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Science 301 (5633): 640-643

Copyright © 2003 by the American Association for the Advancement of Science

Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway

Masahiro Yamamoto,1 Shintaro Sato,1,2 Hiroaki Hemmi,1 Katsuaki Hoshino,1,4 Tsuneyasu Kaisho,1,4 Hideki Sanjo,1 Osamu Takeuchi,1 Masanaka Sugiyama,1 Masaru Okabe,3 Kiyoshi Takeda,1,2 Shizuo Akira1,2*

Abstract: Stimulation of Toll-like receptors (TLRs) triggers activation of a common MyD88-dependent signaling pathway as well as a MyD88-independent pathway that is unique to TLR3 and TLR4 signaling pathways leading to interferon (IFN)-ß production. Here we disrupted the gene encoding a Toll/IL-1 receptor (TIR) domain-containing adaptor, TRIF. TRIF-deficient mice were defective in both TLR3- and TLR4-mediated expression of IFN-ß and activation of IRF-3. Furthermore, inflammatory cytokine production in response to the TLR4 ligand, but not to other TLR ligands, was severely impaired in TRIF-deficient macrophages. Mice deficient in both MyD88 and TRIF showed complete loss of nuclear factor kappa B activation in response to TLR4 stimulation. These findings demonstrate that TRIF is essential for TLR3- and TLR4-mediated signaling pathways facilitating mammalian antiviral host defense.

1 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita Osaka 565-0871, Japan.
2 ERATO, Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita Osaka 565-0871, Japan.
3 Genome Information Research Center, 3-1 Yamada-oka, Suita Osaka 565-0871, Japan.
4 RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumiku, Yokohama, Kanagawa 230-0045, Japan

* To whom correspondence should be addressed. E-mail: sakira{at}biken.osaka-u.ac.jp

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I. D. Jung, S. K. Jeong, C.-M. Lee, K. T. Noh, D. R. Heo, Y. K. Shin, C.-H. Yun, W.-J. Koh, S. Akira, J. Whang, et al. (2011)
Cancer Res. 71, 2858-2870
   Abstract »    Full Text »    PDF »
Mal Mediates TLR-Induced Activation of CREB and Expression of IL-10.
M. Mellett, P. Atzei, R. Jackson, L. A. O'Neill, and P. N. Moynagh (2011)
J. Immunol. 186, 4925-4935
   Abstract »    Full Text »    PDF »
Age-Related Macular Degeneration and the Other Double Helix The Cogan Lecture.
J. Ambati (2011)
Invest. Ophthalmol. Vis. Sci. 52, 2166-2169
   Abstract »    Full Text »    PDF »
N1L Is an Ectromelia Virus Virulence Factor and Essential for In Vivo Spread upon Respiratory Infection.
M. S. Gratz, Y. Suezer, M. Kremer, A. Volz, M. Majzoub, K.-M. Hanschmann, U. Kalinke, A. Schwantes, and G. Sutter (2011)
J. Virol. 85, 3557-3569
   Abstract »    Full Text »    PDF »
Antigen-Specific T-Cell Responses to a Recombinant Fowlpox Virus Are Dependent on MyD88 and Interleukin-18 and Independent of Toll-Like Receptor 7 (TLR7)- and TLR9-Mediated Innate Immune Recognition.
E. L. Lousberg, K. R. Diener, C. K. Fraser, S. Phipps, P. S. Foster, W. Chen, S. Uematsu, S. Akira, S. A. Robertson, M. P. Brown, et al. (2011)
J. Virol. 85, 3385-3396
   Abstract »    Full Text »    PDF »
TLR-signaling Networks: An Integration of Adaptor Molecules, Kinases, and Cross-talk.
J. Brown, H. Wang, G. N. Hajishengallis, and M. Martin (2011)
Journal of Dental Research 90, 417-427
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Raftlin Is Involved in the Nucleocapture Complex to Induce Poly(I:C)-mediated TLR3 Activation.
A. Watanabe, M. Tatematsu, K. Saeki, S. Shibata, H. Shime, A. Yoshimura, C. Obuse, T. Seya, and M. Matsumoto (2011)
J. Biol. Chem. 286, 10702-10711
   Abstract »    Full Text »    PDF »
Impaired Wound Healing with Defective Expression of Chemokines and Recruitment of Myeloid Cells in TLR3-Deficient Mice.
Q. Lin, D. Fang, J. Fang, X. Ren, X. Yang, F. Wen, and S. B. Su (2011)
J. Immunol. 186, 3710-3717
   Abstract »    Full Text »    PDF »
Kaposi Sarcoma-associated Herpesvirus Degrades Cellular Toll-Interleukin-1 Receptor Domain-containing Adaptor-inducing {beta}-Interferon (TRIF).
H. Ahmad, R. Gubbels, E. Ehlers, F. Meyer, T. Waterbury, R. Lin, and L. Zhang (2011)
J. Biol. Chem. 286, 7865-7872
   Abstract »    Full Text »    PDF »
TRIF Is a Critical Survival Factor in Viral Cardiomyopathy.
A. Riad, D. Westermann, C. Zietsch, K. Savvatis, P. M. Becher, S. Bereswill, M. M. Heimesaat, O. Lettau, D. Lassner, A. Dorner, et al. (2011)
J. Immunol. 186, 2561-2570
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Differential Expression of NLRP3 among Hematopoietic Cells.
G. Guarda, M. Zenger, A. S. Yazdi, K. Schroder, I. Ferrero, P. Menu, A. Tardivel, C. Mattmann, and J. Tschopp (2011)
J. Immunol. 186, 2529-2534
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Absence of MyD88 Results in Enhanced TLR3-Dependent Phosphorylation of IRF3 and Increased IFN-{beta} and RANTES Production.
J. Siednienko, T. Gajanayake, K. A. Fitzgerald, P. Moynagh, and S. M. Miggin (2011)
J. Immunol. 186, 2514-2522
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Nrf2-mediated induction of p62 controls Toll-like receptor-4-driven aggresome-like induced structure formation and autophagic degradation.
K.-i. Fujita, D. Maeda, Q. Xiao, and S. M. Srinivasula (2011)
PNAS 108, 1427-1432
   Abstract »    Full Text »    PDF »
Bryostatin-1, a Naturally Occurring Antineoplastic Agent, Acts as a Toll-like Receptor 4 (TLR-4) Ligand and Induces Unique Cytokines and Chemokines in Dendritic Cells.
M. E. Ariza, R. Ramakrishnan, N. P. Singh, A. Chauhan, P. S. Nagarkatti, and M. Nagarkatti (2011)
J. Biol. Chem. 286, 24-34
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MyD88 Signaling Is Indispensable for Primary Influenza A Virus Infection but Dispensable for Secondary Infection.
S.-U. Seo, H.-J. Kwon, J.-H. Song, Y.-H. Byun, B. L. Seong, T. Kawai, S. Akira, and M.-N. Kweon (2010)
J. Virol. 84, 12713-12722
   Abstract »    Full Text »    PDF »
Phosphatidylinositol 3-Kinase Activation Attenuates the TLR2-Mediated Macrophage Proinflammatory Cytokine Response to Francisella tularensis Live Vaccine Strain.
E. A. Medina, I. R. Morris, and M. T. Berton (2010)
J. Immunol. 185, 7562-7572
   Abstract »    Full Text »    PDF »
The cysteine protease domain of porcine reproductive and respiratory syndrome virus non-structural protein 2 antagonizes interferon regulatory factor 3 activation.
H. Li, Z. Zheng, P. Zhou, B. Zhang, Z. Shi, Q. Hu, and H. Wang (2010)
J. Gen. Virol. 91, 2947-2958
   Abstract »    Full Text »    PDF »
Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality.
E. Marchlik, P. Thakker, T. Carlson, Z. Jiang, M. Ryan, S. Marusic, N. Goutagny, W. Kuang, G. R. Askew, V. Roberts, et al. (2010)
J. Leukoc. Biol. 88, 1171-1180
   Abstract »    Full Text »    PDF »
Identification of a polyI:C-inducible membrane protein that participates in dendritic cell-mediated natural killer cell activation.
T. Ebihara, M. Azuma, H. Oshiumi, J. Kasamatsu, K. Iwabuchi, K. Matsumoto, H. Saito, T. Taniguchi, M. Matsumoto, and T. Seya (2010)
J. Exp. Med. 207, 2675-2687
   Abstract »    Full Text »    PDF »
Cactin Targets the MHC Class III Protein I{kappa}B-like (I{kappa}BL) and Inhibits NF-{kappa}B and Interferon-regulatory Factor Signaling Pathways.
P. Atzei, S. Gargan, N. Curran, and P. N. Moynagh (2010)
J. Biol. Chem. 285, 36804-36817
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Glaucomatous Tissue Stress and the Regulation of Immune Response through Glial Toll-like Receptor Signaling.
C. Luo, X. Yang, A. D. Kain, D. W. Powell, M. H. Kuehn, and G. Tezel (2010)
Invest. Ophthalmol. Vis. Sci. 51, 5697-5707
   Abstract »    Full Text »    PDF »
Editorial: Pattern recognition receptors and factor B: "complement"ary pathways converge.
A. Prakash and J. Hellman (2010)
J. Leukoc. Biol. 88, 605-607
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