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IRF3
IRF3
IRF3
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IRF3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIRF3, entrez:3661, IIAE7, interferon regulatory factor 3
External IDsOMIM: 603734; MGI: 1859179; HomoloGene: 1208; GeneCards: IRF3; OMA:IRF3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3661

54131

Ensembl

ENSG00000126456

ENSMUSG00000003184

UniProt

Q14653

P70671

RefSeq (mRNA)

NM_016849

RefSeq (protein)

NP_058545

Location (UCSC)Chr 19: 49.66 – 49.67 MbChr 7: 44.65 – 44.65 Mb
PubMed search[3][4]
Wikidata
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Interferon regulatory factor 3, also known as IRF3, is an interferon regulatory factor.[5]

Function

[edit]

IRF3 is a member of the interferon regulatory transcription factor (IRF) family.[5] 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.[6] IRF3 is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP.[7] The complex translocates into the nucleus for the transcriptional activation of interferons alpha and beta, and further interferon-induced genes.[8]

IRF3 plays an important role in the innate immune system's response to viral infection.[9] Aggregated MAVS have been found to activate IRF3 dimerization.[10] 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.[11] Another study has shown that IRF3-/- knockouts protect from myocardial infarction.[12] The same study identified IRF3 and the type I IFN response as a potential therapeutic target for post-myocardial infarction cardioprotection.[12]

Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations

Interactions

[edit]

IRF3 has been shown to interact with IRF7.[13]

References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

IRF3

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from Grokipedia
Interferon regulatory factor 3 (IRF3) is a member of the interferon regulatory factor (IRF) family of transcription factors that plays a central role in the innate , particularly in the activation of type I s and interferon-stimulated genes (ISGs) in response to viral infections. Encoded by the IRF3 gene located on human chromosome 19q13.33, IRF3 is ubiquitously expressed across tissues, with highest levels observed in the and lymph nodes, and exists primarily as an inactive 55-kDa protein in the of unstimulated cells. Upon detection of viral pathogens through pattern recognition receptors such as RIG-I, TLR3, or cGAS-STING, IRF3 undergoes at multiple serine and residues (e.g., Ser396–Thr405) by kinases including TBK1 and IKKε, leading to its dimerization, nuclear translocation, and binding to interferon-stimulated response elements (ISREs) or PRDI/III motifs in target gene promoters. This enables IRF3 to orchestrate antiviral defenses by inducing the expression of type I interferons (IFN-α and IFN-β), which in turn amplify immune signaling and restrict , as well as direct induction of ISGs like ISG15 and such as RANTES. Beyond its canonical antiviral functions, IRF3 contributes to broader immune regulation, including modulation of , via Bax activation, and inhibition of activity to balance pro- and anti-inflammatory responses. Structurally, IRF3 features an N-terminal with five conserved residues for ISRE recognition, a central proline-rich region, and a C-terminal that interacts with coactivators like CBP/p300, while autoinhibitory domains maintain its cytoplasmic sequestration until . Mutations or deficiencies in IRF3 are associated with increased susceptibility to viral infections, such as and , and have been implicated in conditions like infection-induced and chronic inflammatory diseases including systemic (SLE) and non-alcoholic (NASH). Recent research highlights IRF3's emerging roles in adaptive immunity, macrophage polarization, and potential therapeutic targeting for modulating antiviral and inflammatory responses, underscoring its multifaceted impact on host-pathogen interactions.

Gene and Expression

Genomic Location and Structure

The IRF3 gene in humans is located on the long (q) arm of chromosome 19 at cytogenetic band q13.33, with genomic coordinates spanning 19:49,659,572-49,665,857 (GRCh38.p14). This positioning places it within a region associated with immune response regulation. The orthologous gene in mice (Mus musculus) maps to chromosome 7 at band B3. The human IRF3 gene occupies approximately 6.3 kb of genomic DNA and comprises 8 exons separated by 7 introns, producing a primary transcript that encodes a 427-amino-acid protein. Alternative splicing generates multiple isoforms, though the canonical form predominates in most tissues. This compact gene structure reflects the evolutionary optimization of IRF family members for rapid transcription in response to immune stimuli.

Expression Patterns

IRF3 is constitutively expressed at low levels across a wide range of tissues, reflecting its ubiquitous role in innate immune readiness. Expression is particularly elevated in immune-related organs such as the (RPKM 23.8) and lymph nodes (RPKM 21.2), as well as in key immune cell types including dendritic cells, macrophages, and fibroblasts, where it supports baseline antiviral surveillance. While IRF3 mRNA steady-state levels typically remain unchanged following viral infection or type I treatment, its expression can be induced in non-immune cells such as epithelial and endothelial cells upon exposure to (TLR) ligands or viral pathogens, enhancing local immune responses at barrier sites. of the IRF3 gene produces multiple isoforms, including at least five distinct variants (e.g., IRF3b, IRF3c, IRF3d, IRF3e, and IRF3f), some of which lack the C-terminal (TAD), potentially modulating transcriptional activity. These splice variants display tissue-specific patterns, with higher prevalence of IRF3b–f observed in liver and tumor tissues compared to adjacent normal tissues, suggesting a role in organ-specific immune regulation or pathology. During development, IRF3 exhibits low expression in embryonic tissues, with detectable but baseline levels in the at embryonic day 15; this persists similarly at postnatal day 1 and into adulthood, though postnatal microbial exposure may contribute to fine-tuning of immune-related expression patterns.

Protein Structure

Domain Architecture

The IRF3 protein comprises three principal modular domains: an N-terminal DNA-binding domain (DBD), a central IRF association domain (IAD), and a C-terminal transactivation domain (TAD), which collectively ensure its structural integrity and facilitate initial molecular interactions. The DBD spans approximately residues 1–112 and adopts a compact α/β fold featuring a helix-turn-helix motif, characterized by five conserved tryptophan-rich repeats that enable sequence-specific recognition of interferon-stimulated response elements (ISREs) on target DNA. Crystal structures of the IRF3 DBD, both in apo and DNA-bound forms, reveal a trihelical bundle (α1–α3) flanked by a four-stranded antiparallel β-sheet, with flexible loops (L1–L3) contributing to DNA adaptability (PDB ID: 3QU6). The central IAD, encompassing residues 202–360, serves as the primary interface for protein-protein associations and exhibits a conserved consisting of a central β-sandwich core connected to an α-helical bundle that promotes homodimer and heterodimer formation for enhanced stability. Structural analyses confirm this domain's role in maintaining quaternary interactions through hydrophobic contacts within the helical bundle. The C-terminal TAD, covering residues 361–427, functions as an extended, atypical module that is largely intrinsically disordered, featuring clusters of serine and residues poised for regulatory modifications. This disordered allows conformational flexibility essential for coactivator recruitment upon signaling cues. In the basal state, IRF3 maintains a monomeric topology in the , with its domain organization supporting latency prior to .

Conformational Changes

In its inactive state, IRF3 exists as a cytoplasmic in an auto-inhibited conformation, where the C-terminal (TAD) folds over the core, masking the nuclear localization signal (NLS) and preventing nuclear translocation. This autoinhibitory arrangement maintains IRF3 in the under resting conditions, ensuring it remains sequestered until stimulated by pathogen-associated molecular patterns. The NLS, located within the C-terminal region spanning residues approximately 400-427, is physically obstructed by the folded TAD, which blocks access to importin-mediated nuclear machinery. Upon activation by , primarily at serine residues such as Ser386 in the ortholog, IRF3 undergoes a conformational shift that promotes parallel dimerization through its C-terminal association domain (IAD). This phosphorylation-induced change disrupts the autoinhibitory fold, allowing the TAD to undergo a dramatic unfolding and conformational shift, thereby exposing the masked NLS and facilitating nuclear entry as a dimer. The dimer interface is stabilized by interactions involving positively charged pockets, including residues like Arg211 and Arg380, which enable the parallel orientation essential for subsequent transcriptional activity. Crystal structures of phosphorylated IRF3 bound to (CBP) at resolutions of 1.68 Å () and 2.23 Å () illustrate this unfolding and unmasking, highlighting how the TAD repositions to recruit coactivators like CBP/p300. In its nuclear form, the IRF3 dimer adopts a DNA-binding conformation where the N-terminal (DBD) interacts with specific promoter elements, inducing bends in the DNA helix. The DBD binds to the positive regulatory domains I (PRDI) and III (PRDIII) of the interferon-β (IFN-β) enhancer, with each exhibiting distinct curvature: PRDIII bends the DNA by about 21° in one direction, while PRDI bends it by approximately 24° in the opposite direction, facilitating cooperative assembly of the enhanceosome complex with other transcription factors. This bending enhances accessibility to the transcriptional machinery, underscoring the role of conformational adaptability in IRF3's regulatory function.

Activation Mechanisms

Signal Transduction Pathways

IRF3 activation is primarily initiated through upstream pathways triggered by pathogen-associated molecular patterns, such as viral or bacterial nucleic acids, leading to the recruitment of adaptor proteins and kinase complexes that converge on IRF3 . These pathways are central to the , enabling rapid detection of cytosolic or endosomal threats and subsequent production. In the RIG-I/ pathway, cytosolic RNA sensors retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 () recognize distinct viral double-stranded motifs, undergoing conformational changes to expose their N-terminal caspase activation and recruitment domains (CARDs). This exposes CARDs that interact with the (MAVS), forming prion-like aggregates on mitochondrial membranes that propagate the signal.01002-2) MAVS then recruits TNF receptor-associated factor 3 (TRAF3), which promotes K63-linked ubiquitination and assembly of the kinase complex comprising (TBK1) and IKKε, directing the cascade toward IRF3. RIG-I preferentially senses short 5'-triphosphorylated RNAs from viruses like , while detects longer dsRNAs from picornaviruses, ensuring complementary coverage of RNA threats.00461-1) The TLR3 and TLR4 pathways engage endosomal or membrane-bound Toll-like receptors to detect extracellular double-stranded or , respectively, utilizing TIR-domain-containing adapter-inducing interferon-β (TRIF) as the key adaptor. For TLR3, binding induces receptor dimerization and recruitment of TRIF via the receptor's TIR domain, while TLR4 signals through TRIF via the transmembrane adaptor in a MyD88-independent branch. TRIF interacts with TRAF3 and RIP1 to activate TBK1/IKKε, mirroring the RLR pathway's kinase convergence and facilitating IRF3 engagement. This mechanism is critical for responses to viruses like reovirus (TLR3) and (TLR4). Cytosolic DNA sensing occurs via the cGAS-STING pathway, where cyclic GMP-AMP synthase (cGAS) detects double-stranded DNA from pathogens or damaged cells, catalyzing the production of the second messenger 2'3'-cyclic GMP-AMP (cGAMP). cGAMP binds and activates (STING) on the , inducing STING oligomerization and translocation to perinuclear sites where it recruits TRAF3 and the TBK1/IKKε complex, thereby linking DNA detection to IRF3 signaling. This pathway is essential for antiviral defense against DNA viruses like and for detecting self-DNA during tumorigenesis or autoimmunity.00445-1) Non-canonical pathways involve DNA-dependent protein kinase (DNA-PK) and ataxia-telangiectasia mutated () in responses to genotoxic stress or DNA damage, where these kinases directly or indirectly phosphorylate IRF3 independent of the canonical TBK1/IKKε axis. DNA-PK senses DNA breaks and activates IRF3 to induce interferon-independent antiviral states, while ATM coordinates with IFI16 to engage STING in a TBK1-bypass manner during nuclear DNA damage, highlighting adaptive immune signaling under cellular stress.30603-8)

Phosphorylation and Nuclear Translocation

Upon activation by upstream signals such as those from the RIG-I pathway, interferon regulatory factor 3 (IRF3) undergoes primarily at multiple serine residues within its C-terminal regulatory domain by the kinases (TBK1) and IκB kinase ε (IKKε). These kinases target a phospho-acceptor motif comprising Serine 396, Serine 398, Serine 402, and Serine 405, with additional phosphorylation at Serine 385 and Serine 386 in some contexts, leading to conformational changes that relieve autoinhibition.54739-X/fulltext) This multi-site phosphorylation is essential for IRF3 activation, as mutations at these residues abolish its transcriptional activity. The phosphorylated form of IRF3 undergoes dimerization mediated by its IRF association domain (IAD), which exposes a bipartite nuclear localization signal (NLS) previously masked in the monomeric state.00259-6) Structural studies reveal that phosphorylation at these C-terminal sites promotes parallel dimer formation, enabling the IAD to interface and unmask the NLS spanning residues 390–410 and 303–318, which is critical for nuclear entry. This dimerization step is indispensable, as phosphomimetic mutants demonstrate enhanced dimer stability and DNA-binding affinity compared to wild-type IRF3. Nuclear translocation of dimeric IRF3 occurs via a CRM1-independent mechanism involving the importin-α/β heterodimer, which recognizes the unmasked bipartite NLS and facilitates transport through nuclear pore complexes. Once in the nucleus, IRF3 is retained through direct binding to interferon-stimulated response elements (ISREs) on target gene promoters, such as the IFN-β enhancer, stabilizing its transcriptional role.00259-6) Signal termination involves of IRF3 by protein phosphatase 2A (PP2A), recruited via the adaptor protein RACK1, which reverses the at key serines like Serine 396 and Serine 386, promoting monomerization, nuclear export, and cytoplasmic degradation. This PP2A-mediated deactivation ensures transient IRF3 activity, preventing prolonged production.

Regulatory Processes

Negative Regulators

Negative regulators of IRF3 activity play crucial roles in limiting excessive type I interferon production and preventing uncontrolled during innate immune responses. These mechanisms primarily target IRF3 for deactivation through proteasomal degradation or , or inhibit upstream components in the signaling pathway to curb IRF3 activation. Key cellular processes involve ubiquitin-mediated degradation and phosphatase-mediated reversal of activating modifications. Proteasomal degradation represents a major inhibitory pathway for activated IRF3. The peptidyl-prolyl isomerase Pin1 binds to phosphorylated IRF3 following viral stimulation, such as by double-stranded , inducing a conformational change that promotes K48-linked ubiquitination and subsequent proteasomal degradation. This Pin1-mediated process attenuates IRF3-dependent antiviral , as demonstrated in studies using Pin1-deficient cells that exhibit prolonged IRF3 activity and enhanced interferon-beta production. Phosphatase activity provides another layer of direct inhibition by reversing IRF3 phosphorylation, essential for its dimerization and nuclear translocation. Protein phosphatase 2C (PP2C, specifically PPM1A) dephosphorylates key sites on upstream regulators like TBK1 and STING, thereby preventing IRF3 phosphorylation and activation in response to cytosolic RNA or DNA sensing. Similarly, protein phosphatase 4 (PP4) targets TBK1 at Ser-172, inhibiting its autophosphorylation and kinase function, which in turn suppresses IRF3 phosphorylation and type I interferon induction during viral infections like vesicular stomatitis virus. These phosphatases ensure timely termination of signaling, as evidenced by enhanced IRF3 activation and interferon production in cells depleted of PP2C or PP4. Viruses have evolved antagonists that exploit these regulatory mechanisms to evade IRF3-mediated immunity. For instance, SARS-CoV non-structural protein 1 (NSP1) suppresses host gene expression, including interferon-beta, by inhibiting mRNA translation. Likewise, hepatitis C virus (HCV) NS3/4A protease cleaves mitochondrial antiviral-signaling protein (MAVS) at specific sites, disrupting the RIG-I-MAVS-TBK1 axis and preventing IRF3 activation, which allows persistent viral replication. Cellular inhibitors further restrain IRF3 signaling by sequestering pathway components. , a family member, binds and sequesters STING in the , limiting its trafficking to puncta and subsequent recruitment of TBK1 for phosphorylation in response to cyclic dinucleotides or DNA viruses. This interaction reduces STING-TBK1 association, thereby attenuating IRF3-dependent antiviral responses without affecting basal STING function.

Feedback Loops

IRF3 activation initiates a loop through the induction of IFN-β expression, which subsequently amplifies the antiviral response by upregulating IRF7 via STAT1/STAT2 signaling. Upon and dimerization, IRF3 translocates to the nucleus and binds to the IFN-β promoter as part of the enhanceosome complex, driving robust transcription of the Ifnb1 . The secreted IFN-β then engages the IFNAR receptor, activating the JAK1/TYK2-/STAT2 pathway to form the ISGF3 complex, which induces expression of interferon-stimulated genes, including Irf7. This secondary amplification by IRF7 sustains and broadens type I IFN production, ensuring a coordinated innate immune response to viral infection. In parallel, IRF3-mediated IFN-β production establishes negative feedback mechanisms to prevent excessive signaling, including the induction of DUSP4 and SOCS1, which dampen downstream pathways. IFN-β signaling upregulates DUSP4, a dual-specificity phosphatase that forms a complex with TBK1, IRF3, and ERK1/2, dephosphorylating TBK1 at key sites to limit further IRF3 activation and type I IFN expression. Similarly, IFN-β induces SOCS1 expression through STAT activation, where SOCS1 inhibits JAK activity, thereby attenuating the JAK-STAT pathway and reducing sustained IFN responsiveness. These loops fine-tune the response, avoiding immunopathology from prolonged inflammation.33051-9/fulltext) Another regulatory circuit involves TRAF6-mediated K63-linked ubiquitination of IRF3, which initially promotes its but culminates in degradation to terminate signaling. TRAF6, recruited downstream of RIG-I/MAVS, catalyzes K63 polyubiquitination on IRF3, enhancing its by TBK1 and facilitating nuclear translocation for transcriptional activity. Subsequent shifts to K48-linked ubiquitination or deubiquitination lead to proteasomal degradation of activated IRF3, providing a self-limiting mechanism that resolves the acute phase of the response. IRF3 also participates in chromatin remodeling feedback loops by recruiting histone deacetylases (HDACs) to ensure transient access to target promoters like Ifnb1. In the enhanceosome assembly, IRF3 coordinates with co-factors to initially recruit HATs for chromatin opening, followed by HDAC recruitment—such as HDAC8 via intermediaries like TOB1—to restore repressive acetylation states post-transcription. This dynamic acetylation/deacetylation cycle limits promoter occupancy and IFN-β expression duration, preventing chronic activation while allowing rapid response initiation.

Biological Functions

Transcriptional Regulation

IRF3 functions as a key in the innate immune response by directly regulating the expression of type I interferons and other interferon-stimulated genes (ISGs). Upon activation, IRF3 primarily induces the transcription of interferon-beta (IFN-β) by binding to interferon-stimulated response elements (ISREs) within the IFN-β promoter. This binding is essential for the rapid and robust induction of IFN-β in response to viral infections and other pathogen-associated molecular patterns. Additionally, IRF3 cooperates with other transcription factors, such as and the ATF2/c-Jun heterodimer, to form a multicomponent enhanceosome complex at the IFN-β enhancer, which synergistically drives high-level . The (DBD) of IRF3 specifically recognizes a , typically 5'-GAAANNGAAA-3', which constitutes the core ISRE motif found in the promoters and enhancers of type I IFN genes. This sequence is present in the positive regulatory domains (PRDs) I and III of the IFN-β promoter, where IRF3 homodimers bind with high affinity following phosphorylation-induced conformational changes. The precise recognition of this motif ensures selective targeting of immune-related genes, distinguishing IRF3's activity from other IRF family members that may bind similar but divergent sites. Activated IRF3 recruits transcriptional coactivators such as (CBP) and p300 through its phosphorylated (TAD), particularly at serine residues like Ser386 and Ser396. This interaction enables CBP/p300 to exert (HAT) activity, acetylating histones at target promoters to promote opening and facilitate recruitment. The phospho-TAD-CBP/p300 association is critical for amplifying transcriptional output, as mutations disrupting this binding abolish IRF3's transactivation potential. Furthermore, IRF3 contributes to epigenetic reprogramming by facilitating the deposition of lysine 4 trimethylation () marks at loci of immune genes, including IFN-β and ISGs. This process involves IRF3's association with chromatin remodelers and methyltransferases, such as through interactions with ARID1A and NSD2, which deposit to establish active enhancer states and sustain during innate immune activation. Such epigenetic modifications ensure long-term accessibility of immune gene promoters beyond the initial signaling event.

Immune Response Roles

IRF3 plays a central role in antiviral defense by orchestrating the expression of interferon-stimulated genes (ISGs) such as protein kinase R (PKR) and 2'-5'-oligoadenylate synthetase (OAS). Upon activation, IRF3 induces type I interferons, which in turn upregulate PKR to phosphorylate eIF2α, thereby inhibiting viral protein translation and blocking . Similarly, OAS activation by double-stranded RNA leads to the production of 2-5A oligonucleotides that stimulate RNase L, resulting in the degradation of viral and cellular single-stranded to limit viral spread. In inflammatory signaling, IRF3 contributes to the production of like (IP-10), which is directly activated by IRF3 binding to the CXCL10 promoter in response to viral infections such as (HCV), independent of in some contexts. This chemokine induction facilitates the recruitment of T cells and other immune effectors to sites of infection, amplifying the inflammatory response and coordinating leukocyte trafficking. Recent studies (as of 2024) also reveal IRF3's role in repressing NF-κB-driven inflammation in macrophages and modulating neuroinflammatory responses to endotoxins like LPS, further balancing immune activation. IRF3 also mediates crosstalk between innate and adaptive immunity by promoting (DC) maturation and enhancing . Through type I induction, IRF3 upregulates molecules on DCs, improving the presentation of viral antigens to CD8+ T cells and fostering cytotoxic T lymphocyte responses. Additionally, IRF3 in DCs supports IL-12 production, which drives Th1 polarization and strengthens adaptive antiviral immunity. Beyond immunity, IRF3 briefly influences metabolic regulation in adipocytes by promoting inflammatory cytokine expression and repressing thermogenic programs, such as browning of , though its primary functions remain in immune responses.

Molecular Interactions

Protein Partners

IRF3, a pivotal in innate immunity, interacts with a diverse array of proteins to regulate its activation, dimerization, and transcriptional output. These protein-protein interactions primarily occur through specific domains of IRF3, such as the regulatory domain and (TAD), and are modulated by post-translational modifications like and ubiquitination. Key partners include kinases, scaffolds, co-activators, and adaptors that collectively fine-tune IRF3's role in antiviral signaling. Central to IRF3 activation are interactions with the kinases TBK1 and IKKε, which bind to IRF3's C-terminal regulatory domain to phosphorylate serine residues (e.g., Ser385 and Ser386), inducing a conformational shift that enables dimerization and nuclear translocation. Upstream adaptor proteins MAVS and STING function as scaffolds, recruiting IRF3 alongside TBK1/IKKε to facilitate proximity-dependent phosphorylation; for instance, phosphorylated MAVS directly binds IRF3 via a pLxIS motif, promoting efficient access. These scaffold interactions are essential in - and DNA-sensing pathways, respectively, ensuring rapid IRF3 activation upon detection. In the nucleus, activated IRF3 engages co-factors CBP and p300 through its TAD, forming a complex that acetylates histones and IRF3 itself to synergistically drive transcription of type I interferons and interferon-stimulated genes (ISGs). Crystal structures reveal that this binding stabilizes IRF3's association with promoters, enhancing transcriptional efficiency. Additionally, IRF3 forms heterodimers with IRF7, particularly during the late phase of interferon induction, where the phosphorylated forms of both proteins interact via their DNA-binding domains to amplify expression of a broader IFN repertoire compared to IRF3 homodimers. Adaptor proteins TRAF3 and TRAF6 further modulate IRF3 by undergoing K63-linked ubiquitination, which recruits TBK1 to the signaling complex and sustains IRF3 activation; TRAF3 specifically promotes IRF3-dependent IFN production, while TRAF6 links to parallel pathways. For regulation, the prolyl Pin1 binds phosphorylated Ser339-Pro340 on IRF3, catalyzing cis-trans that exposes ubiquitination sites, leading to proteasomal degradation and termination of the response. High-throughput interactome analyses, including affinity purification-mass spectrometry, have identified numerous IRF3 binding partners, with enrichment in innate immunity and antiviral pathways, underscoring its central hub role in immune signaling networks. Recent studies (as of 2024) have identified additional partners such as AXIN1, which interacts with IRF3 to stabilize it and enhance antiviral responses against DNA and RNA viruses, and DYRK4, which promotes IRF3 phosphorylation to upregulate innate immunity.

DNA and RNA Binding

IRF3 primarily interacts with DNA through its N-terminal DNA-binding domain (DBD), which recognizes interferon-stimulated response elements (ISREs) and IRF-E motifs, such as the PRDIII-I sequence in the IFN-β enhancer (5'-TTGTTTCATTT-3'). The DBD adopts a helix-turn-helix fold stabilized by five conserved tryptophan residues that form a hydrophobic core, enabling insertion of the recognition helix (α3) into the major groove of DNA. Key base-specific contacts are mediated by arginine residues; for instance, Arg81 forms hydrogen bonds with guanine in the core GAAA motif, while Arg78 and Arg86 interact with adjacent adenine bases, ensuring sequence specificity. Crystal structures, such as that of the IRF3 DBD bound to the IFN-β enhancer (PDB: 1T2K), reveal that these interactions induce DNA bending by approximately 23° and widening of the minor groove, facilitating stable complex formation. The binding affinity of the IRF3 DBD to ISRE motifs is moderate, with a (Kd) of approximately 486 nM, as measured by assays. This affinity is enhanced through cooperative interactions with family members at composite enhancer elements, such as the IFN-β promoter, where tandem binding sites allow synergistic stabilization of the enhanceosome complex without direct protein-protein contacts between IRF3 and ; instead, DNA deformation propagates cooperative effects. In the context of , activated IRF3 preferentially accesses open promoters following virus-induced hyperacetylation of and H4 tails, which loosens structure and exposes ISRE sites, as observed at the IFN-β locus post-infection. This epigenetic modification, mediated by histone acetyltransferases recruited alongside IRF3, ensures targeted transcriptional activation. IRF3 does not directly bind RNA, lacking a dedicated RNA-recognition motif, but indirectly modulates RNA sensing pathways through transcriptional feedback. Activation of IRF3 induces type I interferons, which in turn upregulate RIG-I expression via an ISRE in its promoter, creating a loop that amplifies responses to viral RNA agonists recognized by RIG-I. This mechanism sustains antiviral signaling without requiring physical interaction of IRF3 with RNA molecules.

Clinical and Pathological Relevance

Associated Diseases

Dysregulation of IRF3 has been implicated in various primary immunodeficiencies, particularly those involving impaired antiviral responses. Heterozygous mutations in IRF3, such as the R285Q variant, lead to functional deficiency that disrupts (IFN) production, rendering individuals susceptible to severe infections like (HSE). This mutation impairs IRF3 phosphorylation, dimerization, and transcriptional activation, specifically hindering signaling through the TLR3-TRIF pathway in response to herpes simplex virus type 1 (HSV-1), thereby reducing type I IFN induction and exacerbating infections. In autoimmune disorders, hyperactivation of IRF3 contributes to through excessive type I IFN signaling. In systemic lupus erythematosus (SLE), gain-of-function mutations in STING, an upstream activator of IRF3, promote constitutive IRF3 activation and downstream IFN production, driving chronic inflammation and formation in a subset of patients. This STING-IRF3 axis amplifies maturation and type I IFN responses to self-nucleic acids, correlating with disease severity in STING-associated vasculopathy and SLE-like phenotypes. IRF3 exhibits context-dependent roles in cancer, acting as a tumor suppressor in some malignancies while promoting oncogenesis in others via chronic inflammation. Loss of IRF3 function or expression in cells correlates with increased metastatic potential, as IRF3 via the cGAS-STING pathway enhances type I IFN signaling to suppress tumor progression and invasion. Conversely, persistent IRF3 in chronic inflammatory settings, such as through IL-33 induction, fosters a pro-tumorigenic microenvironment that supports in models of inflammation-driven cancers like . In metabolic diseases, IRF3 mediates obesity-associated and . Genetic knockout of IRF3 in adipocytes protects against high-fat diet-induced adipose , , and glucose intolerance in mouse models, as IRF3 drives IFN-dependent suppression of and exacerbates metabolic dysfunction. Studies as of 2024 highlight that IRF3 ablation mitigates these effects by reducing pro-inflammatory production in visceral fat, underscoring its role in linking innate immunity to metabolic pathology. Recent studies (2024-2025) have further linked IRF3 dysregulation to additional conditions. In , IRF3 modulates inflammatory responses and influences changes, contributing to . In , IRF3 drives neuroinflammation, exacerbating disease progression. Additionally, IRF3 shows paradoxical effects in , regulating vascular inflammation in a context-dependent manner.

Therapeutic Targeting

Therapeutic targeting of IRF3 primarily focuses on modulating its through upstream kinases or pathway components to treat conditions involving dysregulated innate immunity. Inhibitors of TBK1, such as BX795, block IRF3 and subsequent production, demonstrating efficacy in preclinical models of autoimmune diseases by attenuating excessive type I responses. Similarly, broader TBK1 inhibition has shown potential in reducing in interferonopathies, with ongoing exploring its translation to clinical settings. On the activation side, STING agonists like ADU-S100 (also known as MIW815) indirectly enhance IRF3 signaling to boost antitumor immunity, particularly in . In a phase Ib completed in 2022, intratumoral administration of ADU-S100 combined with the PD-1 inhibitor spartalizumab showed initial promising antitumor activity and safety in patients with advanced solid tumors, including , leading to increased responses and immune cell infiltration. However, further development of ADU-S100 has been terminated due to limited overall clinical efficacy as of 2025. Preclinical studies further support its role in promoting IRF3-dependent type I production to overcome tumor immune evasion. Gene therapy approaches, including /-mediated editing of IRF3, have been employed in viral susceptibility models to dissect its protective roles. In knockout models, IRF3 disruption via / increases vulnerability to virus, highlighting IRF3's essential antiviral function and potential for therapeutic restoration in susceptibility disorders. Additionally, in salmonid cell lines, IRF3 knockouts abolish induction upon viral mimics, underscoring opportunities for targeted editing to enhance antiviral defenses. Antisense oligonucleotides (ASOs) targeting negative regulators like NLRC3, which suppresses STING-IRF3 signaling, represent another strategy to amplify IRF3 activity, though primarily validated in preclinical contexts for bolstering anti-tumor immunity. Recent research (2024) highlights additional therapeutic opportunities, including AXIN1-mediated stabilization of IRF3 to enhance antiviral responses and IRF3 inhibition in models to mitigate excessive inflammation. In , targeting oncogenic IRF3 signaling shows promise for reducing proliferation. Challenges in IRF3 targeting include off-target effects that exacerbate , such as systemic storms from STING agonists or unintended immune suppression from inhibitors. To address these, biomarkers like phosphorylated IRF3 levels enable patient stratification by assessing pathway activation status, guiding precise interventions in trials for autoimmune and oncologic conditions.

References

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