antiviral signaling (MAVS), VISA, Cardif), the adapter of the RIG-I/MDA5 dsRNA-recognition proteins. In both the TLR and virus-mediated IFN-inducing pathways, I
B kinase-related kinase 
and TANK-binding kinase 1 participated in IFN- induction. Thus, RSV as well as other viruses induces replication-mediated activation of the IFN- promoter, which is intracellularly initiated by the RIG-I/MDA5 but not the TLR3 pathway. Both the cytoplasmic and TLR3-mediated dsRNA recognition pathways converge upon NAP1 for the activation of the IRF-3 and IFN- promoter.
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 This work was supported in part by Core Research for Engineering, Science, and Technology, Japan Science and Technology Corporation, by Grants-in-Aid from the Ministry of Education, Science, and Culture (Specified Project for Advanced Research) and the Hepatitis C Virus project in National Institutes of Health of Japan, and by the Naito Memorial Foundation, Uehara Memorial Foundation, Mitsubishi Foundation, and Osaka Community Foundation. M.Sa. is supported by fellowships from the Japanese Society for the Promotion of Science.
2 Address correspondence and reprint requests to Dr. Tsukasa Seya, Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, Japan. E-mail address: seya-tu{at}pop.med.hokudai.ac.jp
3 Abbreviations used in this paper: RIG-I, retinoic acid-inducible gene I; mDC, myeloid dendritic cell; MDA5, melanoma differentiation-associated gene 5; IRF, IFN regulatory factor; RSV, respiratory syncytial virus; TICAM-1, Toll-IL-1R homology domain-containing adapter molecule 1; TRIF, Toll/IL-1R domain-containing adapter-inducing IFN-; IPS-1, IFN- promoter stimulator 1; MAVS, mitochondria antiviral signaling; IKK, IB kinase-related kinase ; TBK1, TANK-binding kinase 1; NAP1, NAK-associated protein 1; RNAi, RNA interference; pAb, polyclonal Ab; TIRAP, Toll/IL-1R domain-containing adaptor protein; CARD, caspase activation and recruitment domain; VSV, vesicular stomatitis virus; MOI, multiplicity of infection; siRNA, small interference RNA; IRES, internal ribosome entry site; sih, small interference hairpin-loop; Q-PCR, quantitative PCR; NAP1 DN, NAP1 dominant negative.
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