Interferon Regulatory Factor Transcription Factors Proteins


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 Interferon Regulatory Factor Transcription Factors Proteins Background

Three members of the Interferon Regulatory Factor (IRF) family, IRF 3, 5, and 7 have been shown to be involved in TLR signaling. However, these and the other members of the IRF family have diverse roles, not only in innate immunity, but in mediating cell growth signals and development of cells of the adaptive immune system. Members of this family of transcription factors share a conserved DNA-binding domain of approximately 120 amino acids in their N-terminus. This domain forms a helix-tum-helix motif which binds to IFN-stimulated response elements (ISRE, also known as IRF-E). In the type I IFN gene promoter regions, VREs (virus-responsive elements) contain ISREs as well as sites for other transcription factors. The C-terminal domains of all IRFs, except IRF-1 and IRF-2, share homology with the C-terminal domains of the Smad family transcription factors. 
IRF-1 was the first IRF family member discovered and was identified by its role in type I IFN promoter activation. In addition, IRF-1 was found to activate transcription of the p21 gene along with p53. Much work has been done defining the role of IRF-1 as a tumor suppressor. Loss of both IRF-1 and p53 results in a higher incidence of tumor formation. In addition to its ability to transactivate the p21 promoter, full activation of p21 in irradiated cells requires both IRF-1 and p53. This cooperation is thought to be mediated by ATM kinase. The cross-talk between p53 and IRF-1 became more defined when it was found that IRF-1 stimulates p53 acetylation by stabilization of the interaction between p300 and p53. This stabilization enhanced p53 activity. IRF-1 is also required for inducing apoptosis in mitogenically activated mature T lymphocytes and plays a role in many stages of TH1 mediated immune response. 
IRF-2 was discovered as a factor that is structurally related to IRF-1. IRF-2 represses IRF-1 transcriptional activation and its overexpression can induce transformation in NIH3T3 cells. 
IRF-3 mediates apoptosis resulting from Sendai Virus infection; a mutant IRF-3 with a N-terminal deletion blocks apoptosis after Sendai Virus infection. A constitutively phosphorylated, and thus activated IRF-3 also induces apoptosis through the same pathway which activates caspase 8, caspase 9, and caspase 3. After virus infection, IRF-3 has also been shown to be an in vivo target of DNA-PK, a kinase that is activated by DNA damage. In addition, TRAIL, an important member of the apoptotic pathway, is upregulated by IRF-3 after paramyxovirus infection. 
IRF-4 is involved in T and B cell development, regulation of TLR signaling, and has been shown to have oncogene-like properties in certain settings. IRF-5, besides its role in TLR signaling and the induction of pro-inflammatory cytokines and IFN, is a target of p53 transcriptional activation, can inhibit soft agar colony growth of cancer cell lines, and induces transcription of several genes related to apoptosis and cell cycle arrest. IRF-6 has not yet been characterized. Although IRF-7 plays a very important role in innate immunity, other functions have yet to be described. 
IRF-8, otherwise known as interferon consensus sequence binding protein (ICSBP), was originally identified as a protein that binds to the ISRE in the promoter of the MHC class I gene, H-2L. It is required for development along the lymphoid and myeloid lineages. IRF-8 increases its affinity for binding DNA through interaction with other IRFs and transcription factors. IRF-8 knock out mice manifest a syndrome similar to human chronic myelogenous leukemia (CML). The role of IRF-9, which is also called p48/ISGF3Y, in the interferon system, is well described. There are indications that IRF-9 may be involved in oncogenesis; the p48 gene is regulated by c-myc.