Triggering the Innate Antiviral Response through IRF-3 Activation

Rapid induction of type I interferon (IFN) expression is a central event in the establishment of the innate immune response against viral infection and requires the activation of multiple transcriptional proteins following engagement and signaling through Toll-like receptor-dependent and -independent pathways. The transcription factor interferon regulatory factor-3 (IRF-3) contributes to a first line of defense against viral infection by inducing the production of IFN-β that in turn amplifies the IFN response and the development of antiviral activity. In murine knock-out models, the absence of IRF-3 and the closely related IRF-7 ablates IFN production and increases viral pathogenesis, thus supporting a pivotal role for IRF-3/IRF-7 in the development of the host antiviral response. Rapid induction of type I interferon (IFN) expression is a central event in the establishment of the innate immune response against viral infection and requires the activation of multiple transcriptional proteins following engagement and signaling through Toll-like receptor-dependent and -independent pathways. The transcription factor interferon regulatory factor-3 (IRF-3) contributes to a first line of defense against viral infection by inducing the production of IFN-β that in turn amplifies the IFN response and the development of antiviral activity. In murine knock-out models, the absence of IRF-3 and the closely related IRF-7 ablates IFN production and increases viral pathogenesis, thus supporting a pivotal role for IRF-3/IRF-7 in the development of the host antiviral response. Upon recognition of specific molecular components of viruses, the host cell activates multiple signaling cascades that stimulate an innate antiviral response, resulting in the disruption of viral replication and the mobilization of the adaptive arm of the immune system (1Kawai T. Akira S. Nat. Immunol. 2006; 7: 131-137Crossref PubMed Scopus (1408) Google Scholar, 2van Boxel-Dezaire A.H. Rani M.R. Stark G.R. Immunity. 2006; 25: 361-372Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar). Central to the host antiviral response is the production of type I interferons (IFNs), 2The abbreviations used are: IFN, interferon; IRF, IFN regulatory factor; TLR, Toll-like receptor; ds, double-stranded; IRAK, IL-1R-associated kinase; IL, interleukin; TRAF, tumor necrosis factor receptor-associated factor; TRIF, TLR domain containing adapter-inducing IFNβ; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; MAVS, mitochondrial antiviral signaling; IKK, IκB kinase; IKKi, inducible IKK; pDC, plasmacytoid dendritic cell; PRD, positive regulatory domain; CBP, CREB-binding protein; CREB, cAMP-response element-binding protein; DBD, DNA binding domain; ISG, IFN-stimulated gene; IAD, IRF association domain; MEF, mouse embryonic fibroblast; MyD88, myeloid differentiation factor 88; IBiD, IRF-3 binding domain; RIG, retinoic acid-inducible gene; CARD, caspase recruitment domain.2The abbreviations used are: IFN, interferon; IRF, IFN regulatory factor; TLR, Toll-like receptor; ds, double-stranded; IRAK, IL-1R-associated kinase; IL, interleukin; TRAF, tumor necrosis factor receptor-associated factor; TRIF, TLR domain containing adapter-inducing IFNβ; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; MAVS, mitochondrial antiviral signaling; IKK, IκB kinase; IKKi, inducible IKK; pDC, plasmacytoid dendritic cell; PRD, positive regulatory domain; CBP, CREB-binding protein; CREB, cAMP-response element-binding protein; DBD, DNA binding domain; ISG, IFN-stimulated gene; IAD, IRF association domain; MEF, mouse embryonic fibroblast; MyD88, myeloid differentiation factor 88; IBiD, IRF-3 binding domain; RIG, retinoic acid-inducible gene; CARD, caspase recruitment domain. a large family of multifunctional immunoregulatory proteins (3Honda K. Takaoka A. Taniguchi T. Immunity. 2006; 25: 349-360Abstract Full Text Full Text PDF PubMed Scopus (934) Google Scholar). Multiple Toll-like receptor (TLR)-dependent (TLR-3, -4, -7, and -9) and -independent (RIG-I and Mda5) pathways are involved in the cell-specific regulation of type I IFNs, with evidence accumulating that cooperation between different pathways is required to ensure a robust and controlled activation of antiviral response (1Kawai T. Akira S. Nat. Immunol. 2006; 7: 131-137Crossref PubMed Scopus (1408) Google Scholar). Signal-induced activation of latent transcription factors such as nuclear factor κB (NF-κB) and interferon regulatory factors (IRF) via post-translational modifications, primarily phosphorylation events, leads to the recruitment of these factors to the type I IFN promoters in a temporally and spatially coordinated manner. This review will focus on the mechanisms of activation and the physiological functions of IRF-3 and the closely related IRF-7, whereas other articles in this series from Drs. Akira and Fujita will detail aspects of TLR-dependent and -independent signaling pathways that trigger innate antiviral responses. The best understood example of a virus-inducible transcription unit is the IFN-β promoter. A 60-bp DNA fragment, located –110 and –36 relative to the transcription start site, is a virus-inducible molecular switch composed of four positive regulatory domains (PRDI–IV). The IFN-β gene is activated by the cooperative binding of three transcription factor families (NF-κB, IRFs, and ATF-2/c-Jun) and an architectural protein (HMG I(Y)) to the nucleosome-free PRD regions of the promoter to form an enhanceosome (4Merika M. Thanos D. Curr. Opin. Genet. Dev. 2001; 11: 205-208Crossref PubMed Scopus (338) Google Scholar). The enhanceosome modifies and repositions a nucleosome that blocks the formation of a transcriptional preinitiation complex on the IFN-β promoter; this is accomplished by the ordered recruitment of histone acetyltransferases, SWI/SNF, and basal transcription factors. Acetylation of the nucleosome by the GCN5 histone acetyltransferase-containing complex is followed by the recruitment of the CBP-PolII holoenzyme. Next, nucleosome structure is altered by the SWI/SNF remodeling machine, thus permitting the recruitment of TFIID to the TATA element (5Lomvardas S. Thanos D. Cell. 2001; 106: 685-696Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 6Agalioti T. Chen G. Thanos D. Cell. 2002; 111: 381-392Abstract Full Text Full Text PDF PubMed Scopus (527) Google Scholar). The DNA bending induced upon TFIID binding to the promoter causes sliding of the SWI/SNF-modified nucleosome to a new position 36 bp downstream, thus allowing the initiation of transcription (5Lomvardas S. Thanos D. Cell. 2001; 106: 685-696Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). Specificity of type I IFN induction is achieved by members of the IRF transcription factor family. In all, nine human IRFs have been identified (IRF-1–IRF-9); each member shares extensive homology in the N-terminal DNA binding domain (DBD), characterized by five tryptophan repeat elements located within the first 150 amino acids of the protein. The IRF DNA binding domain mediates specific binding to GAAANN and AANNNGAA sequences, termed the IFN-stimulated regulatory element in IFN-stimulated genes (ISGs). In addition to their role in immune regulation, IRFs are also involved in regulation of cell cycle, apoptosis, and tumor suppression (3Honda K. Takaoka A. Taniguchi T. Immunity. 2006; 25: 349-360Abstract Full Text Full Text PDF PubMed Scopus (934) Google Scholar). Each IRF contains a unique C-terminal domain, termed the IRF association domain (IAD); the unique function of a particular IRF is accounted for by the ability of the IAD to interact with other members of the IRF family and other factors, its intrinsic transactivation potential, and cell type-specific expression of the IRFs. IRF-3, a critical player in the induction of type I IFNs following virus infection, is a constitutively expressed phosphoprotein of 427 amino acids (7Au W.-C. Moore P.A. Lowther W. Juang Y.-T. Pitha P.M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 11657-11661Crossref PubMed Scopus (346) Google Scholar). Transcriptional activity of IRF-3 is controlled by virus and dsRNA-induced, C-terminal phosphorylation events on serines 385 and 386, as well as the serine/threonine cluster between amino acids 396 and 405 (8Yoneyama M. Suhara W. Fukuhara Y. Fukada M. Nishida E. Fujita T. EMBO J. 1998; 17: 1087-1095Crossref PubMed Scopus (686) Google Scholar, 9Lin R. Heylbroeck C. Pitha P.M. Hiscott J. Mol. Cell. Biol. 1998; 18: 2986-2996Crossref PubMed Scopus (751) Google Scholar), mediated by the IKK-related kinases TBK-1 and IKKϵ (10Sharma S. tenOever B.R. Grandvaux N. Zhou G.P. Lin R. Hiscott J. Science. 2003; 300: 1148-1151Crossref PubMed Scopus (1347) Google Scholar, 11Fitzgerald K.A. McWhirter S.M. Faia K.L. Rowe D.C. Latz E. Golenbock D.T. Coyle A.J. Liao S.M. Maniatis T. Nat. Immunol. 2003; 4: 491-496Crossref PubMed Scopus (2049) Google Scholar) (Fig. 1). Based on available biochemical data, a model for IRF-3 activation proposes that C-terminal phosphorylation induces a conformational change in IRF-3 that allows homo- and heterodimerization, nuclear localization, and association with the co-activator CBP/p300 (12Lin R. Mamane Y. Hiscott J. Mol. Cell. Biol. 1999; 19: 2465-2474Crossref PubMed Scopus (269) Google Scholar). Inactive IRF-3 constitutively shuttles into and out of the nucleus, whereas phosphorylation-dependent association with CBP/p300 retains IRF-3 in the nucleus and induces transcription of IFN-β and other genes (13Kumar K.P. McBride K.M. Weaver B.K. Dingwall C. Reich N.C. Molecular and Cellular Biology. 2000; 20: 4159-4168Crossref PubMed Scopus (173) Google Scholar). IRF-7 was first described to bind and repress the Epstein-Barr virus Qp promoter regulating Epstein-Barr virus nuclear antigen 1 (14Zhang L. Pagano J.S. Mol. Cell. Biol. 1997; 17: 5748-5757Crossref PubMed Scopus (227) Google Scholar), but its importance in virus-induced IFN-α gene regulation was quickly recognized (15Sato M. Hata N. Asagiri M. Nakaya T. Taniguchi T. Tanaka N. FEBS Lett. 1998; 441: 106-110Crossref PubMed Scopus (460) Google Scholar, 16Au W.C. Moore P.A. LaFleur D.W. Tombal B. Pitha P.M. J. Biol. Chem. 1998; 273: 29210-29217Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 17Marie I. Durbin J.E. Levy D.E. EMBO J. 1998; 17: 6660-6669Crossref PubMed Google Scholar). IRF-7 is a multifunctional protein with transcriptional activity that, like IRF-3, depends on C-terminal phosphorylation (15Sato M. Hata N. Asagiri M. Nakaya T. Taniguchi T. Tanaka N. FEBS Lett. 1998; 441: 106-110Crossref PubMed Scopus (460) Google Scholar, 18Lin R. Mamane Y. Hiscott J. J. Biol. Chem. 2000; 275: 34320-34327Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar). However, constitutive IRF-7 expression is restricted to B cells and dendritic cells; in other cells, IRF-7 is virus- and IFN-inducible. Also distinct from IRF-3, IRF-7 has a half-life of ∼30 min, which may represent a mechanism that ensures transient IFN induction (15Sato M. Hata N. Asagiri M. Nakaya T. Taniguchi T. Tanaka N. FEBS Lett. 1998; 441: 106-110Crossref PubMed Scopus (460) Google Scholar, 16Au W.C. Moore P.A. LaFleur D.W. Tombal B. Pitha P.M. J. Biol. Chem. 1998; 273: 29210-29217Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 17Marie I. Durbin J.E. Levy D.E. EMBO J. 1998; 17: 6660-6669Crossref PubMed Google Scholar). In addition to the DBD, IRF-7 contains multiple regulatory domains in the C-terminal region that regulate its activity (Fig. 1) (19Lin R. Genin Mamane Y. Hiscott J. Mol. Cell. Biol. 2000; 20: PubMed Scopus (236) Google Scholar). In the C-terminal region between amino acids and (Fig. 1) is the of virus-induced C-terminal phosphorylation the transactivation function of IRF-7 R. Mamane Y. Hiscott J. J. Biol. Chem. 2000; 275: 34320-34327Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, A. Levy D.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), IFN and transcription of the IRF-7 gene R. W.C. N. Pitha P.M. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), IRF-7 regulation on and to of activation (15Sato M. Hata N. Asagiri M. Nakaya T. Taniguchi T. Tanaka N. FEBS Lett. 1998; 441: 106-110Crossref PubMed Scopus (460) Google Scholar, B.R. S. W. Grandvaux N. I. M. Akira S. W.C. Lin R. Hiscott J. J. PubMed Scopus Google of the with the also leads to the of a constitutively IRF-7 B.R. S. W. Grandvaux N. I. M. Akira S. W.C. Lin R. Hiscott J. J. PubMed Scopus Google Scholar). IRF-3 and IRF-7 distinct and in the response to virus infection (3Honda K. Takaoka A. Taniguchi T. Immunity. 2006; 25: 349-360Abstract Full Text Full Text PDF PubMed Scopus (934) Google Scholar, K. Taniguchi T. Nat. Immunol. 2006; PubMed Scopus Google Scholar). and gene have and virus-induced genes G. G. J. R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar) and have to IRF-3 and IRF-7 genes N. tenOever B. S. Lin R. Hiscott J. J. 2002; PubMed Scopus Google Scholar, J. M. S. L. Pitha P.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and on activation cell expressed and promoters are by IRF-3 whereas and promoters are induced by IRF-7 (19Lin R. Genin Mamane Y. Hiscott J. Mol. Cell. Biol. 2000; 20: PubMed Scopus (236) Google Scholar). DNA binding that IRF-3 and IRF-7 to the in virus-inducible in of the will IRF-3 binding and transactivation activity but IRF-7 transactivation (19Lin R. Genin Mamane Y. Hiscott J. Mol. Cell. Biol. 2000; 20: PubMed Scopus (236) Google Scholar, A. Genin Lin R. Hiscott J. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). IRF-3 a restricted DNA binding and with CBP, whereas IRF-7 has a DNA binding that contributes to its to stimulate IFN-α A of genes in cells a constitutively form of IRF-3 identified IRF-3 for that in addition to its role in IFN-β regulation, IRF-3 IFN-stimulated regulatory genes involved in the establishment of the antiviral N. tenOever B. S. Lin R. Hiscott J. 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S. A. Fujita T. J. Immunol. PubMed Scopus Google Scholar). In a related was to interact with to and signaling to the IFN response T. R. D. Akira S. Fujita T. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). IRF-3 and IRF-7 are as of type I IFN activation and are within the TLR-dependent and -independent pathways of the innate immune response to viral a of these transcription IRF-3/IRF-7 and The of genes by IRF-3 and IRF-7 to of IRF-7 have been is available for IRF-7 other signaling pathways may on IRF-3 and IRF-7 requires the regulation of IRF-3 and IRF-7 is and IRF pathways is The to these and other will have for immune response

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