ID:IRF3_HUMAN DESCRIPTION: RecName: Full=Interferon regulatory factor 3; Short=IRF-3; FUNCTION: Key transcriptional regulator of type I interferon (IFN)-dependent immune responses and plays a critical role in the innate immune response against DNA and RNA viruses. Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters. Acts as a more potent activator of the IFN-beta (IFNB) gene than the IFN-alpha (IFNA) gene and plays a critical role in both the early and late phases of the IFNA/B gene induction. Found in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, becomes phosphorylated by IKBKE and TBK1 kinases. This induces a conformational change, leading to its dimerization and nuclear localization and association with CREB binding protein (CREBBP) to form dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I IFN and ISG genes. Can activate distinct gene expression programs in macrophages and can induce significant apoptosis in primary macrophages. ENZYME REGULATION: In the absence of viral infection, maintained as a monomer in an autoinhibited state and phosphorylation disrupts this autoinhibition leading to the liberation of the DNA- binding and dimerization activities and its nuclear localization where it can activate type I IFN and ISG genes. SUBUNIT: Monomer. Homodimer; phosphorylation-induced. Heterodimer with IRF7. Interacts with CREBBP. May interact with MAVS. Interacts with IKBKE and TBK1. Interacts with TICAM1 and TICAM2. Interacts with rotavirus A NSP1 (via C-terminus); this interaction leads to the proteasome-dependent degradation of IRF3. Interacts with RBCK1. Interacts with TRIM21. Interacts with HERC5. INTERACTION: Self; NbExp=9; IntAct=EBI-2650369, EBI-2650369; Q92793:CREBBP; NbExp=3; IntAct=EBI-2650369, EBI-81215; Q9Y5Q3:MAFB; NbExp=4; IntAct=EBI-2650369, EBI-3649340; P06400:RB1; NbExp=2; IntAct=EBI-2650369, EBI-491274; P28749:RBL1; NbExp=2; IntAct=EBI-2650369, EBI-971402; O43765:SGTA; NbExp=3; IntAct=EBI-2650369, EBI-347996; Q9UHD2:TBK1; NbExp=4; IntAct=EBI-2650369, EBI-356402; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Shuttles between cytoplasmic and nuclear compartments, with export being the prevailing effect. When activated, IRF3 interaction with CREBBP prevents its export to the cytoplasm. TISSUE SPECIFICITY: Expressed constitutively in a variety of tissues. PTM: Constitutively phosphorylated on many serines residues. C- terminal serine/threonine cluster is phosphorylated in response of induction by IKBKE and TBK1. Ser-385 and Ser-386 may be specifically phosphorylated in response to induction. An alternate model propose that the five serine/threonine residues between 396 and 405 are phosphorylated in response to a viral infection. Phosphorylation, and subsequent activation of IRF3 is inhibited by vaccinia virus protein E3. PTM: Ubiquitinated; ubiquitination involves RBCK1 leading to proteasomal degradation. Polyubiquitinated; ubiquitination involves TRIM21 leading to proteasomal degradation. PTM: ISGylated by HERC5 resulting in sustained IRF3 activation and in the inhibition of IRF3 ubiquitination by disrupting PIN1 binding. The phosphorylation state of IRF3 does not alter ISGylation. SIMILARITY: Belongs to the IRF family. SIMILARITY: Contains 1 IRF tryptophan pentad repeat DNA-binding domain.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q14653
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000978 RNA polymerase II core promoter proximal region sequence-specific DNA binding GO:0000981 RNA polymerase II transcription factor activity, sequence-specific DNA binding GO:0001077 transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding GO:0001078 transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding GO:0001228 transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding GO:0003677 DNA binding GO:0003700 transcription factor activity, sequence-specific DNA binding GO:0003712 transcription cofactor activity GO:0005515 protein binding GO:0019904 protein domain specific binding GO:0042802 identical protein binding GO:0042803 protein homodimerization activity GO:0043565 sequence-specific DNA binding GO:0044212 transcription regulatory region DNA binding
Biological Process: GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0002376 immune system process GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006366 transcription from RNA polymerase II promoter GO:0006915 apoptotic process GO:0006974 cellular response to DNA damage stimulus GO:0009617 response to bacterium GO:0016032 viral process GO:0031663 lipopolysaccharide-mediated signaling pathway GO:0032479 regulation of type I interferon production GO:0032480 negative regulation of type I interferon production GO:0032481 positive regulation of type I interferon production GO:0032496 response to lipopolysaccharide GO:0032727 positive regulation of interferon-alpha production GO:0032728 positive regulation of interferon-beta production GO:0035666 TRIF-dependent toll-like receptor signaling pathway GO:0039530 MDA-5 signaling pathway GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling GO:0043330 response to exogenous dsRNA GO:0045087 innate immune response GO:0045351 type I interferon biosynthetic process GO:0045358 negative regulation of interferon-beta biosynthetic process GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0050689 negative regulation of defense response to virus by host GO:0050715 positive regulation of cytokine secretion GO:0051607 defense response to virus GO:0060333 interferon-gamma-mediated signaling pathway GO:0060337 type I interferon signaling pathway GO:0060340 positive regulation of type I interferon-mediated signaling pathway GO:0071222 cellular response to lipopolysaccharide GO:0071359 cellular response to dsRNA GO:0071888 macrophage apoptotic process GO:0097300 programmed necrotic cell death
Protein Q14653 (Reactome details) participates in the following event(s):
R-HSA-1169394 ISGylation of IRF3 R-HSA-1606345 Recruitment of IRF3 to activated ZBP1:TBK1 R-HSA-1834939 STING recruits TBK1 and IRF3 R-HSA-2395992 p-T,4S-IRF3 is dimerized R-HSA-1606327 Phosphorylation and release of IRF3 R-HSA-2396007 IRF3 is phosphorylated by TBK1 R-HSA-2396002 TBK1 is phosphorylated within STING:TBK1:IRF3 complex R-HSA-3249392 NLRP4 and DTX4 associate with p-S172-TBK1 within STING:TBK1:IRF3 R-HSA-8948709 DTX4 ubiquitinates p-S172-TBK1 within NLRP4:DTX4:STING:TBK1:IRF3 R-HSA-166271 IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR4 R-HSA-918232 Recruitment of IRF3,IRF7 R-HSA-9013979 IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR3 R-HSA-1028816 Translocation of phosphorylated IRF3,IRF7 dimers into nucleus R-HSA-2032396 Dimerized phospho-IRF3 migrates to the nucleus R-HSA-1028821 Dimerization of Phospho IRF3 or phospho IRF7 R-HSA-168933 Dimerization of phosphorylated IRF3/IRF7 R-HSA-166245 Phosphorylation of IRF-3/IRF7 and their release from the activated TLR complex R-HSA-918229 Phosphorylation and release of IRF3/IRF7 R-HSA-9013978 Phosphorylation of IRF-3/IRF7 and their release from the activated TLR3 complex R-HSA-1028817 CREBBP, EP300 binds p-T,4S-IRF3:p-T,4S-IRF3 R-HSA-3134883 Beta-catenin enhances association of IRF3 with CBP/p300 R-HSA-1028820 Formation of VAF (virus-activated factor) complex R-HSA-936380 Interaction of PIN1 with p-IRF3 R-HSA-177671 Dimerized phospho-IRF3/IRF7 is transported to the nucleus R-HSA-1028815 p-T,4S-IRF3:p-T,4S-IRF3:CREBBP, EP300 binds promoters of Interferon-beta R-HSA-1028819 VAF/pIRF7:CBP/p300 binds the promoters of type-I IFN genes R-HSA-1169408 ISG15 antiviral mechanism R-HSA-1606341 IRF3 mediated activation of type 1 IFN R-HSA-3270619 IRF3-mediated induction of type I IFN R-HSA-3134975 Regulation of innate immune responses to cytosolic DNA R-HSA-936964 Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon R-HSA-918233 TRAF3-dependent IRF activation pathway R-HSA-9013973 TICAM1-dependent activation of IRF3/IRF7 R-HSA-909733 Interferon alpha/beta signaling R-HSA-877300 Interferon gamma signaling R-HSA-1169410 Antiviral mechanism by IFN-stimulated genes R-HSA-1606322 ZBP1(DAI) mediated induction of type I IFNs R-HSA-1834941 STING mediated induction of host immune responses R-HSA-3134973 LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production R-HSA-933541 TRAF6 mediated IRF7 activation R-HSA-936440 Negative regulators of DDX58/IFIH1 signaling R-HSA-1834949 Cytosolic sensors of pathogen-associated DNA R-HSA-937061 TRIF(TICAM1)-mediated TLR4 signaling R-HSA-168928 DDX58/IFIH1-mediated induction of interferon-alpha/beta R-HSA-168164 Toll Like Receptor 3 (TLR3) Cascade R-HSA-913531 Interferon Signaling R-HSA-168249 Innate Immune System R-HSA-166166 MyD88-independent TLR4 cascade R-HSA-168898 Toll-Like Receptors Cascades R-HSA-1280215 Cytokine Signaling in Immune system R-HSA-168256 Immune System R-HSA-166016 Toll Like Receptor 4 (TLR4) Cascade
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Common Gene Haplotype Alleles 
