Interferon regulatory factor 3 (IRF3)

The protein contains 427 amino acids for an estimated molecular weight of 47219 Da.

 

Key transcriptional regulator of type I interferon (IFN)-dependent immune responses which plays a critical role in the innate immune response against DNA and RNA viruses (PubMed:22394562, PubMed:25636800, PubMed:27302953). 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 (PubMed:11846977, PubMed:16846591, PubMed:16979567, PubMed:20049431, PubMed:32972995). 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 (PubMed:16846591, PubMed:16979567, PubMed:20049431). 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, is phosphorylated by IKBKE and TBK1 kinases (PubMed:22394562, PubMed:25636800, PubMed:27302953). 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 (PubMed:16154084, PubMed:27302953, PubMed:33440148). Can activate distinct gene expression programs in macrophages and can induce significant apoptosis in primary macrophages (PubMed:16846591). In response to Sendai virus infection, is recruited by TO (updated: April 7, 2021)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  3. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Interpro domains
Total structural coverage: 86%
Model score: 100

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VariantDescription
dbSNP:rs968457
dbSNP:rs34745118
dbSNP:rs1049486
dbSNP:rs7251
IIAE7
Decreased IFNB induction upon Sendai virus infection
No effect on IFNB induction upon Sendai virus infection
No effect on IFNB induction upon Sendai virus infection

Biological Process

Apoptotic process GO Logo
Cellular response to DNA damage stimulus GO Logo
Cellular response to dsRNA GO Logo
Cellular response to exogenous dsRNA GO Logo
Cellular response to virus GO Logo
Cytokine-mediated signaling pathway GO Logo
Defense response to virus GO Logo
Immune system process GO Logo
Innate immune response GO Logo
Interferon-gamma-mediated signaling pathway GO Logo
Lipopolysaccharide-mediated signaling pathway GO Logo
Macrophage apoptotic process GO Logo
MDA-5 signaling pathway GO Logo
MyD88-independent toll-like receptor signaling pathway GO Logo
Negative regulation of defense response to virus by host GO Logo
Negative regulation of interferon-beta biosynthetic process GO Logo
Negative regulation of transcription by RNA polymerase II GO Logo
Negative regulation of type I interferon production GO Logo
Positive regulation of cytokine secretion GO Logo
Positive regulation of I-kappaB kinase/NF-kappaB signaling GO Logo
Positive regulation of interferon-alpha production GO Logo
Positive regulation of interferon-beta production GO Logo
Positive regulation of transcription by RNA polymerase II GO Logo
Positive regulation of type I interferon production GO Logo
Positive regulation of type I interferon-mediated signaling pathway GO Logo
Programmed necrotic cell death GO Logo
Regulation of apoptotic process GO Logo
Regulation of inflammatory response GO Logo
Regulation of transcription by RNA polymerase II GO Logo
Regulation of type I interferon production GO Logo
Response to exogenous dsRNA GO Logo
Toll-like receptor 3 signaling pathway GO Logo
Toll-like receptor 4 signaling pathway GO Logo
Toll-like receptor signaling pathway GO Logo
Transcription by RNA polymerase II GO Logo
TRIF-dependent toll-like receptor signaling pathway GO Logo
Type I interferon biosynthetic process GO Logo
Type I interferon production GO Logo
Type I interferon signaling pathway GO Logo
Viral process GO Logo

The reference OMIM entry for this protein is 603734

Interferon regulatory factor 3; irf3

CLONING

The virus-induced expression of interferon (IFN; e.g., 147570) genes in infected cells involves the interplay of several constitutively expressed and virus-activated transcription factors. A family of IFN regulatory factors (IRFs), which includes the activator IRF1 (147575) and the repressor IRF2 (147576), have been shown to play a role in the transcription of IFN genes as well as IFN-stimulated genes. By searching an EST database for sequences that are similar to IRF1 and IRF2, Au et al. (1995) identified IRF3, a novel member of the IRF family. The IRF3 gene is present in a single copy in the human genome. Northern blot analysis detected a 1.6-kb constitutively expressed IRF3 transcript. The deduced 427-amino acid IRF3 protein is 34 to 40% identical to other members of the IRF family in the N-terminal region. Au et al. (1995) showed that IRF3 is a 50-kD protein.

MAPPING

By linkage analysis using a highly polymorphic marker located in an intron of IFR3, Bellingham et al. (1998) mapped the IRF3 gene to 19q13.3-q13.4, between D19S604 and D19S206.

GENE FUNCTION

Au et al. (1995) showed that IRF3 bound specifically to the IFN-stimulated response element (ISRE), but not to the IRF1-binding site positive regulatory domain (PRD)-I, a DNA-binding specificity similar to that of ISGF3 (see 147574). Although IRF3 increased transcriptional activity from an ISRE-containing promoter, expression of IRF3 as a Gal4 fusion protein did not activate expression of a chloramphenicol acetyltransferase (CAT) reporter gene containing repeats of the Gal4-binding sites. Au et al. (1995) suggested that IRF3 increases transcriptional activity of targeted promoters through association with another transcriptional activator(s). Weaver et al. (1998) identified IRF3 as a component of DRAF1 (double-stranded RNA-activated factor-1), a positive regulator of IFN-stimulated gene transcription that functions as a direct response to viral infection. They demonstrated that IRF3 preexists in the cytoplasm of uninfected cells and translocates to the nucleus following viral infection. Translocation of IRF3 was accompanied by an increase in serine and threonine phosphorylation. The transcriptional activators CREBBP (600140) and EP300 (602700) coimmunoprecipitated with IRF3 only subsequent to viral infection, and the authors stated that these are also subunits of DRAF1. Wathelet et al. (1998) identified a virus-activated factor (VAF) that binds to a regulatory element shared by different virus-inducible genes. VAF contains 2 members of the IRF family of transcriptional activator proteins, IRF3 and IRF7 (605047), and the transcriptional coactivator proteins p300 (602700) and CBP (600140). Remarkably, VAF and recombinant IRF3 and IRF7 proteins bind weakly to the IFNB (see 147640) gene promoter in vitro. However, in virus-infected cells, both proteins are recruited to the endogenous IFNB promoter as part of a protein complex that includes ATF2/c-jun (123811, 165160) and NF-kappa-B (see 164011). These observations demonstrated the coordinate activation of multiple transcriptional activator proteins and their highly cooperative assembly into a transcriptional enhancer complex in vivo. Sharma et al. (2003) demonstrated that IKKE (605048) and TANK-binding kinase-1 (TBK1; 604834) are components of the virus-activated kinase (VAK) that phosphorylate IRF3 and IRF7 (605047). They demonstrated an essential role for an IKK-related kinase pathway in trigge ... More on the omim web site

Subscribe to this protein entry history

April 10, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 16, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.

May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

June 20, 2017: Protein entry updated
Automatic update: comparative model was added.

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 603734 was added.

Jan. 24, 2016: Protein entry updated
Automatic update: model status changed