IRF component

  1. Discovery:

    IRF-7

    IRF-7 were first discovered by Dr. Luwen Zhang's group in the School of Biological Sciences at the University of Nebraska-Lincoln in 1997. Function: IRF- 7 is very important in viral latency, immune regulation, and host defense mechanisms. Epstein-Barr virus (EBV) latency is the best available system to study the functions of IRF-7.

    IRF-3

    IRF-3 were identified and named by Dr. Pitha,PM group in John Hopkins School of Medicine in 1995. Function: increasing transcriptional activity of targeted promoters. The IRF-3 gene is present in a single copy in human genomic DNA.

    IRF Experiment ID 10399
    Pattern Id: GC10095
    Clone number: 489387
    GenBank Acc: AA054502

  2. Function:

    3. Interferon (IFN) regulatory factors (IRFs) are a family of transcription factors which consist of nine members and several viral IRFs homologs so far. They play an essential role in the regulated expression of type I IFN genes, IFN-stimulated genes (ISG), and other cytokins and chemokines. IRFs bind to a specific DNA sequence, which is termed interferon response element (IRF-E; consensus sequence AANNGAAA), located in the promoter region of their target genes. IRF-3, IRF-5, IRF-7 are identified as acting as direct transducers of virus-mediated signaling. In infected cell, these factors are activated by phosphotulation on the serine residues, transported to the nucleus, where they bind to the promoters of IFNA and IFNB genes and tether histone transacetylases to the transcription complex enhanceosome. The ratio of IRF-3 and IRF-7 was shown to play an important role in the inducible expression of type I IFN genes.

  3. Structure:

    PDB files from the protein data bank:

    1IF1

    Structure of IRF-1 (Mus Musculus) bound in the DNA major groove. View is along the axis of the binding helix of the H-T-H motif:

    2IRF

    Structure of IRF-2 (Mus Musculus) bound in the DNA major groove. View is along the axis of the binding helix of the H-T-H motif:

    Structure of IRF-2, from a different perspective:

  4. References :

    1. Zhang, L. and J.S. Pagano. IRF-7, a new interferon regulatory factor associated with Epstein-Barr virus latency. Mol. Cell. Biol. 17:5748-5757, 1997.
    2. Zhang, L. and J.S. Pagano. Interferon regulatory factor 7 is induced by Epstein-Barr virus latent membrane protein 1. J. Virol. 74:5748-57. 2000.
    3. Zhang, L. and J.S. Pagano. Interferon regulatory factor 7 mediates the activation of the transporter associated with antigen processing 2 (Tap-2) by Epstein-Barr virus latent membrane protein 1. J. Virol. 75:341-350. 2000.
    4. Zhang, L. and J.S. Pagano. Interferon Regulatory Factor 7: a Key Cellular Mediator of LMP-1 in EBV Latency and Transformation. Seminars in Cancer Biology. 11: 445-453, 2001.
    5. Zhang, L., L. Wu, K. Hong, and J.S. Pagano. Intracellular signaling molecules activated by Epstein Barr virus for induction of interferon regulatory factor 7. J. Virol. 75:12393-401, 2001.
    6. Lu, R., and Pitha, P.M. Monocyte differentiation to macrophase requires interferon regulatory factor 7, J. Biol. Chem., 276, 2001. In press.
    7. Au, W.-C., Moore, P.A., LaFleur, D.W., Tombal, B., and Pitha, P.M. (1998) Characterization of the interferon regulatory factor-7, and its potential role in the transcription activation of interferon A genes. J. Biol. Chem. 273, 29210.
    8. Zhang, LW, Pagano, JS. Structure and function of IRF-7. Journal of interferon and cytokine research 22(1): 95-101 2002
    9. Au, WC, Yeow, WS, Pitha, PM Analysis of functional domains of interferon regulatory factor 7 and its association with IRF-3 Virology 280 (2) :273-287 2001
    10. Au, W.-C., Moore, P.A., Lowther, W., Juang, Y.-T., and Pitha, P.M. (1995) 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. Proc. Natl. Acad. Sci. USA 92, 11657.
    11. Juang, Y.-T., Lowther, W., Kellum, M., Au, W.-C., Lin, R., Hiscott, J., and Pitha, P.M. (1998) Primary activation of interferon A and interferon B gene transcription by interferon regulatory factor 3. Proc. Natl. Acad. Sci. USA 95, 9837.
    12. Lubyova, B., Pitha, P.M. Characterization of a Novel Human Herpesvirus 8- Encoded protein, vIRF-3, that Shows Homology to Viral and Cellular Interferon Regulatory Factors. J. Virol. 74:8194, 2000.
    13. Kim, T., Kim, T.Y., Song, Y.-H., Min, I.M., Yim, J., and Kim, T.K. Activation of IRF3 in response to DNA damaging agents. J. Biol. Chem. 274: 30686, 1999.
    14. Juang YT, Lowther W, Kellum M, Au WC, Lin R, Hiscott J, Pitha PM. Primary activation of IFNa and IFN§ gene expression by IRF-3. Proc. Nat. Acad. Sci. 95: 9837-9842 (1998).
    15. Lin R, Heylbroeck C, Pitha PM, Hiscott J. Virus dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential and proteasome mediated degradation. Mol. Cell. Biol. 18: 2986-2996 (1998).
    16. Lin R, Heylbroeck C, Genin P, Pitha PM, Hiscott J. Essential role of IRF-3 in direct activation of RANTES gene transcription. Mol Cell Biol. 19: 959-966 (1999).
    17. Hiscott J, Pitha P, Genin P, Nguyen H, Heylbroeck C, Mamane Y, Algarte M, Lin R. Triggering the interferon response: the role of IRF-3 transcription factor. J. Interferon Cytokine Res. 19: 1-14 (1999).
    18. Schafer SL, Lin RT, Moore PA, Hiscott J, Pitha PM Regulation of type I interferon gene expression by interferon regulatory factor-3 journal of biological chemistry 273 (5): 2714-2720 1998
    19. Lin RT, Mamane Y, Hiscott J Structural and functional analysis of interferonregulatory factor 3 : localization of the transactivation and autoinhibitory domains Molecular and cellular biology 19(4) : 2465-2474 1999
    20. Monocyte differentiation to macrophage requires interferon regulator factor 7 Lu RQ, Pitha PM JOURNAL OF BIOLOGICAL CHEMISTRY 276 (48): 45491-45496 NOV 30 2001
    21. On the role of IRF in host defense Barnes B, Lubyova B, Pitha PM JOURNAL OF INTERFERON AND CYTOKINE RESEARCH 22 (1): 59-71 JAN 2002
    22. Nguyen, H., Hiscott, J., and Pitha, P. M. (1997) Cytokine Growth Factor Rev. 8, 293-312
    23. Taniguchi, T., Ogasawara, K., Takaoka, A., and Tanaka, N. (2001) Annu. Rev. Immunol. 19, 623-655
    24. Lohoff, M., Duncan, G. S., Ferrick, D., Mittrucker, H. W., Bischof, S., Prechtl, S., Rollinghoff, M., Schmitt, E., Pahl, A., and Mak, T. W. (2000) J. Exp. Med. 192, 325-336
    25. Escalante, C. R. et al., Structure of IRF-1 with Bound DNA Reveals Determinants of Interferon Regulation, Nature, 391, pp.103 (1998)
    26. Fuji, Y. et al., Crystal Structure of an IRF-DNA Complex Reveals Novel DNA Recognition and Cooperative Binding to a Tandem Repeat of Core Sequence, EMBO J., 18, pp.5028 (1999)

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