IRF3

IRF3 is a member of the interferon regulatory transcription factor (IRF) family. IRF3 was originally discovered as a homolog of IRF1 and IRF2. IRF3 has been further characterized and shown to contain several functional domains including a nuclear export signal, a DNA-binding domain, a C-terminal IRF association domain and several regulatory phosphorylation sites.{{cite journal | vauthors = Lin R, Heylbroeck C, Genin P, Pitha PM, Hiscott J | title = Essential Role of Interferon Regulatory Factor 3 in Direct Activation of RANTES Chemokine Transcription | journal = Mol Cell Biol | volume = 19 | issue = 2 | pages = 959–66 | date = Feb 1999 | pmid = 9891032 | pmc = 116027 | doi = 10.1128/MCB.19.2.959}} IRF3 is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP.{{cite journal | vauthors = Yoneyama M, Suhara W, Fujita T | title = Control of IRF-3 activation by phosphorylation | journal = J. Interferon Cytokine Res. | volume = 22 | issue = 1 | pages = 73–6 | year = 2002 | pmid = 11846977 | doi = 10.1089/107999002753452674 }} The complex translocates into the nucleus for the transcriptional activation of interferons alpha and beta, and further interferon-induced genes.{{cite web | title = Entrez Gene: IRF3 interferon regulatory factor 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3661}}

IRF3 plays an important role in the innate immune system's response to viral infection.{{cite journal | vauthors = Collins SE, Noyce RS, Mossman KL | title = Innate Cellular Response to Virus Particle Entry Requires IRF3 but Not Virus Replication | journal = J Virol | volume = 78 | issue = 4 | pages = 1706–17 | date = Feb 2004 | pmid = 14747536 | pmc = 369475 | doi = 10.1128/JVI.78.4.1706-1717.2004 }} Aggregated MAVS have been found to activate IRF3 dimerization.{{cite journal | vauthors = Hou F, Sun L, Zheng H, Skaug B, Jiang QX, Chen ZJ | title = MAVS Forms Functional Prion-Like Aggregates To Activate and Propagate Antiviral Innate Immune Response | journal = Cell | volume = 146 | issue = 3 | pages = 448–61 | date = Aug 5, 2011 | pmid = 21782231 | pmc = 3179916 | doi = 10.1016/j.cell.2011.06.041 }} A 2015 study shows phosphorylation of innate immune adaptor proteins MAVS, STING and TRIF at a conserved pLxIS motif recruits and specifies IRF3 phosphorylation and activation by the Serine/threonine-protein kinase TBK1, thereby activating the production of type-I interferons.{{cite journal | vauthors = Liu S, Cai X, Wu J, Cong Q, Chen X, Li T, Du F, Ren J, Wu Y, Grishin N, and Chen ZJ | title = Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. | journal = Science | volume = 347 | issue = 6227 | pages = aaa2630 | date = Mar 13, 2015 | pmid = 25636800 | doi = 10.1126/science.aaa2630 | doi-access = free }} Another study has shown that IRF3-/- knockouts protect from myocardial infarction.{{cite journal | vauthors = King KR, Aguirre AD, Ye YX, Sun Y, Roh JD, Ng Jr RP, Kohler RH, Arlauckas SP, Iwamoto Y, Savol A, Sadreyev RI, Kelly M, Fitzgibbons TP, Fitzgerald KA, Mitchison T, Libby P, Nahrendorf M, Weissleder R | title = IRF3 and type I interferons fuel a fatal response to myocardial infarction. | journal = Nature Medicine | volume = 23 | issue = 12 | pages = 1481–1487 | date = Nov 6, 2017 | pmid = 29106401 | pmc = 6477926 | doi = 10.1038/nm.4428 }} The same study identified IRF3 and the type I IFN response as a potential therapeutic target for post-myocardial infarction cardioprotection.

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IRF3 has been shown to interact with IRF7.{{cite journal | vauthors = Au WC, Yeow WS, Pitha PM | title = Analysis of functional domains of interferon regulatory factor 7 and its association with IRF-3 | journal = Virology | volume = 280 | issue = 2 | pages = 273–82 | date = Feb 2001 | pmid = 11162841 | doi = 10.1006/viro.2000.0782 | doi-access = free }}

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• {{cite journal | vauthors = Pitha PM, Au WC, Lowther W, Juang YT, Schafer SL, Burysek L, Hiscott J, Moore PA | title = Role of the interferon regulatory factors (IRFs) in virus-mediated signaling and regulation of cell growth | journal = Biochimie | volume = 80 | issue = 8–9 | pages = 651–8 | year = 1999 | pmid = 9865487 | doi = 10.1016/S0300-9084(99)80018-2 | doi-access = free }}
• {{cite journal | vauthors = Yoneyama M, Suhara W, Fujita T | title = Control of IRF-3 activation by phosphorylation | journal = J. Interferon Cytokine Res. | volume = 22 | issue = 1 | pages = 73–6 | year = 2002 | pmid = 11846977 | doi = 10.1089/107999002753452674 }}
• {{cite journal | vauthors = Au WC, Moore PA, Lowther W, Juang YT, Pitha PM | title = 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 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 92 | issue = 25 | pages = 11657–61 | year = 1996 | pmid = 8524823 | pmc = 40461 | doi = 10.1073/pnas.92.25.11657 | doi-access = free }}
• {{cite journal | vauthors = Yoneyama M, Suhara W, Fukuhara Y, Fukuda M, Nishida E, Fujita T | title = Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300 | journal = EMBO J. | volume = 17 | issue = 4 | pages = 1087–95 | year = 1998 | pmid = 9463386 | pmc = 1170457 | doi = 10.1093/emboj/17.4.1087 }}
• {{cite journal | vauthors = Weaver BK, Kumar KP, Reich NC | title = Interferon Regulatory Factor 3 and CREB-Binding Protein/p300 Are Subunits of Double-Stranded RNA-Activated Transcription Factor DRAF1 | journal = Mol. Cell. Biol. | volume = 18 | issue = 3 | pages = 1359–68 | year = 1998 | pmid = 9488451 | pmc = 108849 | doi = 10.1128/MCB.18.3.1359}}
• {{cite journal | vauthors = Lin R, Heylbroeck C, Pitha PM, Hiscott J | title = Virus-Dependent Phosphorylation of the IRF-3 Transcription Factor Regulates Nuclear Translocation, Transactivation Potential, and Proteasome-Mediated Degradation | journal = Mol. Cell. Biol. | volume = 18 | issue = 5 | pages = 2986–96 | year = 1998 | pmid = 9566918 | pmc = 110678 | doi = 10.1128/MCB.18.5.2986}}
• {{cite journal | vauthors = Ronco LV, Karpova AY, Vidal M, Howley PM | title = Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity | journal = Genes Dev. | volume = 12 | issue = 13 | pages = 2061–72 | year = 1998 | pmid = 9649509 | pmc = 316980 | doi = 10.1101/gad.12.13.2061 }}
• {{cite journal | vauthors = Bellingham J, Gregory-Evans K, Gregory-Evans CY | title = Mapping of human interferon regulatory factor 3 (IRF3) to chromosome 19q13.3-13.4 by an intragenic polymorphic marker | journal = Annals of Human Genetics | volume = 62 | issue = Pt 3 | pages = 231–4 | year = 1999 | pmid = 9803267 | doi = 10.1046/j.1469-1809.1998.6230231.x | s2cid = 46070705 | doi-access = free }}
• {{cite journal | vauthors = Lowther WJ, Moore PA, Carter KC, Pitha PM | title = Cloning and functional analysis of the human IRF-3 promoter | journal = DNA Cell Biol. | volume = 18 | issue = 9 | pages = 685–92 | year = 1999 | pmid = 10492399 | doi = 10.1089/104454999314962 }}
• {{cite journal | vauthors = Kim T, Kim TY, Song YH, Min IM, Yim J, Kim TK | title = Activation of interferon regulatory factor 3 in response to DNA-damaging agents | journal = J. Biol. Chem. | volume = 274 | issue = 43 | pages = 30686–9 | year = 1999 | pmid = 10521456 | doi = 10.1074/jbc.274.43.30686 | doi-access = free }}
• {{cite journal | vauthors = Kumar KP, McBride KM, Weaver BK, Dingwall C, Reich NC | title = Regulated Nuclear-Cytoplasmic Localization of Interferon Regulatory Factor 3, a Subunit of Double-Stranded RNA-Activated Factor 1 | journal = Mol. Cell. Biol. | volume = 20 | issue = 11 | pages = 4159–68 | year = 2000 | pmid = 10805757 | pmc = 85785 | doi = 10.1128/MCB.20.11.4159-4168.2000 }}
• {{cite journal | vauthors = Suhara W, Yoneyama M, Iwamura T, Yoshimura S, Tamura K, Namiki H, Aimoto S, Fujita T | title = Analyses of virus-induced homomeric and heteromeric protein associations between IRF-3 and coactivator CBP/p300 | journal = J. Biochem. | volume = 128 | issue = 2 | pages = 301–7 | year = 2000 | pmid = 10920266 | doi = 10.1093/oxfordjournals.jbchem.a022753 }}
• {{cite journal | vauthors = Servant MJ, ten Oever B, LePage C, Conti L, Gessani S, Julkunen I, Lin R, Hiscott J | title = Identification of distinct signaling pathways leading to the phosphorylation of interferon regulatory factor 3 | journal = J. Biol. Chem. | volume = 276 | issue = 1 | pages = 355–63 | year = 2001 | pmid = 11035028 | doi = 10.1074/jbc.M007790200 |doi-access=free }}
• {{cite journal | vauthors = Smith EJ, Marié I, Prakash A, García-Sastre A, Levy DE | title = IRF3 and IRF7 phosphorylation in virus-infected cells does not require double-stranded RNA-dependent protein kinase R or Ikappa B kinase but is blocked by Vaccinia virus E3L protein | journal = J. Biol. Chem. | volume = 276 | issue = 12 | pages = 8951–7 | year = 2001 | pmid = 11124948 | doi = 10.1074/jbc.M008717200 | doi-access = free }}
• {{cite journal | vauthors = Au WC, Yeow WS, Pitha PM | title = Analysis of functional domains of interferon regulatory factor 7 and its association with IRF-3 | journal = Virology | volume = 280 | issue = 2 | pages = 273–82 | year = 2001 | pmid = 11162841 | doi = 10.1006/viro.2000.0782 | doi-access = free }}
• {{cite journal | vauthors = Barnes BJ, Moore PA, Pitha PM | title = Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes | journal = J. Biol. Chem. | volume = 276 | issue = 26 | pages = 23382–90 | year = 2001 | pmid = 11303025 | doi = 10.1074/jbc.M101216200 | doi-access = free }}
• {{cite journal | vauthors = Mach CM, Hargrove BW, Kunkel GR | title = The Small RNA gene activator protein, SphI postoctamer homology-binding factor/selenocysteine tRNA gene transcription activating factor, stimulates transcription of the human interferon regulatory factor-3 gene | journal = J. Biol. Chem. | volume = 277 | issue = 7 | pages = 4853–8 | year = 2002 | pmid = 11724783 | doi = 10.1074/jbc.M108308200 | doi-access = free }}
• {{cite journal | vauthors = Morin P, Bragança J, Bandu MT, Lin R, Hiscott J, Doly J, Civas A | title = Preferential binding sites for interferon regulatory factors 3 and 7 involved in interferon-A gene transcription | journal = J. Mol. Biol. | volume = 316 | issue = 5 | pages = 1009–22 | year = 2002 | pmid = 11884139 | doi = 10.1006/jmbi.2001.5401 }}
• {{cite journal | vauthors = Dang O, Navarro L, Anderson K, David M | title = Cutting edge: anthrax lethal toxin inhibits activation of IFN-regulatory factor 3 by lipopolysaccharide | journal = Journal of Immunology | volume = 172 | issue = 2 | pages = 747–51 | year = 2004 | pmid = 14707042 | doi = 10.4049/jimmunol.172.2.747 | doi-access = free }}

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{{Commons category|Interferon regulatory factor 3, IRF-3}}

• {{MeshName|Interferon+Regulatory+Factor-3}}
• {{FactorBook|IRF3}}

{{PDB Gallery|geneid=3661}}

{{Adaptor proteins}}

{{Transcription factors|g3}}

{{TLR signaling pathway}}

{{JAK-STAT signaling pathway}}

Category:Transcription factors