Triggering the Interferon Antiviral Response Through an IKK-Related Pathway

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 κB 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 IκB kinase (IKK)–related kinases IKKϵ 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.

[1]  D. Baltimore,et al.  NF‐κB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK‐related kinase , 1999, The EMBO journal.

[2]  J. Hiscott,et al.  Virus-Dependent Phosphorylation of the IRF-3 Transcription Factor Regulates Nuclear Translocation, Transactivation Potential, and Proteasome-Mediated Degradation , 1998, Molecular and Cellular Biology.

[3]  C. Samuel,et al.  Antiviral Actions of Interferons , 2001, Clinical Microbiology Reviews.

[4]  J. Hiscott,et al.  Selective DNA Binding and Association with the CREB Binding Protein Coactivator Contribute to Differential Activation of Alpha/Beta Interferon Genes by Interferon Regulatory Factors 3 and 7 , 2000, Molecular and Cellular Biology.

[5]  A. Leonardi,et al.  Association of the Adaptor TANK with the IκB Kinase (IKK) Regulator NEMO Connects IKK Complexes with IKKε and TBK1 Kinases* , 2002, The Journal of Biological Chemistry.

[6]  N. Reich,et al.  Interferon Regulatory Factor 3 and CREB-Binding Protein/p300 Are Subunits of Double-Stranded RNA-Activated Transcription Factor DRAF1 , 1998, Molecular and Cellular Biology.

[7]  D. Levy,et al.  IRF3 and IRF7 Phosphorylation in Virus-infected Cells Does Not Require Double-stranded RNA-dependent Protein Kinase R or IκB Kinase but Is Blocked by Vaccinia Virus E3L Protein* , 2001, The Journal of Biological Chemistry.

[8]  T. Maniatis,et al.  IKKε Is Part of a Novel PMA-Inducible IκB Kinase Complex , 2000 .

[9]  T. Taniguchi,et al.  Distinct and Essential Roles of Transcription Factors IRF-3 and IRF-7 in Response to Viruses for IFN-α/β Gene Induction , 2000 .

[10]  E. Nishida,et al.  Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF‐3 and CBP/p300 , 1998, The EMBO journal.

[11]  D. Levy,et al.  Differential viral induction of distinct interferon‐α genes by positive feedback through interferon regulatory factor‐7 , 1998, The EMBO journal.

[12]  M. Karin,et al.  Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. , 2000, Annual review of immunology.

[13]  M. Karin,et al.  NAK is an IκB kinase-activating kinase , 2000, Nature.

[14]  T. Maniatis,et al.  Virus infection induces the assembly of coordinately activated transcription factors on the IFN-beta enhancer in vivo. , 1998, Molecular cell.

[15]  S. Akira,et al.  Toll-like receptors: critical proteins linking innate and acquired immunity , 2001, Nature Immunology.

[16]  T. Maniatis,et al.  A new family of IKK-related kinases may function as IκB kinase kinases , 2001 .

[17]  J. Hiscott,et al.  Identification of Distinct Signaling Pathways Leading to the Phosphorylation of Interferon Regulatory Factor 3* , 2001, The Journal of Biological Chemistry.

[18]  T. Mak,et al.  Deficiency of T2K leads to apoptotic liver degeneration and impaired NF‐κB‐dependent gene transcription , 2000, The EMBO journal.

[19]  J. Hiscott,et al.  Identification of the Minimal Phosphoacceptor Site Required for in Vivo Activation of Interferon Regulatory Factor 3 in Response to Virus and Double-stranded RNA* , 2003, The Journal of Biological Chemistry.

[20]  J. Hiscott,et al.  Recognition of the Measles Virus Nucleocapsid as a Mechanism of IRF-3 Activation , 2002, Journal of Virology.

[21]  G. Sen,et al.  Viruses and interferons. , 2001, Annual review of microbiology.

[22]  S. Akira,et al.  NF‐κB activation through IKK‐i‐dependent I‐TRAF/TANK phosphorylation , 2000, Genes to cells : devoted to molecular & cellular mechanisms.

[23]  Joshua M. Korn,et al.  The plasticity of dendritic cell responses to pathogens and their components. , 2001, Science.

[24]  S. Akira,et al.  IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases. , 1999, International immunology.