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Science 300 (5622): 1148-1151

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

Triggering the Interferon Antiviral Response Through an IKK-Related Pathway

Sonia Sharma,* Benjamin R. tenOever,* Nathalie Grandvaux,* Guo-Ping Zhou, Rongtuan Lin,{dagger} John Hiscott{dagger}

Abstract: Rapid induction of type I interferon expression, a central event in establishing the innate antiviral response, requires cooperative activation of numerous transcription factors. Although signaling pathways that activate the transcription factors nuclear factor {kappa}B and ATF-2/c-Jun have been well characterized, activation of the interferon regulatory factors IRF-3 and IRF-7 has remained a critical missing link in understanding interferon signaling. We report here that the I{kappa}B kinase (IKK)–related kinases IKK{epsilon} and TANK-binding kinase 1 are components of the virus-activated kinase that phosphorylate IRF-3 and IRF-7. These studies illustrate an essential role for an IKK-related kinase pathway in triggering the host antiviral response to viral infection.

Lady Davis Institute for Medical Research–Jewish General Hospital, Departments of Microbiology and Immunology and Medicine, McGill University, Montreal, Quebec H3T 1E2, Canada.

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* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed at the Lady Davis Institute for Medical Research, 3755 Cote Ste. Catherine, Montreal, Quebec H3T 1E2, Canada. E-mail: john.hiscott{at}mcgill.ca (J.H.); rongtuan.lin{at}mcgill.ca (R.L.)


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Activation of the Interferon Response by Human Cytomegalovirus Occurs via Cytoplasmic Double-Stranded DNA but Not Glycoprotein B.
V. R. DeFilippis, T. Sali, D. Alvarado, L. White, W. Bresnahan, and K. J. Fruh (2010)
J. Virol. 84, 8913-8925
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A Role for the Human Nucleotide-binding Domain, Leucine-rich Repeat-containing Family Member NLRC5 in Antiviral Responses.
A. Neerincx, K. Lautz, M. Menning, E. Kremmer, P. Zigrino, M. Hosel, H. Buning, R. Schwarzenbacher, and T. A. Kufer (2010)
J. Biol. Chem. 285, 26223-26232
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The 3C Protein of Enterovirus 71 Inhibits Retinoid Acid-Inducible Gene I-Mediated Interferon Regulatory Factor 3 Activation and Type I Interferon Responses.
X. Lei, X. Liu, Y. Ma, Z. Sun, Y. Yang, Q. Jin, B. He, and J. Wang (2010)
J. Virol. 84, 8051-8061
   Abstract »    Full Text »    PDF »
Respiratory Syncytial Virus-Mediated NF-{kappa}B p65 Phosphorylation at Serine 536 Is Dependent on RIG-I, TRAF6, and IKK{beta}.
F. Yoboua, A. Martel, A. Duval, E. Mukawera, and N. Grandvaux (2010)
J. Virol. 84, 7267-7277
   Abstract »    Full Text »    PDF »
A Molecular Mechanism for Toll-IL-1 Receptor Domain-containing Adaptor Molecule-1-mediated IRF-3 Activation.
M. Tatematsu, A. Ishii, H. Oshiumi, M. Horiuchi, F. Inagaki, T. Seya, and M. Matsumoto (2010)
J. Biol. Chem. 285, 20128-20136
   Abstract »    Full Text »    PDF »
Synoviocyte Innate Immune Responses: II. Pivotal Role of IFN Regulatory Factor 3.
S. E. Sweeney, T. B. Kimbler, and G. S. Firestein (2010)
J. Immunol. 184, 7162-7168
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Positive Regulation of Interferon Regulatory Factor 3 Activation by Herc5 via ISG15 Modification.
H. X. Shi, K. Yang, X. Liu, X. Y. Liu, B. Wei, Y. F. Shan, L. H. Zhu, and C. Wang (2010)
Mol. Cell. Biol. 30, 2424-2436
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High-Throughput Screening for TLR3-IFN Regulatory Factor 3 Signaling Pathway Modulators Identifies Several Antipsychotic Drugs as TLR Inhibitors.
J. Zhu, K. Smith, P. N. Hsieh, Y. K. Mburu, S. Chattopadhyay, G. C. Sen, and S. N. Sarkar (2010)
J. Immunol. 184, 5768-5776
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Kaposi Sarcoma-associated Herpesvirus Latency-associated Nuclear Antigen Inhibits Interferon (IFN) {beta} Expression by Competing with IFN Regulatory Factor-3 for Binding to IFNB Promoter.
N. Cloutier and L. Flamand (2010)
J. Biol. Chem. 285, 7208-7221
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Viral Induction of the Zinc Finger Antiviral Protein Is IRF3-dependent but NF-{kappa}B-independent.
N. Wang, Q. Dong, J. Li, R. K. Jangra, M. Fan, A. R. Brasier, S. M. Lemon, L. M. Pfeffer, and K. Li (2010)
J. Biol. Chem. 285, 6080-6090
   Abstract »    Full Text »    PDF »
Critical Role of the IFN-Stimulated Gene Factor 3 Complex in TLR-Mediated IL-27p28 Gene Expression Revealing a Two-Step Activation Process.
C. Molle, M. Goldman, and S. Goriely (2010)
J. Immunol. 184, 1784-1792
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Human T Cell Lymphotropic Virus 1 Manipulates Interferon Regulatory Signals by Controlling the TAK1-IRF3 and IRF4 Pathways.
S. Suzuki, Y. Zhou, A. Refaat, I. Takasaki, K. Koizumi, S. Yamaoka, Y. Tabuchi, I. Saiki, and H. Sakurai (2010)
J. Biol. Chem. 285, 4441-4446
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Thogoto virus ML protein is a potent inhibitor of the interferon regulatory factor-7 transcription factor.
N. Buettner, C. Vogt, L. Martinez-Sobrido, F. Weber, Z. Waibler, and G. Kochs (2010)
J. Gen. Virol. 91, 220-227
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Human Cytomegalovirus Induces the Interferon Response via the DNA Sensor ZBP1.
V. R. DeFilippis, D. Alvarado, T. Sali, S. Rothenburg, and K. Fruh (2010)
J. Virol. 84, 585-598
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The Tpl2 Mutation Sluggish Impairs Type I IFN Production and Increases Susceptibility to Group B Streptococcal Disease.
N. Xiao, C. Eidenschenk, P. Krebs, K. Brandl, A. L. Blasius, Y. Xia, K. Khovananth, N. G. Smart, and B. Beutler (2009)
J. Immunol. 183, 7975-7983
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