HGNC Approved Gene Symbol: IRF3
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38) : 19:49,659,572-49,665,857 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 7} | 616532 | Autosomal dominant | 3 |
The IRF3 gene encodes interferon regulatory factor-3, a transcription factor that activates transcription of interferon (see, e.g., IFNB1, 147640)-related genes that have antiviral activity (summary by Andersen et al., 2015). The virus-induced expression of interferon genes in infected cells involves the interplay of several constitutively expressed and virus-activated transcription factors. IFN regulatory factors (IRFs), including 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 (summary by Au et al., 1995).
By searching an EST database for sequences similar to those of 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.
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.
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 triggering the host antiviral response to viral infection. Sharma et al. (2003) demonstrated that expression of IKKE or TBK1 is sufficient to induce phosphorylation of IRF3 and IRF7. This modification permits IRF3 dimerization and translocation to the nucleus, where it induces transcription of interferon and ISG56 genes.
Foy et al. (2003) showed that the hepatitis C virus NS3/4A serine protease blocks the phosphorylation and effector action of IRF3 to generate persistent infection. Disruption of the NS3/4A protease function by mutation or a ketoamide peptidomimetic inhibitor relieved this blockade and restored IRF3 phosphorylation after cellular challenge with an unrelated virus. Foy et al. (2003) also showed that dominant-negative or constitutively active IRF3 mutants, respectively, enhanced or suppressed hepatitis C virus RNA replication in hepatoma cells. Foy et al. (2003) concluded that the NS3/4A protease represents a dual therapeutic target, the inhibition of which may both block viral replication and restore IRF3 control of hepatitis C infection.
Using microarray technology to compare gene expression profiles of mouse B lymphocytes stimulated with CD40LG (300386) or lipopolysaccharide, Doyle et al. (2002) identified IRF3 as a factor specifically induced by stimulation of TLR3 (603029) or TLR4 (603030), but not by TLR2 (603028), TLR9 (605474), or CD40 (109535). The primary response genes induced by this activation were coregulated by the NFKB pathway, common for both TLRs and TNFRs, and the IRF3 pathway. Additional secondary response genes were activated by autocrine and paracrine secretion of IFNB. Selective TLR3/TLR4-IRF3 pathway activation potently inhibited viral replication. Doyle et al. (2002) concluded that TLR3 and TLR4 have evolutionarily diverged from other TLRs to activate IRF3, which mediates a specific gene program responsible for innate antiviral responses.
Stetson and Medzhitov (2006) found that cytosolic DNA activated a potent type I interferon response to the invasive bacterium Listeria monocytogenes in mice. The noninvasive Legionella pneumophila triggered an identical response through its type IV secretion system. Transfection of 45-bp DNA oligonucleotides devoid of contiguous CpG into different murine cell types recapitulated the interferon-inducing activity of Listeria and Legionella in an Irf3-dependent, TLR-independent manner. Microarray analysis revealed that cytosolic DNA activated a unique but overlapping gene expression program compared with Tlr9- and Rigi (DDX58; 609631)/Mda5 (IFIH1; 606951)-dependent responses.
Manel et al. (2010) showed that, when dendritic cell resistance to infection is circumvented, HIV-1 induces dendritic cell maturation, an antiviral type I interferon response, and activation of T cells. This innate response is dependent on the interaction of newly synthesized HIV-1 capsid with cellular cyclophilin A (CYPA; 123840) and the subsequent activation of the transcription factor IRF3. Because the peptidylprolyl isomerase CYPA also interacts with HIV-1 capsid to promote infectivity, the results of Manel et al. (2010) indicated that capsid conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell-intrinsic sensor for HIV-1 exists in dendritic cells and mediates an antiviral immune response, but it is not typically engaged owing to the absence of dendritic cell infection.
Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING (612374). Through biochemical fractionation and quantitative mass spectrometry, Sun et al. (2013) identified a cGAMP synthase (cGAS; 613973), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced interferon-beta (147640) in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and interferon-beta induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. Sun et al. (2013) concluded that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP.
Wu et al. (2013) found that mammalian cytosolic extracts synthesized cGAMP in vitro from adenosine triphosphate (ATP) and guanosine triphosphate (GTP) in the presence of DNA but not RNA. DNA transfection or DNA virus infection of mammalian cells also triggered cGAMP production. cGAMP bound to STING, leading to the activation of IRF3 and induction of interferon-beta. Thus, Wu et al. (2013) concluded that cGAMP is present in metazoans and functions as an endogenous second messenger that triggers interferon production in response to cytosolic DNA.
Using biochemical and mouse cell- and human cell-based assays, Liu et al. (2015) found that both MAVS (609676) and STING interacted with IRF3 in a phosphorylation-dependent manner. The authors showed that both MAVS and STING are phosphorylated in response to stimulation at their respective C-terminal pLxIS consensus motifs (p, hydrophilic residue; x, any residue; S, phosphorylation site). This phosphorylation event then recruits IRF3 to the active adaptor protein and is essential for IRF3 activation. Point mutations that impair the phosphorylation of MAVS or STING at their consensus motif abrogated IRF3 binding and subsequent interferon (see 147660) induction. Liu et al. (2015) found that MAVS is phosphorylated by the kinases TBK1 (604834) and IKK (see 600664), whereas STING is phosphorylated by TBK1. Phosphorylated MAVS and STING subsequently bind to conserved, positively charged surfaces of IRF3, thereby recruiting IRF3 for its phosphorylation and activation by TBK1. Liu et al. (2015) also showed that TRIF (607601)-mediated activation of IRF3 depends of TRIF phosphorylation at the pLxIS motif commonly found in MAVS, STING, and IRF3. The authors concluded that phosphorylation of innate immune adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate type I interferon production.
Huai et al. (2019) found that deficiency of lysine acetyltransferase-8 (KAT8; 609912) selectively enhanced production of Ifna (IFNA1; 147660) and Ifnb triggered by viral infection in mouse immune cells. Immunoprecipitation and mass spectrometric analyses showed that Kat8 bound Irf3 directly and promoted acetylation of Irf3 at lys359 (K359). Chromatin immunoprecipitation assays and mutation analysis demonstrated that acetylation of Irf3 K359 inhibited recruitment of Irf3 to promoters of type I IFN genes. The authors concluded that KAT8 selectively inhibits antiviral immunity by acetylating IRF3.
Using immunoprecipitation analysis in mouse and human cells, Cai et al. (2020) showed that ubiquitin-specific protease-22 (USP22; 612116) interacted with IRF3 in cytoplasm after viral infection. Domain mapping analysis suggested that the C-terminal ubiquitin peptidase domain of USP22 was responsible for its association with IRF3. Knockdown of USP22 in human cell lines inhibited IRF3 nuclear accumulation. Analysis with Usp22 -/- mouse embryonic fibroblasts (MEFs) confirmed that Usp22 was essential for virus-triggered nuclear translocation of Irf3 and for subsequent cellular antiviral responses. Consequently, loss of Usp22 in mice led to increased susceptibility to viral infection. Usp22 was required for optimal induction of type I interferons after viral infection in mice, and Irf3 nuclear accumulation and antiviral signaling required Usp22 deubiquitinating activity. However, Usp22 did not directly target Irf3 for deubiquitination, but instead regulated Irf3 nuclear translocation by directly targeting the intermediate protein Kpna2 (600685) for deubiquitination. Kpna2 interacted constitutively with Usp22 through the C-terminal peptidase domain of Usp22, and it interacted with Irf3 or phosphorylated Irf3 in a viral infection-dependent manner. Deubiquitination of Kpna2 by Usp22 inhibited Kpna2 degradation, which promoted of virus-triggered signaling by facilitating nuclear translocation of Irf3.
Escalante et al. (2007) cocrystallized the DNA-binding domain of human IRF3 (amino acids 1 to 113) with a 33-bp sequence covering the PRDIII-I region of the IFN-beta enhancer and resolved the structure to 2.3-angstrom resolution. They found that 4 IRF3 DNA-binding domains came together in tandem on the PRDIII-I element to bind both consensus and nonconsensus sequences. The ability of IRF3 DNA-binding domains to bind these sites derived in part from 2 nonconserved arginines (arg78 and arg86) that partook in alternate protein-DNA contacts. The protein-DNA contacts were highly overlapped, and all 4 IRF3-binding sites were required for gene activation in vivo.
Acute Infection-Induced (Herpes-Specific) Encephalopathy 7, Susceptibility to
In a 15-year-old girl of Danish descent with herpes simplex encephalitis (HSE) (IIAE7; 616532), Andersen et al. (2015) identified a heterozygous missense mutation in the IRF3 gene (R285Q; 603734.0001). The mutation, which was found by whole-exome sequencing, was also present in the unaffected father, consistent with incomplete penetrance. Studies of patient cells and in vitro studies showed that the mutant protein failed to undergo phosphorylation and homodimerization, resulting in impaired ability to activate transcription of interferon-related genes in response to stimulation or infection. The findings were consistent with haploinsufficiency.
In a 34-year-old Danish man (P2) with adult-onset herpes simplex encephalitis, Mork et al. (2015) identified a heterozygous missense mutation in the IRF3 gene (A277T; 603734.0002). The mutation was found by whole-exome sequencing of a cohort of 16 patients with adult-onset HSE (including the patient reported by Andersen et al., 2015) and confirmed by Sanger sequencing. Patient peripheral blood mononuclear cells showed significantly lower beta-interferon (IFNB; 147640), CXCL10 (147310), and TNFA (191160) responses to poly(I;C) stimulation and/or HSV-1 infection compared to controls, suggesting defective antiviral response and a loss of function. The findings suggested that IRF3 variants may also contribute to HSE susceptibility in adults.
Associations Pending Confirmation
Bigham et al. (2011) tested 360 common haplotype-tagging and/or functional SNPs in 86 genes encoding immune function regulators in 422 individuals with symptomatic West Nile virus (WNV; see 610379) infections and 331 WNV-infected individuals without symptoms. After correcting for multiple tests, they found that SNPs in IRF3 and MX1 (147150) were associated with symptomatic WNV infection and that a single SNP in OAS1 (164350) was associated with increased risk of WNV encephalitis and paralysis. Bigham et al. (2011) concluded that genetic variation in the interferon response pathway is associated with risk for symptomatic WNV infection and WNV disease progression.
Chen et al. (2013) observed highly increased viral titers, but no mortality over 30 days, in mice lacking both Irf3 and Irf7 following infection with Dengue virus type 2 (DENV2) compared with wildtype mice and mice lacking only Irf3 or Irf7. Viral burden was even higher in Ifnar1 (107450)-null mice, which died within 7 days of infection. Irf7 -/- mice and Irf3-/- Irf7-/- mice expressed significantly low levels of Ifna and Ifnb, but induction of Cxcl10 (147310) and Ifna2 (147562) was not impaired. Multiple other cytokines, including Ifng, were present at high levels in serum of Irf3-/- Irf7-/- mice within 24 hours, at which time DENV2 began to be cleared. DENV replication was restricted by Ifng, Cxcl10, and Cxcr3 (300574) in Irf3-/- Irf7-/- mice. Additionally, other Ifn-stimulated genes were induced independently of Irf3 and Irf7. Chen et al. (2013) concluded that IRF3 and IRF7 are required for early control of DENV infection, but that a late IRF3- and IRF7-independent pathway contributes to anti-DENV immunity.
Menachery et al. (2010) found that Irf3-null mice had impaired ability to control herpes simplex virus (HSV)-1 replication in brain tissue following corneal or intracranial infection compared to wildtype mice. Irf3-null mice had an increased inflammatory cytokine response and decreased interferon production in the brain, resulting in increased lethality. These findings demonstrated a critical role for IRF3 in the control of central nervous system infection following HSV-1 challenge.
In a 15-year-old girl of Danish descent with herpes simplex encephalitis (IIAE7; 616532), Andersen et al. (2015) identified a heterozygous c.854G-A transition (c.854G-A, NM_001571.5) in the IRF3 gene, resulting in an arg285-to-gln (R285Q) substitution at a highly conserved residue in the regulatory domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP database. The unaffected father was also heterozygous for the mutation, consistent with incomplete penetrance; DNA from the mother was not available, and the patient had no sibs. Patient peripheral blood cells showed normal expression of the mutant protein, but significantly impaired interferon response upon stimulation with synthetic pathogen-associated molecular patterns as well as variably decreased responses to HSV-1, HSV-2, and HSV-8 compared to controls. In vitro functional expression assays in HEK293 cells showed that the mutant protein was not properly phosphorylated at S386 and did not form homodimers upon infection or pathway-specific stimulation. The TLR3 (603029)/TRIF (607601) pathway was most affected. There was no evidence of a dominant-negative effect, and Andersen et al. (2015) postulated that haploinsufficiency was responsible for the phenotype. Expression of wildtype IRF3 in patient cells restored the ability to express interferon-beta (IFNB1; 147640) in response to infection.
Mork et al. (2015) stated that the R285Q variant was present at a low frequency (0.000066) in the ExAC database.
In a 34-year-old man (P2) who presented with adult-onset herpes simplex encephalitis (IIAE7; 616532), Mork et al. (2015) identified a heterozygous c.829G-A transition (c.829G-A, NM_001197122.1) in the IRF3 gene, resulting in an ala277-to-thr (A277T) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found at a low frequency (0.0036) in the ExAC database. Patient peripheral blood mononuclear cells showed significantly lower beta-interferon (IFNB1; 147640), CXCL10 (147310), and TNFA (191160) responses to poly(I;C) stimulation and/or HSV-1 infection compared to controls, suggesting defective antiviral response and a loss of function.
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