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(TRIF) Associates with TNF Receptor-Associated Factor 6 and TANK-Binding Kinase 1, and Activates Two Distinct Transcription Factors, NF-
B and IFN-Regulatory Factor-3, in the Toll-Like Receptor Signaling 1
* Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and
Exploratory Research for Advanced Technology, Japan Science and Technology Corporation, Osaka, Japan
We previously reported a new Toll/IL-1R (TIR)-containing molecule, named TIR domain-containing adaptor inducing IFN-
(TRIF). Although initial study indicated that TRIF possesses the ability to activate not only the NF-
B-dependent but also the IFN- promoters, the molecular mechanisms of TRIF-induced signaling are poorly understood. In this study, we investigated the signaling cascades through TRIF. TNF receptor-associated factor (TRAF)6 interacted with TRIF through the TRAF domain of TRAF6 and TRAF6-binding motifs found in the N-terminal portion of TRIF. Disruption of TRAF6-binding motifs of TRIF disabled it from associating with TRAF6, and resulted in a reduction in the TRIF-induced activation of the NF-B-dependent but not IFN- promoter. TANK-binding kinase (TBK)-1, which was recently reported to be a kinase of IFN regulatory factor-3, which is an essential transcription factor for IFN- expression, also associated with the N-terminal region of TRIF. Moreover, the association between TRIF and TBK1 appeared to require the kinase activity of TBK1, as well as phosphorylation of TRIF. Because TRAF6 and TBK1 bind close the region of TRIF, it seems that TRAF6 physically prevents the association between TRIF and TBK1. Taken together, these results demonstrate that TRIF associates with TRAF6 and TBK1 independently, and activates two distinct transcription factors, NF-B and IFN regulatory factor-3, respectively.
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 H. Bjorkbacka, K. A. Fitzgerald, F. Huet, X. Li, J. A. Gregory, M. A. Lee, C. M. Ordija, N. E. Dowley, D. T. Golenbock, and M. W. Freeman The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades Physiol Genomics, February 7, 2005; 19(3): 319 - 330. [Abstract] [Full Text] [PDF]
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 K. Takeda Evolution and integration of innate immune recognition systems: the Toll-like receptors Innate Immunity, February 1, 2005; 11(1): 51 - 55. [Abstract] [PDF]
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T. Saitoh, M. Yamamoto, M. Miyagishi, K. Taira, M. Nakanishi, T. Fujita, S. Akira, N. Yamamoto, and S. Yamaoka A20 Is a Negative Regulator of IFN Regulatory Factor 3 Signaling J. Immunol., February 1, 2005; 174(3): 1507 - 1512. [Abstract] [Full Text] [PDF]
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 K. Takeda and S. Akira Toll-like receptors in innate immunity Int. Immunol., January 1, 2005; 17(1): 1 - 14. [Abstract] [Full Text] [PDF]
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S. Stockinger, B. Reutterer, B. Schaljo, C. Schellack, S. Brunner, T. Materna, M. Yamamoto, S. Akira, T. Taniguchi, P. J. Murray, et al. IFN Regulatory Factor 3-Dependent Induction of Type I IFNs by Intracellular Bacteria Is Mediated by a TLR- and Nod2-Independent Mechanism J. Immunol., December 15, 2004; 173(12): 7416 - 7425. [Abstract] [Full Text] [PDF]
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 S. Pisegna, G. Pirozzi, M. Piccoli, L. Frati, A. Santoni, and G. Palmieri p38 MAPK activation controls the TLR3-mediated up-regulation of cytotoxicity and cytokine production in human NK cells Blood, December 15, 2004; 104(13): 4157 - 4164. [Abstract] [Full Text] [PDF]
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T. Tsujita, H. Tsukada, M. Nakao, H. Oshiumi, M. Matsumoto, and T. Seya Sensing Bacterial Flagellin by Membrane and Soluble Orthologs of Toll-like Receptor 5 in Rainbow Trout (Onchorhynchus mikiss) J. Biol. Chem., November 19, 2004; 279(47): 48588 - 48597. [Abstract] [Full Text] [PDF]
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B. R. tenOever, S. Sharma, W. Zou, Q. Sun, N. Grandvaux, I. Julkunen, H. Hemmi, M. Yamamoto, S. Akira, W.-C. Yeh, et al. Activation of TBK1 and IKK{varepsilon} Kinases by Vesicular Stomatitis Virus Infection and the Role of Viral Ribonucleoprotein in the Development of Interferon Antiviral Immunity J. Virol., October 1, 2004; 78(19): 10636 - 10649. [Abstract] [Full Text] [PDF]
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V. M. Abrahams, P. Bole-Aldo, Y. M. Kim, S. L. Straszewski-Chavez, T. Chaiworapongsa, R. Romero, and G. Mor Divergent Trophoblast Responses to Bacterial Products Mediated by TLRs J. Immunol., October 1, 2004; 173(7): 4286 - 4296. [Abstract] [Full Text] [PDF]
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A. Mansell, E. Brint, J. A. Gould, L. A. O'Neill, and P. J. Hertzog Mal Interacts with Tumor Necrosis Factor Receptor-associated Factor (TRAF)-6 to mediate NF-{kappa}B Activation by Toll-like Receptor (TLR)-2 and TLR4 J. Biol. Chem., September 3, 2004; 279(36): 37227 - 37230. [Abstract] [Full Text] [PDF]
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J. Gohda, T. Matsumura, and J.-i. Inoue Cutting Edge: TNFR-Associated Factor (TRAF) 6 Is Essential for MyD88-Dependent Pathway but Not Toll/IL-1 Receptor Domain-Containing Adaptor-Inducing IFN-{beta} (TRIF)-Dependent Pathway in TLR Signaling J. Immunol., September 1, 2004; 173(5): 2913 - 2917. [Abstract] [Full Text] [PDF]
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K. Ruckdeschel, G. Pfaffinger, R. Haase, A. Sing, H. Weighardt, G. Hacker, B. Holzmann, and J. Heesemann Signaling of Apoptosis through TLRs Critically Involves Toll/IL-1 Receptor Domain-Containing Adapter Inducing IFN-{beta}, but Not MyD88, in Bacteria-Infected Murine Macrophages J. Immunol., September 1, 2004; 173(5): 3320 - 3328. [Abstract] [Full Text] [PDF]
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S. Datta, M. Novotny, X. Li, J. Tebo, and T. A. Hamilton Toll IL-1 Receptors Differ in Their Ability to Promote the Stabilization of Adenosine and Uridine-Rich Elements Containing mRNA J. Immunol., August 15, 2004; 173(4): 2755 - 2761. [Abstract] [Full Text] [PDF]
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M. S. Vivarelli, D. McDonald, M. Miller, N. Cusson, M. Kelliher, and R. S. Geha RIP Links TLR4 to Akt and Is Essential for Cell Survival in Response to LPS Stimulation J. Exp. Med., August 2, 2004; 200(3): 399 - 404. [Abstract] [Full Text] [PDF]
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O. Takeuchi, H. Hemmi, and S. Akira Interferon response induced by Toll-like receptor signaling Innate Immunity, August 1, 2004; 10(4): 252 - 256. [Abstract] [PDF]
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A. Punturieri, R. S. Alviani, T. Polak, P. Copper, J. Sonstein, and J. L. Curtis Specific Engagement of TLR4 or TLR3 Does Not Lead to IFN-{beta}-Mediated Innate Signal Amplification and STAT1 Phosphorylation in Resident Murine Alveolar Macrophages J. Immunol., July 15, 2004; 173(2): 1033 - 1042. [Abstract] [Full Text] [PDF]
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H. Hemmi, O. Takeuchi, S. Sato, M. Yamamoto, T. Kaisho, H. Sanjo, T. Kawai, K. Hoshino, K. Takeda, and S. Akira The Roles of Two I{kappa}B Kinase-related Kinases in Lipopolysaccharide and Double Stranded RNA Signaling and Viral Infection J. Exp. Med., June 21, 2004; 199(12): 1641 - 1650. [Abstract] [Full Text] [PDF]
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A. K. Perry, E. K. Chow, J. B. Goodnough, W.-C. Yeh, and G. Cheng Differential Requirement for TANK-binding Kinase-1 in Type I Interferon Responses to Toll-like Receptor Activation and Viral Infection J. Exp. Med., June 21, 2004; 199(12): 1651 - 1658. [Abstract] [Full Text] [PDF]
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P. M. Pitha Unexpected similarities in cellular responses to bacterial and viral invasion PNAS, January 20, 2004; 101(3): 695 - 696. [Full Text] [PDF]
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S. M. McWhirter, K. A. Fitzgerald, J. Rosains, D. C. Rowe, D. T. Golenbock, and T. Maniatis From The Cover: IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts PNAS, January 6, 2004; 101(1): 233 - 238. [Abstract] [Full Text] [PDF]
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 S. N. Vogel, K. A. Fitzgerald, and M. J. Fenton TLRs: Differential Adapter Utilization by Toll-Like Receptors Mediates TLR-Specific Patterns of Gene Expression Mol. Interv., December 1, 2003; 3(8): 466 - 477. [Abstract] [Full Text] [PDF]
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