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Gene Review

IRF7  -  interferon regulatory factor 7

Homo sapiens

Synonyms: IRF-7, IRF-7H, IRF7A, IRF7B, IRF7C, ...
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Disease relevance of IRF7

  • Therefore, manipulation of the stability and function of IRF7 by the KSHV RTA transcription factor provides an unexpected regulatory strategy for circumventing the innate immune defence system [1].
  • In cells transiently expressing IRF7 or/and IRF3, the VAF level and binding of VAF are clearly increased after Sendai virus infection [2].
  • We have reported evidence for a positive regulatory circuit between interferon regulatory factor 7 (IRF7) and the Epstein-Barr virus (EBV) oncoprotein 1 (LMP1) (S. Ning, A. M. Hahn, and J. S. Pagano, J. Virol. 77:9359-9368, 2003) [3].
  • The herpes simplex virus ICP0 RING finger domain inhibits IRF3- and IRF7-mediated activation of interferon-stimulated genes [4].
  • We have further shown that the previously observed lack of expression of IRF-7 in 2fTGH fibrosarcoma cell line, correlated with hypermethylation of the CpG island in the human IRF-7 promoter [5].

High impact information on IRF7

  • 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 [6].
  • The MyD88 adaptor, which is essential for signaling by many TLRs, recruits members of the IFN regulatory factor (IRF) family of transcription factors, such as IRF5 and IRF7, to evoke the activation of TLR target genes [7].
  • By blocking the phosphorylation and nuclear translocation of IRF-7, ORF45 efficiently inhibits the activation of interferon alpha and beta genes during viral infection [8].
  • We demonstrate for the first time that RIP activates IRF7 and that RIP and IRF7 interact under physiological conditions in EBV-positive Burkitt's lymphoma cells [9].
  • Although IRF-7 was up-regulated by TNF and RA in all cells tested, expression of c-jun and PU.1 correlated with monocytic differentiation [10].

Chemical compound and disease context of IRF7


Biological context of IRF7

  • Although it is likely that IRF7 is subjected to a cascade of events responsible for regulating its biological activity, to date no mechanism other than phosphorylation has been reported to modulate IRF7 activity [12].
  • Together, our results strongly suggest that acetylation of lysine 92 negatively modulates IRF7 DNA binding [12].
  • Although it is now clear that IFN regulatory factor 7 (IRF7) is a multifunctional gene essential for induction of type I IFNs, regulation of the IRF7 promoter (IRF7p) is poorly understood [2].
  • In this study, IRF7 was shown first to activate LMP1p in transient transfection assays [13].
  • Moreover, IRF7 can regulate a viral gene in addition to a host cellular gene such as the IFN-beta gene [13].

Anatomical context of IRF7

  • Here we report the stimulation of IRF-7 expression by 12-O-tetradecanoylphorbol-13-acetate (TPA) and tumor necrosis factor alpha (TNFalpha) in human peripheral blood monocytes [14].
  • In vitro methylation of IRF-7 promoter silenced IRF-7 directed expression of luciferase gene in HeLa cells that express endogenous IRF-7 gene [5].
  • Within cutaneous LE lesions, PDCs accumulated within the dermis and were activated to produce type I IFN, as detected by the expression of the IFNalpha-inducible genes IRF7 and MxA [15].
  • However, the number of IRF7-positive cells was found to be elevated in the reactive hyperplastic lymph nodes and pediatric lymphoma [16].
  • However, IRF7 was expressed strongly in the nuclei of over 50% of the lymphocytes throughout the normal lymph nodes, but the histiocytes and fibroblasts were spared [16].

Associations of IRF7 with chemical compounds


Physical interactions of IRF7

  • However, a mutant that cannot be acetylated by PCAF due to a change in the surrounding amino acid context of lysine 92 showed increased DNA binding and activity compared with wild type IRF7 [12].
  • Furthermore, we find that IRF-7 interacts with four distinct regions of p300/CBP [21].
  • The region by which IRF-7 interacts with IRF-3 was mapped between amino acid 418 and 473 [22].
  • In this study, we demonstrate that TRIF interacts with both IRF-7 and IRF-3 [23].

Regulatory relationships of IRF7

  • RSV infection induces binding of STAT to the IRF-1 gamma-interferon-activated sequence (GAS) and IRF-7 interferon-stimulated responsive element (ISRE) [24].
  • Previously, we characterized human IRF-7 promoter and showed that an interferon-stimulated response element site in the first intron binds interferon-stimulated gene factor 3 (ISGF3) and confers the response to interferon [14].
  • Nuclear proteins from infected and uninfected IRF-7 expressing 2FTGH cells formed multiple DNA-protein complexes with IFNA1 VRE, in which two unique DNA-protein complexes containing IRF-7 were detected [25].
  • Furthermore, IRF7 was activated by the c-Jun NH2-terminal kinase (JNK) in response to DNA-damaging agents [26].
  • Activation of JNK by mitogen-activated protein kinase kinase-4 stimulated the transcriptional activity of IRF7 and induced its translocation into the nucleus [26].

Other interactions of IRF7

  • Acetylation of interferon regulatory factor-7 by p300/CREB-binding protein (CBP)-associated factor (PCAF) impairs its DNA binding [12].
  • IRF5 and IRF7, therefore, emerge from these studies as critical mediators of TLR7 signaling [27].
  • Endogenous IRF5 and IRF7 proteins were shown to physically associate in EBV-positive cells [3].
  • We observed no effect of gamma interferon on Qp activity in transfection assays, whereas we observed a moderate but significant repression of Qp activity in response to alpha interferon, possibly mediated by either the interferon consensus sequence binding protein or IRF-7, a novel alpha interferon-inducible factor identified in this study [28].
  • Moreover, IFNalpha2a directly modulates the expression of: (i) important transcriptional factors, e.g. IRF1 and IRF7 which control pivotal cellular events, and (ii) enzymes involved in the IFNalpha2a-dependent antiviral and apoptotic response [29].

Analytical, diagnostic and therapeutic context of IRF7

  • Two of these proteins, IRF-3 and IRF-7, serve as direct transducers of virus-mediated signaling and play critical roles in the induction of type I interferon genes [30].
  • Using promoter analysis in combination with electrophoretic mobility shift assays, we have demonstrated that an NFkappaB site located next to the TATA box, binds p50 and p65 heterodimer and is required for the induction of the IRF-7 gene by TPA and TNFalpha [14].
  • We show by chromatin immunoprecipitation assay that treatment with the TOPII inhibitor etoposide induces association of acetylated histone 3 with the promoter of IRF-7 gene, indicating that TOPII-mediated changes in chromatin structure could be responsible for the induction [14].
  • Western immunoblot and immunohistochemical analyses confirmed that the cellular IRF7 protein levels were strongly upregulated during the early lytic cycle both in KSHV-infected DMVEC and in the body cavity-based lymphoma BCBL1 PEL cell line [31].
  • To define the role of IRFs in lymphoid disorders, we determined the expression patterns of IRF3 and IRF7 by immunohistochemistry in 5 normal lymph nodes, 12 reactive hyperplastic lymph nodes, and 27 pediatric lymphomas [16].


  1. The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Yu, Y., Wang, S.E., Hayward, G.S. Immunity (2005) [Pubmed]
  2. 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]
  3. Interferon regulatory factor 5 represses expression of the Epstein-Barr virus oncoprotein LMP1: braking of the IRF7/LMP1 regulatory circuit. Ning, S., Huye, L.E., Pagano, J.S. J. Virol. (2005) [Pubmed]
  4. 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]
  5. Regulation of the promoter activity of interferon regulatory factor-7 gene. Activation by interferon snd silencing by hypermethylation. Lu, R., Au, W.C., Yeow, W.S., Hageman, N., Pitha, P.M. J. Biol. Chem. (2000) [Pubmed]
  6. 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]
  7. Evidence for licensing of IFN-{gamma}-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program. Negishi, H., Fujita, Y., Yanai, H., Sakaguchi, S., Ouyang, X., Shinohara, M., Takayanagi, H., Ohba, Y., Taniguchi, T., Honda, K. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. A Kaposi's sarcoma-associated herpesviral protein inhibits virus-mediated induction of type I interferon by blocking IRF-7 phosphorylation and nuclear accumulation. Zhu, F.X., King, S.M., Smith, E.J., Levy, D.E., Yuan, Y. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  9. Interferon Regulatory Factor 7 Is Activated by a Viral Oncoprotein through RIP-Dependent Ubiquitination. Huye, L.E., Ning, S., Kelliher, M., Pagano, J.S. Mol. Cell. Biol. (2007) [Pubmed]
  10. Combination of retinoic acid and tumor necrosis factor overcomes the maturation block in a variety of retinoic acid-resistant acute promyelocytic leukemia cells. Witcher, M., Shiu, H.Y., Guo, Q., Miller, W.H. Blood (2004) [Pubmed]
  11. Clinical manifestations, management, and molecular genetics in congenital factor VII deficiency: the International Registry on Congenital Factor VII Deficiency (IRF7). Mariani, G., Herrmann, F.H., Bernardi, F., Schved, J.F., Auerswald, G., Ingerslev, J. Blood (2000) [Pubmed]
  12. Acetylation of interferon regulatory factor-7 by p300/CREB-binding protein (CBP)-associated factor (PCAF) impairs its DNA binding. Caillaud, A., Prakash, A., Smith, E., Masumi, A., Hovanessian, A.G., Levy, D.E., Marié, I. J. Biol. Chem. (2002) [Pubmed]
  13. Interferon regulatory factor 7 regulates expression of Epstein-Barr virus latent membrane protein 1: a regulatory circuit. Ning, S., Hahn, A.M., Huye, L.E., Pagano, J.S. J. Virol. (2003) [Pubmed]
  14. Stimulation of IRF-7 gene expression by tumor necrosis factor alpha: requirement for NFkappa B transcription factor and gene accessibility. Lu, R., Moore, P.A., Pitha, P.M. J. Biol. Chem. (2002) [Pubmed]
  15. Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: An amplification cycle triggering cutaneous lupus erythematosus. Meller, S., Winterberg, F., Gilliet, M., Müller, A., Lauceviciute, I., Rieker, J., Neumann, N.J., Kubitza, R., Gombert, M., Bünemann, E., Wiesner, U., Franken-Kunkel, P., Kanzler, H., Dieu-Nosjean, M.C., Amara, A., Ruzicka, T., Lehmann, P., Zlotnik, A., Homey, B. Arthritis Rheum. (2005) [Pubmed]
  16. 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]
  17. Virus-induced heterodimer formation between IRF-5 and IRF-7 modulates assembly of the IFNA enhanceosome in vivo and transcriptional activity of IFNA genes. Barnes, B.J., Field, A.E., Pitha-Rowe, P.M. J. Biol. Chem. (2003) [Pubmed]
  18. Multiple regulatory domains control IRF-7 activity in response to virus infection. Lin, R., Mamane, Y., Hiscott, J. J. Biol. Chem. (2000) [Pubmed]
  19. Regulation of B7.1 costimulatory molecule is mediated by the IFN regulatory factor-7 through the activation of JNK in lipopolysaccharide-stimulated human monocytic cells. Lim, W., Gee, K., Mishra, S., Kumar, A. J. Immunol. (2005) [Pubmed]
  20. Characterization of the interferon regulatory factor-7 and its potential role in the transcription activation of interferon A genes. Au, W.C., Moore, P.A., LaFleur, D.W., Tombal, B., Pitha, P.M. J. Biol. Chem. (1998) [Pubmed]
  21. Interferon regulatory factor-7 synergizes with other transcription factors through multiple interactions with p300/CBP coactivators. Yang, H., Lin, C.H., Ma, G., Baffi, M.O., Wathelet, M.G. J. Biol. Chem. (2003) [Pubmed]
  22. 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]
  23. Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways. Han, K.J., Su, X., Xu, L.G., Bin, L.H., Zhang, J., Shu, H.B. J. Biol. Chem. (2004) [Pubmed]
  24. Reactive oxygen species mediate virus-induced STAT activation: role of tyrosine phosphatases. Liu, T., Castro, S., Brasier, A.R., Jamaluddin, M., Garofalo, R.P., Casola, A. J. Biol. Chem. (2004) [Pubmed]
  25. Reconstitution of virus-mediated expression of interferon alpha genes in human fibroblast cells by ectopic interferon regulatory factor-7. Yeow, W.S., Au, W.C., Juang, Y.T., Fields, C.D., Dent, C.L., Gewert, D.R., Pitha, P.M. J. Biol. Chem. (2000) [Pubmed]
  26. Chemotherapeutic DNA-damaging drugs activate interferon regulatory factor-7 by the mitogen-activated protein kinase kinase-4-cJun NH2-terminal kinase pathway. Kim, T.K., Kim, T., Kim, T.Y., Lee, W.G., Yim, J. Cancer Res. (2000) [Pubmed]
  27. The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling. Schoenemeyer, A., Barnes, B.J., Mancl, M.E., Latz, E., Goutagny, N., Pitha, P.M., Fitzgerald, K.A., Golenbock, D.T. J. Biol. Chem. (2005) [Pubmed]
  28. Interferon-independent and -induced regulation of Epstein-Barr virus EBNA-1 gene transcription in Burkitt lymphoma. Nonkwelo, C., Ruf, I.K., Sample, J. J. Virol. (1997) [Pubmed]
  29. Genes transcriptionally modulated by interferon alpha2a correlate with the cytokine activity. Iolascon, A., Volinia, S., Borriello, A., Giordani, L., Moretti, A., Servedio, V., Maiorano, N., Cucciolla, V., Criniti, V., Gasparini, P., Indaco, S., Della Ragione, F. Haematologica (2004) [Pubmed]
  30. 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]
  31. Altered patterns of cellular gene expression in dermal microvascular endothelial cells infected with Kaposi's sarcoma-associated herpesvirus. Poole, L.J., Yu, Y., Kim, P.S., Zheng, Q.Z., Pevsner, J., Hayward, G.S. J. Virol. (2002) [Pubmed]
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