Affinage

IRF3

Interferon regulatory factor 3 · UniProt Q14653

Length
427 aa
Mass
47.2 kDa
Annotated
2026-06-10
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRF3 is a latent cytoplasmic transcription factor that converts innate detection of viral nucleic acids into type I interferon induction (PMID:10048763, PMID:12692549). Upon infection, the phosphorylated adaptors MAVS, STING, and TRIF expose a positively charged surface that recruits IRF3 to a TBK1/IKKε kinase complex, which phosphorylates IRF3 at its C-terminal serines and licenses its activation (PMID:25636800, PMID:12692549); STING acts as a dual scaffold that simultaneously binds TBK1 and IRF3 and serves as the specificity determinant directing TBK1 onto IRF3, with the pS365/pS366 surface defining the IRF3 recruitment site (PMID:22394562, PMID:18818105, PMID:33785602). Phosphorylation drives IRF3 homodimerization through a pSer386-centered pLxIS interface, association with the CBP/p300 coactivator, and nuclear translocation, where IRF3 (and IRF7) homodimers engage ISRE-type sites to activate IFN-β and antiviral genes (PMID:32826280, PMID:10048763, PMID:29361124). IRF3 output is tuned by an extensive layer of post-translational and cofactor control: deglutathionylation by GRX-1 enables productive CBP binding (PMID:18309294), serine pyrophosphorylation by UAP1 and AKT3-mediated Ser385 phosphorylation reinforce dimerization (PMID:36603579, PMID:31882361), while acetylation by KAT8 at K359, inhibitory phosphorylation by Mst1, MID1-driven K48-ubiquitination and proteasomal turnover, and OTUD7B/p62-mediated autophagic degradation restrain it (PMID:30842237, PMID:27125670, PMID:33513265, PMID:35100065); AXIN1/USP35 conversely stabilize resting IRF3 by stripping degradative ubiquitin (PMID:39384753). Nuclear translocation is gated by KPNA2 (stabilized by USP22) and by lncRNA-ISIR, which displaces the suppressor Flightless-1 (PMID:32130408, PMID:34731629), and is opposed by direct binding partners including CALML6, PRMT6, vimentin, and nuclear cFLIPL (PMID:30699354, PMID:29973649, PMID:36223739, PMID:27342840). Beyond IFN induction, IRF3 acts as a non-transcriptional adaptor that, when docked at STING pS358, drives trafficking to late endolysosomes and recruits TRAF6 to activate NF-κB (PMID:40973797), sequesters β-catenin and binds p65 in the cytoplasm to restrain Wnt and NF-κB signaling (PMID:33188184, PMID:36067309), and engages RB to drive senescence and limit fibrosis (PMID:38416816). IRF3 further controls metabolism, promoting adipose inflammation and insulin resistance, suppressing thermogenesis via an ISG15/glycolysis axis, and transcriptionally activating Ppp2r1b to govern hepatic glucose homeostasis (PMID:27400129, PMID:33571167, PMID:35320000).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Established the core activation logic of IRF3 — that a constitutively cytoplasmic factor is switched on by C-terminal phosphorylation that couples nuclear entry, DNA binding, and coactivator recruitment.

    Evidence Phosphorylation, nuclear translocation, CBP/p300 Co-IP and reporter assays in virus-infected cells

    PMID:10048763

    Open questions at the time
    • Identity of the activating kinase(s) not resolved
    • Structural basis of phosphorylation-driven dimerization unknown
  2. 2003 High

    Identified TBK1 and IKKε as the kinases responsible for IRF3 phosphorylation, defining the proximal enzymatic step downstream of viral and TLR3 sensing.

    Evidence Genetic loss-of-function, kinase assays, and pathway epistasis

    PMID:12692549

    Open questions at the time
    • How IRF3 is delivered to these kinases was not yet defined
    • Specificity determinants for IRF3 vs other substrates unaddressed
  3. 2008 High

    Connected the adaptor STING/MITA to IRF3 activation, showing it associates with MAVS at mitochondria, binds IRF3, and recruits TBK1, integrating the sensing platform.

    Evidence Expression cloning, reciprocal Co-IP, knockdown, subcellular fractionation

    PMID:18818105

    Open questions at the time
    • Did not define the molecular recruitment surface on the adaptor
    • Stoichiometry of the STING-TBK1-IRF3 complex unknown
  4. 2012 High

    Resolved STING as a scaffold and specificity determinant — selectively disrupting STING-IRF3 binding blocks IRF3 phosphorylation without impairing TBK1, explaining how kinase output is targeted.

    Evidence In vitro reconstitution and selective mutagenesis with Co-IP

    PMID:22394562

    Open questions at the time
    • Precise phosphosite mediating recruitment not pinpointed here
  5. 2015 High

    Generalized the recruitment mechanism, showing phosphorylated MAVS, STING, and TRIF each expose a conserved positively charged surface that docks IRF3 for phosphorylation.

    Evidence In vitro reconstitution, pulldown, and mutagenesis across three adaptors

    PMID:25636800

    Open questions at the time
    • IRF3 residues contacting the adaptor surface not fully mapped
    • Whether docking dictates dimer geometry unknown
  6. 2020 High

    Provided the structural mechanism of activation, showing phospho-IRF3 dimerizes through a pSer386/pLxIS interface bound to CBP, with pSer386 dominating over pSer396.

    Evidence Crystal structures of phospho-IRF3-CBP with SEC and cell-based mutagenesis

    PMID:32826280

    Open questions at the time
    • Dynamics of the latent-to-active transition not captured
    • Role of additional phosphosites in vivo not resolved structurally
  7. 2018 Medium

    Defined the DNA-recognition logic distinguishing IRF3/IRF7 from IRF5 at ISRE-type IFN response elements through a single specificity-determining residue and affinity-independent allostery.

    Evidence Protein-binding microarrays, mutagenesis, reporter assays

    PMID:29361124

    Open questions at the time
    • In vivo genome occupancy not assessed
    • Contribution of cofactors to site selection unaddressed
  8. 2023 High

    Built out the multilayered post-translational tuning of IRF3 activation, adding pyrophosphorylation (UAP1), arginine methylation (PRMT2), and AKT3 Ser385 phosphorylation as positive inputs cooperating with TBK1.

    Evidence In vitro enzymatic/methylation assays, mutagenesis, and KO mice across studies

    PMID:31882361 PMID:34583098 PMID:36603579

    Open questions at the time
    • Crosstalk and ordering among these modifications unknown
    • Relative contribution in different cell types unquantified
  9. 2019 High

    Defined negative-regulatory modifications that cap IRF3 output — KAT8 acetylation at K359 and Mst1 phosphorylation at Thr75/Thr253 each block dimerization or promoter recruitment.

    Evidence RNAi screens, in vitro acetylation/kinase assays, site mutagenesis, KO mice, ChIP

    PMID:27125670 PMID:30842237

    Open questions at the time
    • Stimuli controlling these brakes not fully defined
    • Interplay with activating modifications unresolved
  10. 2019 High

    Established redox and degradative control of IRF3 — GRX-1 deglutathionylation gates CBP binding, and caspase-3/7 cleavage curtails IFN to prevent cytokine overproduction.

    Evidence Modification assays, knockdown/Co-IP, in vitro cleavage, and caspase KO models

    PMID:18309294 PMID:30878284

    Open questions at the time
    • Triggers coupling caspase activity to IRF3 cleavage in homeostasis unclear
    • Glutathionylation site(s) not all defined
  11. 2021 Medium

    Mapped trafficking-level control of IRF3 — KPNA2 (stabilized by USP22) and lncRNA-ISIR (displacing Flightless-1) drive nuclear translocation, while MID1, OTUD7B/p62, and AXIN1/USP35 set IRF3 abundance through ubiquitin-dependent degradation pathways.

    Evidence Co-IP, (de)ubiquitination assays, RNA pulldown, conditional/global KO mice and rescue

    PMID:32130408 PMID:33513265 PMID:34731629 PMID:35100065 PMID:39384753

    Open questions at the time
    • Hierarchy among degradation routes not established
    • Whether these operate redundantly or in distinct cell types unknown
  12. 2023 High

    Revealed condensate-based regulation, identifying a SUMO-interacting motif in IRF3 that recruits it to MAVS phase-separated droplets, with phosphorylation releasing activated IRF3 from condensates.

    Evidence Phase-separation reconstitution, mutagenesis, SENP1 KO/reconstitution

    PMID:37188808

    Open questions at the time
    • Quantitative contribution of condensate residence to signaling unknown
    • Generality across adaptors not tested
  13. 2022 Medium

    Inventoried inhibitory binding partners that intercept IRF3 at distinct steps — CALML6, PRMT6, vimentin, and nuclear cFLIPL block dimerization, kinase association, or enhanceosome formation.

    Evidence Co-IP, domain binding, ChIP, transgenic/KO mice, reporter assays

    PMID:27342840 PMID:29973649 PMID:30699354 PMID:36223739

    Open questions at the time
    • Physiological contexts selecting each inhibitor unclear
    • Most rest on single-lab Co-IP without reciprocal in vitro reconstitution
  14. 2025 High

    Established a transcription-independent role: IRF3 docked at STING pS358 with delayed kinetics drives endolysosomal trafficking and recruits TRAF6 to activate NF-κB, separating IRF3's adaptor function from IFN induction.

    Evidence STING phosphosite mutagenesis (pS358/pS366), Co-IP, trafficking assays, IRF3 KO cells

    PMID:40973797

    Open questions at the time
    • Structural basis of monomeric IRF3 recruitment at pS358 not solved
    • How kinetic delay between sites is timed unknown
  15. 2024 High

    Extended IRF3 into cell-fate and signaling crosstalk beyond immunity — sequestering β-catenin and p65 in the cytoplasm to restrain Wnt and NF-κB, and binding RB to drive senescence and limit fibrosis.

    Evidence Endogenous Co-IP, global/conditional KO mice, CDK4/6-inhibitor rescue, tumor and fibrosis models

    PMID:33188184 PMID:36067309 PMID:38416816

    Open questions at the time
    • Whether these moonlighting functions require IRF3 activation status differs by context
    • Direct structural interfaces with β-catenin/RB undefined
  16. 2022 High

    Defined IRF3 as a metabolic regulator — promoting adipose inflammation and insulin resistance, repressing thermogenesis via an ISG15/glycolysis axis, and transcriptionally activating Ppp2r1b to control hepatic glucose output.

    Evidence Conditional/global KO mice, ChIP-seq cistrome, ISGylation and PP2A activity assays, metabolic phenotyping

    PMID:27400129 PMID:33571167 PMID:35320000

    Open questions at the time
    • Upstream signals activating metabolic IRF3 in obesity not fully defined
    • Tissue-specific target gene programs incompletely mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many parallel activating and inhibitory inputs are integrated into a single quantitative, context-specific IRF3 output — and what dictates the switch between its transcriptional and non-transcriptional/moonlighting modes — remains unresolved.
  • No unified model ranking the relative weight of competing modifications
  • Determinants selecting IFN vs NF-κB vs metabolic vs senescence programs unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 4 GO:0005768 endosome 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
CBPCTNNB1KPNA2MAVSSTINGTBK1TRAF6TRIF
Complex memberships
STING-TBK1-IRF3 complexTRIF-TRAF3-TBK1-IRF3 complex

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 IKKε (IKKepsilon) and TBK1 are essential kinases that phosphorylate and activate IRF3 in the innate immune signaling pathway downstream of viral infection and TLR3 engagement. Genetic loss-of-function (knockout/knockdown), kinase assays, epistasis in signaling pathway Nature immunology High 12692549
2015 Phosphorylated adaptor proteins MAVS, STING, and TRIF each expose a positively charged surface that directly recruits IRF3, positioning it for phosphorylation by TBK1; this phosphorylation-dependent docking mechanism is conserved across all three adaptors. In vitro reconstitution, biochemical pulldown, mutagenesis, co-immunoprecipitation Science (New York, N.Y.) High 25636800
2008 MITA (STING) localizes to the outer mitochondrial membrane, associates with MAVS/VISA, interacts directly with IRF3, and recruits TBK1 to the MAVS complex; TBK1-mediated phosphorylation of MITA is required for MITA-mediated IRF3 activation. Expression cloning, co-immunoprecipitation, knockdown, subcellular fractionation/localization Immunity High 18818105
2012 STING functions as a scaffold that simultaneously binds both TBK1 and IRF3 via its C-terminal region; STING mutations that selectively disrupt IRF3 binding abolish IRF3 phosphorylation without impairing TBK1 activation, establishing STING as a specificity determinant for TBK1-mediated IRF3 phosphorylation. In vitro reconstitution, mutagenesis, co-immunoprecipitation Science signaling High 22394562
2020 Crystal structures of phosphorylated human and mouse IRF3 bound to CBP reveal that phosphorylated IRF3 dimerizes via pSer386 (human) / pSer379 (mouse) and a downstream pLxIS motif; mutations disrupting the pSer386 interface severely impair IRF3 activation and IFN-β induction, while pSer396 plays only a moderate role. Crystal structure determination, size-exclusion chromatography, cell-based mutagenesis Journal of immunology (Baltimore, Md. : 1950) High 32826280
2019 Apoptotic caspase-3 (human) or caspase-7 (mouse) directly cleaves IRF3 to prevent cytokine overproduction during viral infection; caspase-3-deficient cells show elevated type I IFNs without infection, demonstrating a negative regulatory mechanism. In vitro cleavage assay, caspase knockout cells and mice, flow cytometry, viral infection assays Molecular cell High 30878284
1999 IRF3 is constitutively expressed in the cytoplasm; upon viral infection it undergoes C-terminal serine/threonine phosphorylation, which drives cytoplasmic-to-nuclear translocation, stimulates DNA binding, and promotes association with the CBP/p300 coactivator to activate IFN gene transcription. Phosphorylation analysis, nuclear translocation assays, co-immunoprecipitation with CBP/p300, reporter assays Journal of interferon & cytokine research High 10048763
2016 Mst1 kinase directly phosphorylates IRF3 at Thr75 and Thr253, abolishing virus-induced IRF3 homodimerization and chromatin occupancy, thereby suppressing type I IFN production; Mst1 also impedes TBK1 activation. Kinome screen, in vitro kinase assay, mutagenesis, Co-IP, Mst1-deficient cells and mice Genes & development High 27125670
2019 KAT8 acetyltransferase directly interacts with IRF3 and acetylates IRF3 at lysine 359 via its MYST domain, inhibiting IRF3 recruitment to IFN-I gene promoters and reducing transcriptional activity; KAT8 deficiency enhances IFN-I production and protects mice from viral challenge. RNAi screen, Co-IP, in vitro acetylation assay, mutagenesis, KAT8 KO mice, ChIP The Journal of experimental medicine High 30842237
2008 IRF3 is S-glutathionylated in uninfected cells; upon viral infection, cytoplasmic glutaredoxin-1 (GRX-1) deglutathionylates IRF3, enabling efficient IRF3–CBP interaction and transcriptional activation of IFN-β; knockdown of GRX-1 blocks IFN-β expression without affecting IRF3 phosphorylation, homodimerization, or nuclear translocation. S-glutathionylation assay, GRX-1 knockdown, Co-IP with CBP, reporter assay The EMBO journal High 18309294
2020 USP22 deubiquitinates and stabilizes the importin KPNA2 after viral infection; this stabilization is required for KPNA2-dependent nuclear translocation of IRF3. Viral infection induces USP22–IRF3 association in the cytoplasm in a KPNA2-dependent manner; USP22 or KPNA2 knockout impairs IRF3 nuclear translocation and antiviral gene expression. Co-IP, deubiquitination assay, conditional KO mice, reconstitution of KPNA2 in KO cells, nuclear fractionation The Journal of experimental medicine High 32130408
2016 mTOR effector kinase S6K1 interacts with STING in a cGAS-dependent manner after DNA virus infection; the kinase domain (but not kinase activity) of S6K1 mediates this interaction; a tripartite S6K1–STING–TBK1 complex is necessary for IRF3 activation in the cytosolic DNA pathway. Co-IP, mutagenesis, kinase-dead mutants, genetic knockdown, viral infection assays Nature immunology High 27043414
2021 MID1 ubiquitin E3 ligase physically interacts with IRF3 and induces K48-linked polyubiquitination at Lys313, leading to proteasomal degradation of IRF3 and suppression of type I IFN production. Co-IP, ubiquitination assay, site-directed mutagenesis (K313), protein stability assay, viral infection Immunology Medium 33513265
2022 OTUD7B deubiquitinase interacts with IRF3 and activates the cargo receptor SQSTM1/p62 by removing K63-linked poly-ubiquitin at K7, enhancing SQSTM1 oligomerization and promoting selective autophagic degradation of IRF3 to limit type I IFN signaling. Co-IP, deubiquitination assay, mutagenesis, autophagy inhibitor experiments Autophagy Medium 35100065
2021 lncRNA-ISIR directly binds the DNA-binding domain of IRF3 in the cytoplasm and displaces the suppressor protein Flightless-1 (Fli-1), which normally keeps IRF3 inactive; this promotes IRF3 phosphorylation, dimerization, and nuclear translocation. The human homolog AK131315 has the same function. RNA pulldown, Co-IP, knockdown/overexpression, lncRNA-ISIR KO mice, nuclear fractionation Cell reports Medium 34731629
2023 MAVS poly-SUMOylation (by PIAS3) promotes K63-linked poly-ubiquitination and aggregation, enabling phase separation; a newly identified SUMO-interacting motif (SIM) in IRF3 mediates its enrichment to MAVS phase-separated droplets; phosphorylation of IRF3 at key residues near the SIM disables SUMO-SIM interactions and releases activated IRF3 from MAVS condensates. Co-IP, mutagenesis, phase separation assay, SENP1 knockout/reconstitution, biochemical fractionation Nature structural & molecular biology High 37188808
2005 A yeast two-hybrid screen identified IRF3 as a binding partner of the GRIP1 corepression domain; endogenous GRIP1 and IRF3 interact in mammalian macrophages; glucocorticoid receptor (GR) competes with IRF3 for GRIP1 binding, and GR activation or GRIP1 knockdown blocks IRF3-dependent gene expression, identifying GRIP1 as a cofactor for IRF3-mediated innate immune transcription. Yeast two-hybrid, co-immunoprecipitation of endogenous proteins, knockdown, reporter assay, MyD88/IFNAR-deficient mouse epistasis The EMBO journal High 16362036
2011 IRF8 and IRF3 physically interact in human blood monocytes (interaction independent of IRF8 DNA-binding domain and IRF3 IRF association domain); IRF8 constitutively binds the ETS/IRF composite element of the IFN-β promoter with PU.1, forming a scaffold that facilitates rapid IRF3 recruitment for fast IFN-β induction. Co-IP of endogenous proteins, domain mapping, IRF8 knockdown, IRF8 reconstitution in IRF8−/− cells, in vivo ChIP Blood Medium 21228327
2018 PRMT6 binds IRF3 upon viral infection and blocks the TBK1–IRF3 interaction, preventing IRF3 activation; this inhibitory function is independent of PRMT6 methyltransferase catalytic activity. Co-IP, PRMT6 KO mice, viral infection assays, catalytic mutant rescue experiments Cellular & molecular immunology Medium 29973649
2019 7-dehydrocholesterol (7-DHC) promotes AKT3 expression; AKT3 directly binds and phosphorylates IRF3 at Ser385; this phosphorylation cooperates with TBK1-mediated phosphorylation of Ser386 to achieve IRF3 dimerization and type I IFN production. Co-IP, in vitro kinase assay, mutagenesis, DHCR7 knockout Immunity Medium 31882361
2016 In resting state, IRF3 associates with active β-catenin in the cytoplasm, preventing β-catenin nuclear translocation and intestinal cell proliferation; microbe-induced IRF3 activation relieves this sequestration, linking innate immune sensing to Wnt pathway regulation. Co-IP of endogenous proteins, IRF3 KO mice (AOM/DSS and Apcmin/+ models), nuclear fractionation, proliferation assays Nature communications High 33188184
2024 Activated nuclear IRF3 forms endogenous complexes with retinoblastoma protein (RB), attenuates CDK4/6-mediated RB hyperphosphorylation, and thereby activates RB to suppress E2F transcription factors, driving hepatic stellate cells into senescence and limiting liver fibrosis. Co-IP of endogenous IRF3-RB complexes, IRF3 global and conditional KO mice, CDK4/6 inhibitor rescue, murine liver fibrosis models Science advances High 38416816
2021 IRF3 drives expression of ISG15, which becomes covalently attached (ISGylation) to glycolytic enzymes, reducing their function and decreasing lactate production; reduced lactate suppresses thermogenic gene expression in adipocytes. IRF3 acts upstream of ISG15 in an axis that represses adipose thermogenesis. Conditional IRF3 KO mice, ISG15 KO mice, ISGylation assay, metabolite (lactate) rescue experiments, oxygen consumption assays The Journal of clinical investigation High 33571167
2022 IRF3 directly binds the p65 subunit of NF-κB in the cytoplasm of virus-infected cells, preventing p65 nuclear import and thereby attenuating NF-κB-driven inflammatory gene induction (RIKA function). An IRF3 mutant defective in transcriptional and apoptotic activities retains RIKA activity. Co-IP of IRF3 and p65, Irf3−/− mouse lung infection model, IRF3 mutant functional assays, nuclear fractionation Proceedings of the National Academy of Sciences of the United States of America High 36067309
2018 IRF3 and IRF7 homodimers display common and dimer-specific DNA-binding profiles as determined by protein-binding microarrays; IRF3 and IRF7 (but not IRF5) bind ISRE-type sites in IFN gene virus-response elements; a single specificity-determining residue inhibits IRF5 homodimer binding to these sites. DNA-binding affinity and affinity-independent allostery both contribute to dimer function. Protein-binding microarrays (PBM), mutagenesis, reporter gene assays Nucleic acids research Medium 29361124
2005 Thogoto virus ML protein blocks IRF3 dimerization and association with CBP, suppressing IFN gene transcription, without affecting IRF3 nuclear translocation. Viral infection/expression assays, dimerization assay, Co-IP with CBP, nuclear localization analysis Virology Medium 15582653
2016 cFLIPL binds to IRF3 in the nucleus and disrupts IRF3 interaction with both its IFN-β promoter DNA and the coactivator CBP, preventing IRF3 enhanceosome formation; nuclear localization of cFLIPL is necessary and sufficient for this inhibitory function, and cFLIPL does not degrade or dephosphorylate IRF3. Co-IP, ChIP, cFLIPL nuclear localization mutants, reporter assay, mutagenesis Journal of immunology (Baltimore, Md. : 1950) Medium 27342840
2019 CALML6 (EF-hand protein) directly binds the phosphorylated serine-rich region of IRF3, impairing IRF3 dimerization and nuclear translocation, thereby suppressing type I IFN production; CALML6 transgenic mice show impaired IFN-β and enhanced viral replication. Co-IP, domain binding assay, nuclear fractionation, CALML6 transgenic mice, IFN-β reporter assay Cell reports Medium 30699354
2023 Metabolic enzyme UAP1 acts as a pyrophosphorylase that catalyzes serine pyrophosphorylation of IRF3 at Ser386, promoting robust IRF3 dimerization and type I IFN responses; Uap1-deficient mice are highly susceptible to lethal viral infection. In vitro pyrophosphorylation assay, mutagenesis, Uap1 KO mice, viral infection assays Molecular cell High 36603579
2021 TLR3 signaling, acting through IRF3, activates the Tslp gene promoter in intestinal epithelial cells via IRF-binding sequences, and IRF3 is required for intestinal homeostasis and protection against DSS-induced colitis in mice. IRF3 KO mice (DSS colitis model), promoter reporter assay, ChIP for IRF3 binding Proceedings of the National Academy of Sciences of the United States of America Medium 23213237
2022 Hepatic IRF3 directly transcriptionally activates Ppp2r1b (a PP2A subunit), which amplifies PP2A phosphatase activity leading to dephosphorylation of AMPKα and AKT, thereby suppressing glucose production and causing dysglycemia in obese mice. ChIP-seq (cistrome), IRF3 global and hepatocyte-specific KO mice, antisense oligonucleotide knockdown, PP2A activity assay Science translational medicine High 35320000
2018 IRF3 interacts with YAP and TEAD4 in the nucleus, enhancing their interaction, promoting YAP nuclear retention and activation, and co-binding YAP-TEAD4 target gene loci genome-wide; pharmacological targeting of IRF3 inhibits gastric tumor growth in a YAP-dependent manner. Co-IP of endogenous proteins, ChIP-seq, IRF3 KO/knockdown, YAP-rescue experiments, tumor xenograft The Journal of experimental medicine Medium 29339449
2025 STING activates NF-κB using IRF3 as a non-transcriptional adaptor: monomeric IRF3 is recruited to STING pS358 (with delayed kinetics compared to IRF3 recruitment to pS366 for IFN induction); IRF3 bound at pS358 drives STING trafficking to late endolysosomal compartments, where a TRAF6-binding motif in IRF3 facilitates TRAF6 recruitment and NF-κB activation. This function is independent of type I IFN signaling. Mutagenesis of STING phosphosites (pS358/pS366), Co-IP, subcellular trafficking assays, TRAF6 binding motif identification, IRF3 KO cells, evolutionary conservation analysis Nature immunology High 40973797
2021 ZBP1–TBK1 interaction leads to constitutive IRF3 phosphorylation in multiple myeloma plasma cells; phosphorylated IRF3 directly binds and activates cell cycle gene promoters, in part cooperating with IRF4, to promote myeloma cell proliferation—a non-canonical, pro-proliferative role of IRF3. Co-IP of ZBP1-TBK1-IRF3, ChIP for IRF3 on cell cycle gene promoters, IRF3 knockdown, IRF4 co-binding analysis Haematologica Medium 33596642
2024 AXIN1 stabilizes IRF3 in resting state by recruiting USP35, which removes K48-linked ubiquitination at IRF3 K366 to prevent p62-mediated autophagic degradation; upon viral infection, phosphorylated TBK1 triggers AXIN1 phase separation, increasing IRF3 phosphorylation and IFN-I production. Co-IP, deubiquitination assay with USP35, K366 mutagenesis, AXIN1 phase separation assay, KO experiments, antiviral assays Signal transduction and targeted therapy Medium 39384753
2022 Vimentin interacts with TBK1 and IKKε and disrupts their respective interactions with IRF3, blocking IRF3 phosphorylation and nuclear translocation; vimentin KO mice show suppressed viral replication confirming antiviral relevance. Co-IP, vimentin KO mice, nuclear fractionation, viral replication assays Cell reports Medium 36223739
2015 Casein kinase II (CK2) controls TBK1 and IRF3 activation in TLR, RIG-I-like receptor, and cGAS/STING signaling pathways; CK2 acts indirectly through PP2A phosphatase as an intermediate; CK2 knockdown or kinase inhibition elevates IFN-αβ responses. CK2 knockdown, genetic ablation of CK2 kinase activity, kinase inhibitor experiments, viral infection assays Journal of immunology (Baltimore, Md. : 1950) Medium 25810395
2014 HSP60 (HSPD1) physically interacts with IRF3 and facilitates IRF3 phosphorylation and dimerization upon viral infection; HSPD1 overexpression enhances IFN-β induction upstream of the activated (5D) form of IRF3, while HSPD1 knockdown inhibits the pathway. Co-IP, HSPD1 knockdown/overexpression, IFN-β reporter assay, dimerization assay PloS one Medium 25506707
2021 IRF3 deficiency reduces p21 levels, causing precocious G2/M transition and increased chromosome missegregation (micronuclei formation), placing IRF3 in the cGAS/STING/TBK1/IRF3 pathway as required for chromosomal stability through p21 regulation. IRF3 knockdown, add-back of pathway components, micronuclei quantification, nocodazole-release assay, p21 overexpression rescue Experimental & molecular medicine Medium 32284536
2023 SARS-CoV-2 NSP13 directly interacts with IRF3 via its 1B domain and the IRF3 IRF association domain (IAD), independently of TBK1, blocking IRF3-directed signaling and antiviral gene expression. Co-IP, domain mutagenesis, IRF3-5D reporter assay (TBK1-independent), antiviral gene expression assays Journal of medical virology Medium 37314155
2024 During Ebola virus infection, nucleoprotein/VP35-induced viral inclusion bodies (IBs) recruit and sequester IRF3 (but not TBK1 or IKKε) via STING, blocking TBK1–IRF3 association and preventing IRF3 phosphorylation and nuclear translocation; STING knockdown attenuates IRF3 accumulation in IBs. Virus-like particle (trVLP) infection, co-localization imaging, Co-IP, STING knockdown, nuclear fractionation eLife Medium 38285487
2021 IRF3 transcriptional activity at Ser388/Ser390 is required for HAV-induced liver injury in mice; IRF3 with alanine substitutions at these residues (transcriptionally inactive) markedly attenuates hepatocyte apoptosis and liver inflammation, distinguishing transcription-dependent from non-transcriptional IRF3 functions in hepatitis. IRF3-S388A/S390A knock-in mice (Irf3S1/S1), transcriptome profiling, histological analysis of liver injury PLoS pathogens High 34591933
2021 TBK1 recruitment to STING via the C-terminal tail (CTT) is essential for both IRF3 (IFN) and NF-κB activation; a STING-S365A mutation that disrupts IRF3 binding specifically abolishes type I IFN induction while preserving NF-κB activation and autophagy, demonstrating that pS365/S366 is the IRF3 recruitment site on STING. STING knock-in mice (S365A, L373A, ΔCTT), viral infection (HSV-1), cGAMP antitumor experiments, genetic epistasis Proceedings of the National Academy of Sciences of the United States of America High 33785602
2021 Pim1 kinase promotes IRF3 phosphorylation and nuclear translocation not through its kinase activity per se, but by enhancing the formation of the TRIF–TRAF3–TBK1–IRF3 signaling complex; Pim1-deficient mice produce less serum IFN-β after poly(I:C) treatment. Co-IP, kinase-dead Pim1 mutant, Pim1 KO mice, nuclear fractionation, IFN-β ELISA Experimental & molecular medicine Medium 36446848
2021 IRF3-mediated transcription drives macrophage activation and an IRF3–interferon axis in cardiac macrophages (IFNICs) after myocardial infarction; mice deficient in IRF3 show improved survival, reduced inflammatory cytokine/chemokine expression, decreased inflammatory cell infiltration, attenuated ventricular dilation, and improved cardiac function after MI. IRF3 KO mice, single-cell RNA-seq of cardiac leukocytes, IFNAR-neutralizing antibody treatment, echocardiography Nature medicine High 29106401
2017 IRF3 promotes adipose inflammation: TLR3/TLR4 signaling through IRF3 induces insulin resistance in murine adipocytes; IRF3 knockdown prevents insulin resistance; IRF3-deficient mice on high-fat diet show reduced adipose and systemic inflammation, enhanced subcutaneous fat browning, and increased GLUT4 expression. IRF3 knockdown in adipocytes, IRF3 KO mice (high-fat diet), metabolic phenotyping, gene expression analysis The Journal of clinical investigation High 27400129
2023 PRMT2 methylates IRF3 at Arg285 after LPS stimulation; Arg285 methylation drives IRF3 dimerization and nuclear translocation, and mediates the TLR4–IRF3 interaction via TLR4 Arg812 methylation, enhancing IFN-β production. Arginine methylation assay, Co-IP, mutagenesis (R285, R812), nuclear fractionation, IFN-β reporter Molecular immunology Medium 34583098

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nature immunology 2227 12692549
2015 Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science (New York, N.Y.) 1623 25636800
2008 The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 1285 18818105
2012 STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Science signaling 1092 22394562
2006 Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 825 16413926
2019 STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3. Redox biology 520 31121492
2021 TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections. Proceedings of the National Academy of Sciences of the United States of America 480 33785602
2017 IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nature medicine 474 29106401
2007 Triggering the innate antiviral response through IRF-3 activation. The Journal of biological chemistry 387 17395583
2019 Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3. Molecular cell 274 30878284
1999 Triggering the interferon response: the role of IRF-3 transcription factor. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 205 10048763
2017 STING-associated vasculopathy develops independently of IRF3 in mice. The Journal of experimental medicine 173 28951494
2018 Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1-IKKϵ-IRF3 axis activation. The Journal of biological chemistry 168 29760187
2022 mtDNA-STING Axis Mediates Microglial Polarization via IRF3/NF-κB Signaling After Ischemic Stroke. Frontiers in immunology 153 35450066
2016 IRF3 promotes adipose inflammation and insulin resistance and represses browning. The Journal of clinical investigation 153 27400129
2019 Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection. Immunity 129 31882361
2005 The GRIP1:IRF3 interaction as a target for glucocorticoid receptor-mediated immunosuppression. The EMBO journal 124 16362036
2020 LncRNA Malat1 inhibition of TDP43 cleavage suppresses IRF3-initiated antiviral innate immunity. Proceedings of the National Academy of Sciences of the United States of America 121 32907941
2022 Regulation of IRF3 activation in human antiviral signaling pathways. Biochemical pharmacology 107 35367198
2020 The cGAS/STING/TBK1/IRF3 innate immunity pathway maintains chromosomal stability through regulation of p21 levels. Experimental & molecular medicine 97 32284536
2018 Targeting IRF3 as a YAP agonist therapy against gastric cancer. The Journal of experimental medicine 86 29339449
2020 IRF3 prevents colorectal tumorigenesis via inhibiting the nuclear translocation of β-catenin. Nature communications 78 33188184
2002 Overlapping and distinct mechanisms regulating IRF-3 and IRF-7 function. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 78 11846975
2016 Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation. Genes & development 76 27125670
2024 IRF3 activates RB to authorize cGAS-STING-induced senescence and mitigate liver fibrosis. Science advances 74 38416816
2021 IRF3 reduces adipose thermogenesis via ISG15-mediated reprogramming of glycolysis. The Journal of clinical investigation 74 33571167
2018 DNA-binding landscape of IRF3, IRF5 and IRF7 dimers: implications for dimer-specific gene regulation. Nucleic acids research 72 29361124
2019 KAT8 selectively inhibits antiviral immunity by acetylating IRF3. The Journal of experimental medicine 71 30842237
2020 USP22 promotes IRF3 nuclear translocation and antiviral responses by deubiquitinating the importin protein KPNA2. The Journal of experimental medicine 69 32130408
2011 IRF8 and IRF3 cooperatively regulate rapid interferon-β induction in human blood monocytes. Blood 67 21228327
2022 OTUD7B deubiquitinates SQSTM1/p62 and promotes IRF3 degradation to regulate antiviral immunity. Autophagy 62 35100065
2016 S6K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3. Nature immunology 62 27043414
2008 S-glutathionylation of IRF3 regulates IRF3-CBP interaction and activation of the IFN beta pathway. The EMBO journal 61 18309294
2005 Thogoto virus ML protein suppresses IRF3 function. Virology 60 15582653
2018 The methyltransferase PRMT6 attenuates antiviral innate immunity by blocking TBK1-IRF3 signaling. Cellular & molecular immunology 59 29973649
2020 IRF3 and IRF8 Regulate NF-κB Signaling by Targeting MyD88 in Teleost Fish. Frontiers in immunology 47 32373114
2020 Porcine Epidemic Diarrhea Virus nsp15 Antagonizes Interferon Signaling by RNA Degradation of TBK1 and IRF3. Viruses 46 32486349
2022 IRF3 inhibits nuclear translocation of NF-κB to prevent viral inflammation. Proceedings of the National Academy of Sciences of the United States of America 44 36067309
2020 Of Keeping and Tipping the Balance: Host Regulation and Viral Modulation of IRF3-Dependent IFNB1 Expression. Viruses 43 32645843
2023 MAVS deSUMOylation by SENP1 inhibits its aggregation and antagonizes IRF3 activation. Nature structural & molecular biology 41 37188808
2015 Casein kinase II controls TBK1/IRF3 activation in IFN response against viral infection. Journal of immunology (Baltimore, Md. : 1950) 40 25810395
2023 PARP7-mediated ADP-ribosylation of FRA1 promotes cancer cell growth by repressing IRF1- and IRF3-dependent apoptosis. Proceedings of the National Academy of Sciences of the United States of America 37 38011562
2022 The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma. Haematologica 37 33596642
2019 Inhibition of TLR4/TRIF/IRF3 Signaling Pathway by Curcumin in Breast Cancer Cells. Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 37 31287789
2012 Essential contribution of IRF3 to intestinal homeostasis and microbiota-mediated Tslp gene induction. Proceedings of the National Academy of Sciences of the United States of America 37 23213237
2024 Foot-and-mouth disease virus VP1 degrades YTHDF2 through autophagy to regulate IRF3 activity for viral replication. Autophagy 35 38516932
2022 Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b. Science translational medicine 34 35320000
2022 Vimentin inhibits type I interferon production by disrupting the TBK1-IKKε-IRF3 axis. Cell reports 33 36223739
2019 cGAS/STING/TBK1/IRF3 Signaling Pathway Activates BMDCs Maturation Following Mycobacterium bovis Infection. International journal of molecular sciences 33 30791397
2023 ZBP1 mediates the progression of Alzheimer's disease via pyroptosis by regulating IRF3. Molecular and cellular biochemistry 32 36964897
2021 Ubiquitin E3 ligase MID1 inhibits the innate immune response by ubiquitinating IRF3. Immunology 32 33513265
2021 IRF3-binding lncRNA-ISIR strengthens interferon production in viral infection and autoinflammation. Cell reports 31 34731629
2020 The Structural Basis of IRF-3 Activation upon Phosphorylation. Journal of immunology (Baltimore, Md. : 1950) 31 32826280
2022 Activation of the STING-IRF3 pathway involved in psoriasis with diabetes mellitus. Journal of cellular and molecular medicine 29 35174638
2016 Spliceosome SNRNP200 Promotes Viral RNA Sensing and IRF3 Activation of Antiviral Response. PLoS pathogens 28 27454487
2015 Limited specificity of IRF3 and ISGF3 in the transcriptional innate-immune response to double-stranded RNA. Journal of leukocyte biology 27 25896227
2023 SARS-CoV-2 Nsp15 suppresses type I interferon production by inhibiting IRF3 phosphorylation and nuclear translocation. iScience 22 37680466
2024 ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus. PLoS pathogens 21 38227600
2023 Metabolic enzyme UAP1 mediates IRF3 pyrophosphorylation to facilitate innate immune response. Molecular cell 21 36603579
2023 LncRNA ZNF593-AS alleviates diabetic cardiomyopathy via suppressing IRF3 signaling pathway. Molecular therapy. Nucleic acids 21 37215148
2022 Pim1 promotes IFN-β production by interacting with IRF3. Experimental & molecular medicine 21 36446848
2021 IFIT5 Negatively Regulates the Type I IFN Pathway by Disrupting TBK1-IKKε-IRF3 Signalosome and Degrading IRF3 and IKKε. Journal of immunology (Baltimore, Md. : 1950) 21 33858962
2019 The EF-Hand Protein CALML6 Suppresses Antiviral Innate Immunity by Impairing IRF3 Dimerization. Cell reports 21 30699354
2019 The Fish-Specific Protein Kinase (PKZ) Initiates Innate Immune Responses via IRF3- and ISGF3-Like Mediated Pathways. Frontiers in immunology 21 30984174
2023 Helicobacter pylori promotes gastric intestinal metaplasia through activation of IRF3-mediated kynurenine pathway. Cell communication and signaling : CCS 20 37328804
2018 Differential and Overlapping Immune Programs Regulated by IRF3 and IRF5 in Plasmacytoid Dendritic Cells. Journal of immunology (Baltimore, Md. : 1950) 20 30297339
2015 Inhibition of IRF3 expression reduces TGF-β1-induced proliferation of hepatic stellate cells. Journal of physiology and biochemistry 20 26611114
2014 HSPD1 interacts with IRF3 to facilitate interferon-beta induction. PloS one 20 25506707
2024 IRF3 function and immunological gaps in sepsis. Frontiers in immunology 19 38375470
2022 DDX50 Is a Viral Restriction Factor That Enhances IRF3 Activation. Viruses 19 35215908
2020 PGAM5-MAVS interaction regulates TBK1/ IRF3 dependent antiviral responses. Scientific reports 19 32433485
2019 IRF3 and IRF7 mediate neovascularization via inflammatory cytokines. Journal of cellular and molecular medicine 19 30932349
2025 STING signals to NF-κB from late endolysosomal compartments using IRF3 as an adaptor. Nature immunology 18 40973797
2024 Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer. The EMBO journal 18 38316991
2021 Arginine methylation by PRMT2 promotes IFN-β production through TLR4/IRF3 signaling pathway. Molecular immunology 18 34583098
2017 Swine IRF3/IRF7 attenuates inflammatory responses through TLR4 signaling pathway. Oncotarget 18 28977918
2010 TLR9 and IRF3 cooperate to induce a systemic inflammatory response in mice injected with liposome:DNA. Molecular therapy : the journal of the American Society of Gene Therapy 18 20145605
2024 IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer's disease. Journal of neuroinflammation 17 39215356
2024 AXIN1 boosts antiviral response through IRF3 stabilization and induced phase separation. Signal transduction and targeted therapy 17 39384753
2020 An Alternative Splicing of Tupaia STING Modulated Anti-RNA Virus Responses by Targeting MDA5-LGP2 and IRF3. Journal of immunology (Baltimore, Md. : 1950) 17 32376647
2016 cFLIPL Interrupts IRF3-CBP-DNA Interactions To Inhibit IRF3-Driven Transcription. Journal of immunology (Baltimore, Md. : 1950) 17 27342840
2024 DUSP4 modulates RIG-I- and STING-mediated IRF3-type I IFN response. Cell death and differentiation 16 38383887
2021 Zebrafish Uba1 Degrades IRF3 through K48-Linked Ubiquitination to Inhibit IFN Production. Journal of immunology (Baltimore, Md. : 1950) 16 34193603
2021 IRF3-mediated pathogenicity in a murine model of human hepatitis A. PLoS pathogens 16 34591933
2024 IRF3 inhibits inflammatory signaling pathways in macrophages to prevent viral pathogenesis. Science advances 15 39121222
2023 A p53-TLR3 axis ameliorates pulmonary hypertension by inducing BMPR2 via IRF3. iScience 15 36685041
2022 Identifying a novel IRF3/circUHRF1/miR-1306-5p/ARL4C axis in pancreatic ductal adenocarcinoma progression. Cell cycle (Georgetown, Tex.) 15 34983293
2024 STING dependent BAX-IRF3 signaling results in apoptosis during late-stage Coxiella burnetii infection. Cell death & disease 14 38459007
2023 Downstream STING pathways IRF3 and NF-κB differentially regulate CCL22 in response to cytosolic dsDNA. Cancer gene therapy 14 37990062
2017 Elimination of GPR146-mediated antiviral function through IRF3/HES1-signalling pathway. Immunology 14 28464285
2024 Ebola virus sequesters IRF3 in viral inclusion bodies to evade host antiviral immunity. eLife 13 38285487
2023 Cathelicidin CATH-B1 Inhibits Pseudorabies Virus Infection via Direct Interaction and TLR4/JNK/IRF3-Mediated Interferon Activation. Journal of virology 13 37314341
2022 Grass Carp (Ctenopharyngodon idella) KAT8 Inhibits IFN 1 Response Through Acetylating IRF3/IRF7. Frontiers in immunology 13 35046960
2020 Virus-Intrinsic Differences and Heterogeneous IRF3 Activation Influence IFN-Independent Antiviral Protection. iScience 13 33319181
2015 Molecular characterization and functional analysis of IRF3 in tilapia (Oreochromis niloticus). Developmental and comparative immunology 13 26483348
2023 TBK1 and IRF3 are potential therapeutic targets in Enterovirus A71-associated diseases. PLoS neglected tropical diseases 12 36626364
2023 SARS-CoV-2 NSP13 interacts with host IRF3, blocking antiviral immune responses. Journal of medical virology 12 37314155
2023 Role of OGDH in Atophagy-IRF3-IFN-β pathway during classical swine fever virus infection. International journal of biological macromolecules 12 37604413
2021 Interferon-Inducible LINC02605 Promotes Antiviral Innate Responses by Strengthening IRF3 Nuclear Translocation. Frontiers in immunology 12 34804040
2016 Constitutively Active IRF7/IRF3 Fusion Protein Completely Protects Swine against Foot-and-Mouth Disease. Journal of virology 12 27466421

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