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* Department of Microbiology and Immunology, and
Department of Pathophysiology and Signal Transduction, Department of Pathology, Hokkaido University Graduate School of Medicine, Kita-ku Sapporo, Japan
TLR3 recognizes viral dsRNA and induces antiviral immune responses. TLR3-mediated cell activation relies on Toll/IL-1R (TIR) domain-containing adaptor molecule-1 (TICAM-1, also named TIR domain-containing adaptor inducing IFN-β or TRIF), which recruits downstream signaling molecules to activate the transcription factors IFN regulatory factor 3 (IRF-3) and NF-
B. The mechanisms by which TICAM-1 is activated and transmits signals remain largely unknown. In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. The receptor-interacting protein 1 (RIP1), a crucial signaling molecule for TICAM-1-mediated NF-B activation, accumulated in the TICAM-1 speckles. In addition, NF-B-activating kinase-associated protein 1 (NAP1), a downstream molecule linking TICAM-1 and the IRF-3-activating kinase TBK1 (TANK-binding kinase 1), was also recruited to the TICAM-1 speckles. Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. Thus, the spatiotemporal mobilization of TICAM-1 in response to dsRNA and the formation of the TICAM-1 speckles containing RIP1 and NAP1 are important for the activation of the TLR3-TICAM-1 pathway.
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1 This work was supported in part by Core Research for Engineering, Science, and Technology (CREST), JST (Japan Science and Technology Corporation (JST), grants-in-aid from the Ministry of Education, Science, Sports, and Culture (Specified Project for Advanced Research) and the Hepatitis C Virus (HCV) Project of the National Institute of Health (NIH) of Japan, and by the Uehara Memorial Foundation, Mitsubishi Foundation, Takeda Foundation, and Northtec Foundation.
2 Current address: Center for Integrated Medical Research, Keio University, Tokyo, Japan.
3 Current address: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510.
4 Address correspondence and reprint requests to Dr. Misako Matsumoto, Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku Sapporo, Japan. E-mail address: matumoto{at}pop.med.hokudai.ac.jp
5 Abbreviations used in this paper: TIR, Toll/IL-1 receptor; CFP, cyan fluorescent protein; DAPI, 4',6'-diamidino-2-phenylindole; DC, dendritic cell; EEA1, early endosome Ag 1; FRET, fluorescence resonance energy transfer; FRETC, corrected FRET; IRF-3, IFN regulatory factor 3; MPR, mannose-6-phosphate receptor; NAP1, NF-B activating kinase-associated protein 1; pAb, polyclonal Ab; poly(I:C), polyinosinic/polycytidylic acid; PGN, peptidoglycan; RIP1, receptor-interacting protein 1; TICAM-1, TIR domain-containing adaptor molecule 1; TRAM, TRIF-related adaptor molecule; TRIF, TIR domain-containing adaptor inducing IFN-β; YFP, yellow fluorescent protein; z-VAD-fmk, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone.
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  K. Funami, M. Sasai, H. Oshiumi, T. Seya, and M. Matsumoto Homo-oligomerization Is Essential for Toll/Interleukin-1 Receptor Domain-containing Adaptor Molecule-1-mediated NF-{kappa}B and Interferon Regulatory Factor-3 Activation J. Biol. Chem., June 27, 2008; 283(26): 18283 - 18291. [Abstract] [Full Text] [PDF]
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