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Gene Review

Irf3  -  interferon regulatory factor 3

Mus musculus

Synonyms: C920001K05Rik, IRF-3, Interferon regulatory factor 3
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Disease relevance of Irf3

  • The data suggest that pre-activated IRF-3 is a major factor in the differences in IL-12 production between B10.S and SJL/J macrophages responding to TMEV [1].
  • In vivo interferon regulatory factor 3 tumor suppressor activity in B16 melanoma tumors [2].
  • In this study, we show that polyubiquitination of IRF-3 increases in response to Sendai virus infection [3].
  • Local delivery of murine recombinant IFN-beta protected C57BL/6 and IRF-3(-/-) mice against IVAG HSV-2 challenge [4].
  • The host response to West Nile Virus infection limits viral spread through the activation of the interferon regulatory factor 3 pathway [5].

High impact information on Irf3

  • We show that IRF-3 is a potent transcriptional activator and demonstrate that HPV16 E6 can inhibit its transactivation function [6].
  • Activation of type I interferons by cytosolic DNA is TLR independent and requires IRF3 but occurs without detectable activation of NF-kappaB and MAP kinases [7].
  • In contrast, IkappaBNS-deficient cells showed normal induction of genes that are induced early or induced via IRF-3 activation [8].
  • By generating MAVS-deficient mice, here we show that loss of MAVS abolished viral induction of interferons and prevented the activation of NFkappaB and IRF3 in multiple cell types, except plasmacytoid dendritic cells (pDCs) [9].
  • In these cells, a normal profile of IFN-alpha/beta mRNA induction can be achieved by coexpressing both IRF-3 and IRF-7 [10].

Biological context of Irf3


Anatomical context of Irf3

  • Western blot analysis demonstrated that activation of IRF-3 was also increased in RA synovium [14].
  • In animals receiving IRF-3 B16 melanoma cells, tumors grew at a 4- to 5-fold reduced rate, and tumors that developed from these mice had a moderate-to-dense infiltration of inflammatory cells, whereas only low levels of lymphocyte infiltration were observed in mock-transduced B16 tumors [2].
  • In addition, no degradation of IRF-3 was observed in TBK1(-/-) mouse embryonic fibroblasts [3].
  • Using an E1 temperature-sensitive cell line, we demonstrate that polyubiquitination is required for the observed degradation of IRF-3 [3].
  • Interferon regulatory factor 3 is required for viral induction of beta interferon in primary cardiac myocyte cultures [13].

Associations of Irf3 with chemical compounds


Enzymatic interactions of Irf3


Regulatory relationships of Irf3


Other interactions of Irf3

  • These studies support the distinct activation profiles of IRF-3 in comparison to IRF-5, but reveal a potential shared biological effect [11].
  • We defined the GRIP1:IRF3 interface and showed that endogenous GRIP1 and IRF3 interact in mammalian cells [12].
  • In cells lacking p48, an essential component of IFN stimulated gene factor 3 (ISGF3), ectopic expression of IRF-7 but not IRF-3 can rescue the deficiency to induce IFN-alpha genes [22].
  • GR interference persisted in MyD88- and IFNA receptor-deficient mice, suggesting a specific disruption of TLR3-IRF3 pathway, not of autocrine IFN signaling [12].
  • We have identified two members of the IRF family (IRF-2 and IRF-3) that specifically bind to these sites [23].

Analytical, diagnostic and therapeutic context of Irf3


  1. Reduced expression of IL-12 p35 by SJL/J macrophages responding to Theiler's virus infection is associated with constitutive activation of IRF-3. Dahlberg, A., Auble, M.R., Petro, T.M. Virology (2006) [Pubmed]
  2. In vivo interferon regulatory factor 3 tumor suppressor activity in B16 melanoma tumors. Duguay, D., Mercier, F., Stagg, J., Martineau, D., Bramson, J., Servant, M., Lin, R., Galipeau, J., Hiscott, J. Cancer Res. (2002) [Pubmed]
  3. Involvement of the I{kappa}B Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation. Bibeau-Poirier, A., Gravel, S.P., Cl??ment, J.F., Rolland, S., Rodier, G., Coulombe, P., Hiscott, J., Grandvaux, N., Meloche, S., Servant, M.J. J. Immunol. (2006) [Pubmed]
  4. Induction of Innate Immunity against Herpes Simplex Virus Type 2 Infection via Local Delivery of Toll-Like Receptor Ligands Correlates with Beta Interferon Production. Gill, N., Deacon, P.M., Lichty, B., Mossman, K.L., Ashkar, A.A. J. Virol. (2006) [Pubmed]
  5. The host response to West Nile Virus infection limits viral spread through the activation of the interferon regulatory factor 3 pathway. Fredericksen, B.L., Smith, M., Katze, M.G., Shi, P.Y., Gale, M. J. Virol. (2004) [Pubmed]
  6. Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Ronco, L.V., Karpova, A.Y., Vidal, M., Howley, P.M. Genes Dev. (1998) [Pubmed]
  7. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Stetson, D.B., Medzhitov, R. Immunity (2006) [Pubmed]
  8. IkappaBNS inhibits induction of a subset of Toll-like receptor-dependent genes and limits inflammation. Kuwata, H., Matsumoto, M., Atarashi, K., Morishita, H., Hirotani, T., Koga, R., Takeda, K. Immunity (2006) [Pubmed]
  9. The specific and essential role of MAVS in antiviral innate immune responses. Sun, Q., Sun, L., Liu, H.H., Chen, X., Seth, R.B., Forman, J., Chen, Z.J. Immunity (2006) [Pubmed]
  10. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Sato, M., Suemori, H., Hata, N., Asagiri, M., Ogasawara, K., Nakao, K., Nakaya, T., Katsuki, M., Noguchi, S., Tanaka, N., Taniguchi, T. Immunity (2000) [Pubmed]
  11. Differential activation of IFN regulatory factor (IRF)-3 and IRF-5 transcription factors during viral infection. Cheng, T.F., Brzostek, S., Ando, O., Van Scoy, S., Kumar, K.P., Reich, N.C. J. Immunol. (2006) [Pubmed]
  12. The GRIP1:IRF3 interaction as a target for glucocorticoid receptor-mediated immunosuppression. Reily, M.M., Pantoja, C., Hu, X., Chinenov, Y., Rogatsky, I. EMBO J. (2006) [Pubmed]
  13. Interferon regulatory factor 3 is required for viral induction of beta interferon in primary cardiac myocyte cultures. Noah, D.L., Blum, M.A., Sherry, B. J. Virol. (1999) [Pubmed]
  14. Antiviral gene expression in rheumatoid arthritis: role of IKKepsilon and interferon regulatory factor 3. Sweeney, S.E., Mo, L., Firestein, G.S. Arthritis Rheum. (2007) [Pubmed]
  15. Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Youn, H.S., Saitoh, S.I., Miyake, K., Hwang, D.H. Biochem. Pharmacol. (2006) [Pubmed]
  16. Differential requirement for TANK-binding kinase-1 in type I interferon responses to toll-like receptor activation and viral infection. Perry, A.K., Chow, E.K., Goodnough, J.B., Yeh, W.C., Cheng, G. J. Exp. Med. (2004) [Pubmed]
  17. IRF3-dependent type I interferon response in B cells regulates CpG-mediated antibody production. Oganesyan, G., Saha, S.K., Pietras, E.M., Guo, B., Miyahira, A.K., Zarnegar, B., Cheng, G. J. Biol. Chem. (2008) [Pubmed]
  18. Involvement of the IRF family transcription factor IRF-3 in virus-induced activation of the IFN-beta gene. Sato, M., Tanaka, N., Hata, N., Oda, E., Taniguchi, T. FEBS Lett. (1998) [Pubmed]
  19. Gene induction pathways mediated by distinct IRFs during viral infection. Nakaya, T., Sato, M., Hata, N., Asagiri, M., Suemori, H., Noguchi, S., Tanaka, N., Taniguchi, T. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  20. Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Saitoh, T., Tun-Kyi, A., Ryo, A., Yamamoto, M., Finn, G., Fujita, T., Akira, S., Yamamoto, N., Lu, K.P., Yamaoka, S. Nat. Immunol. (2006) [Pubmed]
  21. Induction of RANTES/CCL5 by herpes simplex virus is regulated by nuclear factor kappa B and interferon regulatory factor 3. Melchjorsen, J., Paludan, S.R. J. Gen. Virol. (2003) [Pubmed]
  22. Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7. Sato, M., Hata, N., Asagiri, M., Nakaya, T., Taniguchi, T., Tanaka, N. FEBS Lett. (1998) [Pubmed]
  23. Lipopolysaccharide activates the expression of ISG15-specific protease UBP43 via interferon regulatory factor 3. Malakhova, O., Malakhov, M., Hetherington, C., Zhang, D.E. J. Biol. Chem. (2002) [Pubmed]
  24. Regulation of DNA-raised immune responses by cotransfected interferon regulatory factors. Sasaki, S., Amara, R.R., Yeow, W.S., Pitha, P.M., Robinson, H.L. J. Virol. (2002) [Pubmed]
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