The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

IRF3  -  interferon regulatory factor 3

Homo sapiens

Synonyms: IRF-3, Interferon regulatory factor 3
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of IRF3

  • In cells transiently expressing IRF7 or/and IRF3, the VAF level and binding of VAF are clearly increased after Sendai virus infection [1].
  • Innate cellular response to virus particle entry requires IRF3 but not virus replication [2].
  • Furthermore, we demonstrate that HSV-1 modifies the IRF3 pathway in a manner different from that of the small RNA viruses most commonly studied [3].
  • The herpes simplex virus ICP0 RING finger domain inhibits IRF3- and IRF7-mediated activation of interferon-stimulated genes [3].
  • Hepatitis A virus suppresses RIG-I-mediated IRF-3 activation to block induction of beta interferon [4].
  • Interferon-beta promoter stimulator-1 and IRF-3 are required for efficient apoptosis following reovirus infection, suggesting a common mechanism of antiviral cytokine induction and activation of the cell death response [5].

High impact information on IRF3

  • Viral infection triggers host innate immune responses through activation of the transcription factors NF-kappaB and IRF 3, which coordinately regulate the expression of type-I interferons such as interferon-beta (IFN-beta) [6].
  • Epistasis experiments show that MAVS is required for the phosphorylation of IRF 3 and IkappaB and functions downstream of RIG-I, an intracellular receptor for viral RNA [6].
  • Dual utilization of an acceptor/donor splice site governs the alternative splicing of the IRF-3 gene [7].
  • Here we describe novel regulation of IRF-3 at the level of RNA splicing [7].
  • IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway [8].

Chemical compound and disease context of IRF3


Biological context of IRF3


Anatomical context of IRF3

  • Moreover, IRF3-deficient, but not IFNalpha/betaR deficient, macrophages still induced Viperin in response to SV [18].
  • These data are the first to show that IL-1beta, in addition to TLRs, can stimulate IRF3, implicating this cytokine as an activator of genes involved in innate antiviral responses in astrocytes [19].
  • In the present study we demonstrate the activation of IRF3 followed by ISG induction after exposure of cells to the bacterial cell wall component lipopolysaccharide [20].
  • These signals may increase expression of inflammatory cytokines, chemokines and ICAM-1 through activation of transcription factors NF-kappaB and/or IRF3 in airway epithelial cells [21].
  • We have generated tetracycline-inducible stable cell lines that express a wild type or kinase-inactive mutant form of IKK-i. Our data suggest that expression of IKK-i can activate both NFkappaB and IRF3, leading to the production of several cytokines including interferon beta [22].

Associations of IRF3 with chemical compounds

  • Engagement of Toll-like receptors by lipopolysaccharide triggered the nuclear translocation of IRF3, followed by its DNA binding and the subsequent induction of several interferon-regulated genes [20].
  • Significantly, virus-induced IRF3 phosphorylation is blocked by GA, whereas GA does not affect the protein level of IRF3 [16].
  • Treatment with DNA-damaging agents, including doxorubicin and UV radiation, caused phosphorylation of the IRF3 transcription factor [23].
  • Virus infection but not IFN treatment induces phosphorylation of IRF-3 on specific serine residues, thereby allowing it to complex with the co-activator CBP/p300 with simultaneous nuclear translocation and its specific DNA binding [24].
  • Expression of IRF-3 as a Gal4 fusion protein does not activate expression of a chloramphenicol acetyltransferase reporter gene containing repeats of the Gal4 binding sites, indicating that this protein does not contain the transcription transactivation domain [25].

Physical interactions of IRF3

  • The region by which IRF-7 interacts with IRF-3 was mapped between amino acid 418 and 473 [26].
  • Following infection, phosphorylated IRF-3 can bind to the CBP/p300 proteins resident in the nucleus [27].
  • IRF-3a lacks half of the DNA binding domain found in IRF-3 and is unable to bind to the classical IRF binding elements, IFN-stimulated response elements [28].
  • IRF-3 binds to the interferon-sensitive response element (ISRE) present in the ISG15 gene promoter and activates its transcriptional activity [29].
  • Therefore, IRF-3 activation by dsRNA is sufficient to induce the transcription of genes with simple promoters such as 561 as well as complex promoters such as IFN-beta [30].
  • Although LPS-induced IRF-3 nuclear translocation was observed both in adult and neonatal moDCs, IRF-3 DNA-binding activity and association with the coactivator CREB-binding protein (CBP) were decreased in neonatal as compared with adult moDCs [31].

Enzymatic interactions of IRF3

  • We report here that the IkappaB kinase (IKK)-related kinases IKKepsilon and TANK-binding kinase 1 are components of the virus-activated kinase that phosphorylate IRF-3 and IRF-7 [32].

Regulatory relationships of IRF3


Other interactions of IRF3

  • Remarkably, VAF, as well as recombinant IRF-3 and IRF-7 proteins, binds very weakly to the interferon-beta (IFN-beta) gene promoter in vitro [36].
  • Furthermore, whereas poly(I.C)-induced NF-kappaB activation is completely abolished inTRAF6-/- MEFs, the signal-induced activation of IRF3 is TRAF6 independent [35].
  • Recent studies have shown that TLR4 also signals independently of MyD88, resulting in the activation of IFN regulatory factor 3 (IRF3), a transcription factor required for the production of primary antiviral response genes such as IFN-beta [19].
  • We also show that IL-1beta induces phosphorylation and nuclear translocation of IRF3 and delayed phosphorylation of STAT1 [19].
  • We have localized the SR-A1 gene between the known genes IRF3 and RRAS on chromosome 19q13 [37].
  • The data support a two-step phosphorylation model for IRF-3 activation mediated by TBK1 [38].

Analytical, diagnostic and therapeutic context of IRF3


  1. Regulation of the transcriptional activity of the IRF7 promoter by a pathway independent of interferon signaling. Ning, S., Huye, L.E., Pagano, J.S. J. Biol. Chem. (2005) [Pubmed]
  2. Innate cellular response to virus particle entry requires IRF3 but not virus replication. Collins, S.E., Noyce, R.S., Mossman, K.L. J. Virol. (2004) [Pubmed]
  3. The herpes simplex virus ICP0 RING finger domain inhibits IRF3- and IRF7-mediated activation of interferon-stimulated genes. Lin, R., Noyce, R.S., Collins, S.E., Everett, R.D., Mossman, K.L. J. Virol. (2004) [Pubmed]
  4. Hepatitis A virus suppresses RIG-I-mediated IRF-3 activation to block induction of beta interferon. Fensterl, V., Grotheer, D., Berk, I., Schlemminger, S., Vallbracht, A., Dotzauer, A. J. Virol. (2005) [Pubmed]
  5. Retinoic acid-inducible gene-I and interferon-beta promoter stimulator-1 augment proapoptotic responses following mammalian reovirus infection via interferon regulatory factor-3. Holm, G.H., Zurney, J., Tumilasci, V., Leveille, S., Danthi, P., Hiscott, J., Sherry, B., Dermody, T.S. J. Biol. Chem. (2007) [Pubmed]
  6. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Seth, R.B., Sun, L., Ea, C.K., Chen, Z.J. Cell (2005) [Pubmed]
  7. Dual utilization of an acceptor/donor splice site governs the alternative splicing of the IRF-3 gene. Karpova, A.Y., Howley, P.M., Ronco, L.V. Genes Dev. (2000) [Pubmed]
  8. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Fitzgerald, 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) [Pubmed]
  9. Legionella pneumophila Induces IFNbeta in Lung Epithelial Cells via IPS-1 and IRF3, Which Also Control Bacterial Replication. Opitz, B., Vinzing, M., van Laak, V., Schmeck, B., Heine, G., G??nther, S., Preissner, R., Slevogt, H., N'guessan, P.D., Eitel, J., Goldmann, T., Flieger, A., Suttorp, N., Hippenstiel, S. J. Biol. Chem. (2006) [Pubmed]
  10. Rhesus cytomegalovirus particles prevent activation of interferon regulatory factor 3. DeFilippis, V., Früh, K. J. Virol. (2005) [Pubmed]
  11. Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Lin, R., Heylbroeck, C., Pitha, P.M., Hiscott, J. Mol. Cell. Biol. (1998) [Pubmed]
  12. Identification of a novel pathway essential for the immediate-early, interferon-independent antiviral response to enveloped virions. Noyce, R.S., Collins, S.E., Mossman, K.L. J. Virol. (2006) [Pubmed]
  13. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Foy, E., Li, K., Wang, C., Sumpter, R., Ikeda, M., Lemon, S.M., Gale, M. Science (2003) [Pubmed]
  14. Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway. Korherr, C., Gille, H., Schäfer, R., Koenig-Hoffmann, K., Dixelius, J., Egland, K.A., Pastan, I., Brinkmann, U. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  15. Cytomegalovirus activates interferon immediate-early response gene expression and an interferon regulatory factor 3-containing interferon-stimulated response element-binding complex. Navarro, L., Mowen, K., Rodems, S., Weaver, B., Reich, N., Spector, D., David, M. Mol. Cell. Biol. (1998) [Pubmed]
  16. Hsp90 regulates activation of interferon regulatory factor 3 and TBK-1 stabilization in Sendai virus-infected cells. Yang, K., Shi, H., Qi, R., Sun, S., Tang, Y., Zhang, B., Wang, C. Mol. Biol. Cell (2006) [Pubmed]
  17. Oncogenic potential of a dominant negative mutant of interferon regulatory factor 3. Kim, T.Y., Lee, K.H., Chang, S., Chung, C., Lee, H.W., Yim, J., Kim, T.K. J. Biol. Chem. (2003) [Pubmed]
  18. Toll-like receptor-dependent and -independent Viperin gene expression and counter-regulation by PRDI-binding factor-1/BLIMP1. Severa, M., Coccia, E.M., Fitzgerald, K.A. J. Biol. Chem. (2006) [Pubmed]
  19. The cytokine IL-1beta activates IFN response factor 3 in human fetal astrocytes in culture. Rivieccio, M.A., John, G.R., Song, X., Suh, H.S., Zhao, Y., Lee, S.C., Brosnan, C.F. J. Immunol. (2005) [Pubmed]
  20. p38-dependent activation of interferon regulatory factor 3 by lipopolysaccharide. Navarro, L., David, M. J. Biol. Chem. (1999) [Pubmed]
  21. Synthetic double-stranded RNA induces multiple genes related to inflammation through Toll-like receptor 3 depending on NF-kappaB and/or IRF-3 in airway epithelial cells. Matsukura, S., Kokubu, F., Kurokawa, M., Kawaguchi, M., Ieki, K., Kuga, H., Odaka, M., Suzuki, S., Watanabe, S., Takeuchi, H., Kasama, T., Adachi, M. Clin. Exp. Allergy (2006) [Pubmed]
  22. IKK-i signals through IRF3 and NFkappaB to mediate the production of inflammatory cytokines. Sankar, S., Chan, H., Romanow, W.J., Li, J., Bates, R.J. Cell. Signal. (2006) [Pubmed]
  23. Activation of interferon regulatory factor 3 in response to DNA-damaging agents. Kim, T., Kim, T.Y., Song, Y.H., Min, I.M., Yim, J., Kim, T.K. J. Biol. Chem. (1999) [Pubmed]
  24. Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300. Yoneyama, M., Suhara, W., Fukuhara, Y., Fukuda, M., Nishida, E., Fujita, T. EMBO J. (1998) [Pubmed]
  25. Identification of a member of the interferon regulatory factor family that binds to the interferon-stimulated response element and activates expression of interferon-induced genes. Au, W.C., Moore, P.A., Lowther, W., Juang, Y.T., Pitha, P.M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  26. Analysis of functional domains of interferon regulatory factor 7 and its association with IRF-3. Au, W.C., Yeow, W.S., Pitha, P.M. Virology (2001) [Pubmed]
  27. Regulated nuclear-cytoplasmic localization of interferon regulatory factor 3, a subunit of double-stranded RNA-activated factor 1. Kumar, K.P., McBride, K.M., Weaver, B.K., Dingwall, C., Reich, N.C. Mol. Cell. Biol. (2000) [Pubmed]
  28. Functional characterization of interferon regulatory factor 3a (IRF-3a), an alternative splice isoform of IRF-3. Karpova, A.Y., Ronco, L.V., Howley, P.M. Mol. Cell. Biol. (2001) [Pubmed]
  29. Regulation of type I interferon gene expression by interferon regulatory factor-3. Schafer, S.L., Lin, R., Moore, P.A., Hiscott, J., Pitha, P.M. J. Biol. Chem. (1998) [Pubmed]
  30. IRF-3-dependent, NFkappa B- and JNK-independent activation of the 561 and IFN-beta genes in response to double-stranded RNA. Peters, K.L., Smith, H.L., Stark, G.R., Sen, G.C. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  31. Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells. Aksoy, E., Albarani, V., Nguyen, M., Laes, J.F., Ruelle, J.L., De Wit, D., Willems, F., Goldman, M., Goriely, S. Blood (2007) [Pubmed]
  32. Triggering the interferon antiviral response through an IKK-related pathway. Sharma, S., tenOever, B.R., Grandvaux, N., Zhou, G.P., Lin, R., Hiscott, J. Science (2003) [Pubmed]
  33. Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling. Sarkar, S.N., Peters, K.L., Elco, C.P., Sakamoto, S., Pal, S., Sen, G.C. Nat. Struct. Mol. Biol. (2004) [Pubmed]
  34. Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20. Lin, R., Yang, L., Nakhaei, P., Sun, Q., Sharif-Askari, E., Julkunen, I., Hiscott, J. J. Biol. Chem. (2006) [Pubmed]
  35. Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta. Jiang, Z., Mak, T.W., Sen, G., Li, X. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  36. Virus infection induces the assembly of coordinately activated transcription factors on the IFN-beta enhancer in vivo. Wathelet, M.G., Lin, C.H., Parekh, B.S., Ronco, L.V., Howley, P.M., Maniatis, T. Mol. Cell (1998) [Pubmed]
  37. Cloning of a gene (SR-A1), encoding for a new member of the human Ser/Arg-rich family of pre-mRNA splicing factors: overexpression in aggressive ovarian cancer. Scorilas, A., Kyriakopoulou, L., Katsaros, D., Diamandis, E.P. Br. J. Cancer (2001) [Pubmed]
  38. Interferon regulatory factor 3 is regulated by a dual phosphorylation-dependent switch. Panne, D., McWhirter, S.M., Maniatis, T., Harrison, S.C. J. Biol. Chem. (2007) [Pubmed]
  39. Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. Barnes, B.J., Moore, P.A., Pitha, P.M. J. Biol. Chem. (2001) [Pubmed]
  40. Cellular recognition of herpes simplex virus infection and virus-induced cytokine production. Melchjorsen, J. Danish medical bulletin. (2005) [Pubmed]
  41. Convergence of the NF-kappaB and interferon signaling pathways in the regulation of antiviral defense and apoptosis. Hiscott, J., Grandvaux, N., Sharma, S., Tenoever, B.R., Servant, M.J., Lin, R. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  42. Interleukin-1beta represses MRP2 gene expression through inactivation of interferon regulatory factor 3 in HepG2 cells. Hisaeda, K., Inokuchi, A., Nakamura, T., Iwamoto, Y., Kohno, K., Kuwano, M., Uchiumi, T. Hepatology (2004) [Pubmed]
  43. Differential expression patterns of IRF3 and IRF7 in pediatric lymphoid disorders. Park, H.S., Kim, Y.J., Bae, Y.K., Lee, N.H., Lee, Y.J., Hah, J.O., Park, T.I., Lee, K.S., Park, J.B., Kim, H.S. Int. J. Biol. Markers (2007) [Pubmed]
WikiGenes - Universities