Disease relevance of IRF3

• In cells transiently expressing IRF7 or/and IRF3, the VAF level and binding of VAF are clearly increased after Sendai virus infection [1].
• Innate cellular response to virus particle entry requires IRF3 but not virus replication [2].
• Furthermore, we demonstrate that HSV-1 modifies the IRF3 pathway in a manner different from that of the small RNA viruses most commonly studied [3].
• The herpes simplex virus ICP0 RING finger domain inhibits IRF3- and IRF7-mediated activation of interferon-stimulated genes [3].
• Hepatitis A virus suppresses RIG-I-mediated IRF-3 activation to block induction of beta interferon [4].
• Interferon-beta promoter stimulator-1 and IRF-3 are required for efficient apoptosis following reovirus infection, suggesting a common mechanism of antiviral cytokine induction and activation of the cell death response [5].

High impact information on IRF3

• Viral infection triggers host innate immune responses through activation of the transcription factors NF-kappaB and IRF 3, which coordinately regulate the expression of type-I interferons such as interferon-beta (IFN-beta) [6].
• Epistasis experiments show that MAVS is required for the phosphorylation of IRF 3 and IkappaB and functions downstream of RIG-I, an intracellular receptor for viral RNA [6].
• Dual utilization of an acceptor/donor splice site governs the alternative splicing of the IRF-3 gene [7].
• Here we describe novel regulation of IRF-3 at the level of RNA splicing [7].
• IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway [8].

Chemical compound and disease context of IRF3

• Legionella pneumophila Induces IFNbeta in Lung Epithelial Cells via IPS-1 and IRF3, Which Also Control Bacterial Replication [9].
• Since infection during inhibition of protein expression by cycloheximide or inactivation of viral gene expression by UV treatment did not trigger IRF3 activation or ISG expression by RhCMV, we conclude that RhCMV virions contain a novel inhibitor of IFN-independent viral induction of ISG expression by IRF3 [10].
• In the present study, we demonstrate that following Sendai virus infection, IRF-3 is posttranslationally modified by protein phosphorylation at multiple serine and threonine residues, which are located in the carboxy terminus of IRF-3 [11].
• The LY294002 inhibitor fails to prevent IRF-3 homodimerization or nuclear translocation upon virus particle entry [12].
• Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease [13].

Biological context of IRF3

• Activation of IRF3 requires signal-dependent phosphorylation, but little is known about the signaling pathway or kinases involved [8].
• Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway [14].
• IRF3, which has previously been shown to possess no intrinsic transcriptional activation potential, interacts with the transcriptional coactivator CREB binding protein, but not with p300, to form CIF [15].
• Knockdown of endogenous Hsp90 by RNA interference attenuates IRF3 activation and its target gene expressions [16].
• IRF3 blocked DNA synthesis and induced apoptosis [17].

Anatomical context of IRF3

• Moreover, IRF3-deficient, but not IFNalpha/betaR deficient, macrophages still induced Viperin in response to SV [18].
• These data are the first to show that IL-1beta, in addition to TLRs, can stimulate IRF3, implicating this cytokine as an activator of genes involved in innate antiviral responses in astrocytes [19].
• In the present study we demonstrate the activation of IRF3 followed by ISG induction after exposure of cells to the bacterial cell wall component lipopolysaccharide [20].
• These signals may increase expression of inflammatory cytokines, chemokines and ICAM-1 through activation of transcription factors NF-kappaB and/or IRF3 in airway epithelial cells [21].
• We have generated tetracycline-inducible stable cell lines that express a wild type or kinase-inactive mutant form of IKK-i. Our data suggest that expression of IKK-i can activate both NFkappaB and IRF3, leading to the production of several cytokines including interferon beta [22].

Associations of IRF3 with chemical compounds

• Engagement of Toll-like receptors by lipopolysaccharide triggered the nuclear translocation of IRF3, followed by its DNA binding and the subsequent induction of several interferon-regulated genes [20].
• Significantly, virus-induced IRF3 phosphorylation is blocked by GA, whereas GA does not affect the protein level of IRF3 [16].
• Treatment with DNA-damaging agents, including doxorubicin and UV radiation, caused phosphorylation of the IRF3 transcription factor [23].
• Virus infection but not IFN treatment induces phosphorylation of IRF-3 on specific serine residues, thereby allowing it to complex with the co-activator CBP/p300 with simultaneous nuclear translocation and its specific DNA binding [24].
• Expression of IRF-3 as a Gal4 fusion protein does not activate expression of a chloramphenicol acetyltransferase reporter gene containing repeats of the Gal4 binding sites, indicating that this protein does not contain the transcription transactivation domain [25].

Physical interactions of IRF3

• The region by which IRF-7 interacts with IRF-3 was mapped between amino acid 418 and 473 [26].
• Following infection, phosphorylated IRF-3 can bind to the CBP/p300 proteins resident in the nucleus [27].
• IRF-3a lacks half of the DNA binding domain found in IRF-3 and is unable to bind to the classical IRF binding elements, IFN-stimulated response elements [28].
• IRF-3 binds to the interferon-sensitive response element (ISRE) present in the ISG15 gene promoter and activates its transcriptional activity [29].
• Therefore, IRF-3 activation by dsRNA is sufficient to induce the transcription of genes with simple promoters such as 561 as well as complex promoters such as IFN-beta [30].
• Although LPS-induced IRF-3 nuclear translocation was observed both in adult and neonatal moDCs, IRF-3 DNA-binding activity and association with the coactivator CREB-binding protein (CBP) were decreased in neonatal as compared with adult moDCs [31].

Enzymatic interactions of IRF3

• We report here that the IkappaB kinase (IKK)-related kinases IKKepsilon and TANK-binding kinase 1 are components of the virus-activated kinase that phosphorylate IRF-3 and IRF-7 [32].

Regulatory relationships of IRF3

• The protein kinase TBK1 is a key regulator inducing phosphorylation of IRF3 [16].
• TLR3 signaling activates the transcription factor IRF-3 by its Ser/Thr phosphorylation, accompanied by its dimerization and nuclear translocation [33].
• Expression of A20 completely blocked CARD domain containing DeltaRIG-I-induced IRF-3 Ser-396 phosphorylation, homodimerization, and DNA binding [34].
• Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta [35].
• Phosphorylation of IRF3 induced its interaction with the transcriptional co-activator cAMP-response element binding protein-binding protein [23].

Other interactions of IRF3

• Remarkably, VAF, as well as recombinant IRF-3 and IRF-7 proteins, binds very weakly to the interferon-beta (IFN-beta) gene promoter in vitro [36].
• Furthermore, whereas poly(I.C)-induced NF-kappaB activation is completely abolished inTRAF6-/- MEFs, the signal-induced activation of IRF3 is TRAF6 independent [35].
• Recent studies have shown that TLR4 also signals independently of MyD88, resulting in the activation of IFN regulatory factor 3 (IRF3), a transcription factor required for the production of primary antiviral response genes such as IFN-beta [19].
• We also show that IL-1beta induces phosphorylation and nuclear translocation of IRF3 and delayed phosphorylation of STAT1 [19].
• We have localized the SR-A1 gene between the known genes IRF3 and RRAS on chromosome 19q13 [37].
• The data support a two-step phosphorylation model for IRF-3 activation mediated by TBK1 [38].

Analytical, diagnostic and therapeutic context of IRF3

• Two of these proteins, IRF-3 and IRF-7, serve as direct transducers of virus-mediated signaling and play critical roles in the induction of type I interferon genes [39].
• Infection of macrophage cell cultures with ICP27-defective virus resulted in enhanced production of antiviral cytokines and an enhanced activation of NF-kappa-B and IRF3 [40].
• Using DNA microarray analysis (8,556 genes) in Jurkat T cells inducibly expressing constitutively active IRF-3, several target genes directly regulated by IRF-3 were identified [41].
• Electrophoretic mobility shift assays with IL-1beta-treated nuclear extracts showed a decrease in the formation of DNA protein complexes, specifically those including interferon regulatory factor 3 (IRF3) [42].
• To define the role of IRFs in lymphoid disorders, we determined the expression patterns of IRF3 and IRF7 by immunohistochemistry in 5 normal lymph nodes, 12 reactive hyperplastic lymph nodes, and 27 pediatric lymphomas [43].

References