Affinage

IRF3

Interferon regulatory factor 3 · UniProt Q14653

Length
427 aa
Mass
47.2 kDa
Annotated
2026-04-28
100 papers in source corpus 47 papers cited in narrative 49 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRF3 is a cytoplasmic transcription factor that serves as a master regulator of type I interferon and antiviral gene expression downstream of pattern recognition receptors sensing viral nucleic acids and cytosolic DNA. In resting cells, IRF3 is maintained in an autoinhibited state by suppressor proteins such as Flightless-1 and HDAC10; upon infection, phosphorylated adaptor proteins MAVS, STING, and TRIF recruit IRF3 through a positively charged surface, positioning it for phosphorylation by TBK1/IKKε at C-terminal serines (Ser385/386), with cooperating kinases AKT3 and pyrophosphorylase UAP1 contributing to full activation, whereupon IRF3 dimerizes, translocates to the nucleus via importin KPNA2, and recruits the coactivator CBP/p300 to drive IFN-β transcription (PMID:12692549, PMID:14555995, PMID:25636800, PMID:10920266, PMID:36603579, PMID:31882361, PMID:32130408). IRF3 activity is terminated by multiple negative regulatory mechanisms including inhibitory phosphorylation by Mst1 (Thr75/253), acetylation by KAT8 (Lys359), K48-linked ubiquitination by MID1 (Lys313) leading to proteasomal degradation, selective autophagy via cargo receptors p62 and NBR1, and apoptotic caspase-3 cleavage (PMID:27125670, PMID:30842237, PMID:33513265, PMID:35100065, PMID:30878284). Beyond interferon induction, activated IRF3 forms nuclear complexes with retinoblastoma protein to drive cellular senescence independently of IFN production and suppresses NF-κB-dependent inflammatory signaling in macrophages (PMID:38416816, PMID:39121222).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 High

    Identifying the phosphorylation sites that trigger IRF3 activation resolved how a constitutively expressed cytoplasmic protein becomes a functional transcription factor: Ser385/386 phosphorylation drives homodimerization and creates a surface recognized by coactivator CBP/p300.

    Evidence Biochemical analysis with synthetic phosphopeptide competition and Co-IP

    PMID:10920266

    Open questions at the time
    • Upstream kinase(s) responsible for Ser385/386 phosphorylation not yet identified
    • Structural basis of phospho-dependent CBP binding not resolved
  2. 2002 High

    Establishing that IRF3 is selectively activated downstream of TLR3/TLR4 but not TLR2/TLR9 defined IRF3 as the specificity factor conferring a distinct antiviral transcriptional program upon pathogen recognition.

    Evidence IRF3 KO cells, dominant-negative IRF3, gene expression analysis across multiple TLRs

    PMID:12354379

    Open questions at the time
    • Adaptor-level mechanism linking specific TLRs to IRF3 unknown
    • Whether IRF3 acts redundantly with IRF7 at endogenous loci unresolved
  3. 2003 High

    Identification of TBK1 and IKKε as the essential IRF3 kinases, and determination of the IRF3 crystal structure revealing a Smad MH2-like fold with a phosphorylation-induced dimerization interface, jointly established the core activation mechanism.

    Evidence Genetic knockdown/kinase assays (TBK1/IKKε); X-ray crystallography at 2.3 Å with functional mutagenesis

    PMID:12692549 PMID:14555995

    Open questions at the time
    • How TBK1/IKKε are recruited to IRF3 unknown
    • Structural basis for phospho-IRF3 dimer–CBP complex not determined
  4. 2006 High

    Demonstrating that cytosolic DNA activates IRF3-dependent type I IFN production independently of TLRs and NF-κB defined a second major pathway converging on IRF3, later linked to cGAS-STING.

    Evidence IRF3 KO mice, TLR-independent bacterial infection model, NF-κB and MAPK reporter exclusion

    PMID:16413926

    Open questions at the time
    • The cytosolic DNA sensor upstream of IRF3 not identified
    • Adaptor connecting DNA sensing to TBK1-IRF3 unknown
  5. 2008 High

    Discovery of STING (MITA) as a mitochondrial membrane adaptor that directly binds IRF3 and recruits TBK1 to MAVS-associated complexes provided the missing scaffold connecting cytosolic nucleic acid sensing to IRF3 phosphorylation.

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

    PMID:18818105

    Open questions at the time
    • Precise binding interface between STING and IRF3 not mapped
    • Whether STING phosphorylation is required for IRF3 recruitment unknown
  6. 2012 High

    Reconstitution experiments separated STING's ability to activate TBK1 from its ability to recruit IRF3, establishing that STING functions as a specificity scaffold rather than merely a TBK1 activator.

    Evidence In vitro reconstitution with STING mutants that retain TBK1 activation but lose IRF3 phosphorylation

    PMID:22394562

    Open questions at the time
    • Structural basis of the STING C-terminal tail–IRF3 interaction not resolved at atomic level
  7. 2015 High

    Demonstration that phosphorylated MAVS, STING, and TRIF all bind a conserved positively charged surface on IRF3 unified the adaptor-to-IRF3 recruitment mechanism across RNA, DNA, and TLR pathways.

    Evidence In vitro reconstitution, phosphopeptide binding assays, mutational analysis

    PMID:25636800

    Open questions at the time
    • Whether other adaptor proteins use the same IRF3 surface unknown
    • Kinetics and stoichiometry of adaptor–IRF3 binding not characterized
  8. 2016 High

    Identification of Mst1 as an inhibitory kinase that phosphorylates IRF3 at Thr75/Thr253 to block dimerization revealed that IRF3 integrates opposing kinase inputs — activating (TBK1) and inhibitory (Mst1) — to tune IFN output.

    Evidence Kinase screen, in vitro kinase assay, site-specific mutagenesis, ChIP

    PMID:27125670

    Open questions at the time
    • Physiological signals that activate Mst1 toward IRF3 unclear
    • Whether Thr75/253 phosphorylation occurs simultaneously or sequentially unknown
  9. 2019 High

    Multiple negative regulators were defined in parallel — KAT8-mediated acetylation at K359 blocking promoter recruitment, AKT3 as a cooperating activating kinase at Ser385, and caspase-3 cleavage linking apoptosis to IRF3 destruction — revealing a multilayered regulatory network.

    Evidence Acetyltransferase assay/ChIP/KAT8 KO mice; in vitro AKT3 kinase assay with site mutagenesis; caspase cleavage assay with caspase-3/7 KO cells and in vivo infection

    PMID:30842237 PMID:30878284 PMID:31882361

    Open questions at the time
    • Whether K359 acetylation and Ser385 phosphorylation are mutually exclusive unknown
    • Caspase-3 cleavage site on IRF3 not precisely mapped
  10. 2020 High

    Identification of USP22-stabilized KPNA2 as the importin mediating IRF3 nuclear translocation established the mechanism by which phosphorylated cytoplasmic IRF3 gains access to the nucleus.

    Evidence USP22 KO/KPNA2 KO cells, nuclear fractionation, deubiquitinase assay, conditional KO mice

    PMID:32130408

    Open questions at the time
    • NLS on IRF3 recognized by KPNA2 not mapped
    • Nuclear export mechanism for IRF3 not characterized
  11. 2021 Medium

    Multiple studies converged on autophagy as a major IRF3 turnover route: HDAC10 acts as a catalysis-independent suppressor degraded by LC3-II-mediated autophagy upon infection, while NBR1 and p62 serve as cargo receptors for IRF3 autophagic degradation regulated by OTUD7B deubiquitinase.

    Evidence Co-IP with HDAC10 KO cells/mice, autophagy flux assays; NBR1 UBA domain binding; OTUD7B deubiquitination of p62 at K7

    PMID:35100065 PMID:35914352 PMID:36538592

    Open questions at the time
    • NBR1-mediated degradation supported by only a single study
    • Whether autophagy-mediated and proteasomal degradation of IRF3 operate in distinct cell types unknown
    • Relative contributions of p62 vs NBR1 as IRF3 cargo receptors not compared
  12. 2021 Medium

    Discovery that MID1 E3 ligase catalyzes K48-linked ubiquitination of IRF3 at K313 defined a direct proteasomal degradation mechanism distinct from autophagic turnover.

    Evidence Co-IP, ubiquitination assay with K313R mutagenesis, cycloheximide chase

    PMID:33513265

    Open questions at the time
    • No independent replication
    • Signals controlling MID1 access to IRF3 not defined
  13. 2023 High

    Discovery that UAP1 pyrophosphorylates IRF3 at Ser386 identified a non-canonical post-translational modification (serine pyrophosphorylation) as critical for robust IFN-β induction, expanding the repertoire of IRF3-activating modifications beyond simple phosphorylation.

    Evidence In vitro pyrophosphorylation assay, UAP1 KO mice, DNA and RNA virus infection models

    PMID:36603579

    Open questions at the time
    • Structural consequence of pyrophosphorylation vs monophosphorylation on IRF3 dimerization interface unknown
    • Whether UAP1 acts constitutively or is itself regulated by infection unclear
  14. 2023 High

    Identification of a SUMO-interacting motif (SIM) on IRF3 that mediates its recruitment to MAVS phase-separated condensates — and whose function is disabled by IRF3 phosphorylation — provided a biophysical mechanism for signal-dependent capture and release of IRF3 at signaling platforms.

    Evidence Phase separation reconstitution, SIM mutagenesis, SENP1 KO/overexpression, SUMOylation assays

    PMID:37188808

    Open questions at the time
    • Whether SIM-dependent recruitment also operates at STING signalosomes unknown
    • Kinetic coupling of SIM release and nuclear import not measured
  15. 2024 High

    IRF3 was shown to form nuclear complexes with retinoblastoma protein (RB), attenuating CDK4/6-mediated RB hyperphosphorylation and driving cellular senescence — establishing an IFN-independent effector function of IRF3.

    Evidence Reciprocal Co-IP, conditional KO mice, CDK4/6 inhibitor rescue, liver fibrosis models

    PMID:38416816

    Open questions at the time
    • IRF3-RB binding interface not structurally characterized
    • Whether IRF3-RB interaction requires IRF3 phosphorylation/dimerization unclear
    • Generalizability beyond hepatic stellate cells not established
  16. 2024 Medium

    AXIN1 was identified as a stability factor that recruits deubiquitinase USP35 to remove K48-linked ubiquitin at IRF3 K366, with phospho-TBK1 triggering AXIN1 phase separation to enhance IRF3 phosphorylation, linking Wnt-pathway scaffolding to innate immunity.

    Evidence Co-IP, USP35 deubiquitination assay, K366 mutagenesis, phase separation imaging

    PMID:39384753

    Open questions at the time
    • Whether AXIN1-IRF3 interaction is relevant in non-immune cell types unknown
    • Relationship between AXIN1 phase separation and MAVS condensates not explored
  17. 2024 Medium

    Macrophage-specific IRF3 deletion revealed a non-redundant anti-inflammatory role: IRF3 suppresses NF-κB and MAPK inflammatory signaling, and its loss causes exaggerated lung inflammation and mortality during respiratory viral infection.

    Evidence Macrophage-specific conditional KO mice, RNA-seq, viral infection model

    PMID:39121222

    Open questions at the time
    • Molecular mechanism of IRF3-mediated NF-κB inhibition not defined at binding-site resolution
    • Whether this anti-inflammatory role operates in non-macrophage cell types unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions remain: the structural basis for the full-length phospho-IRF3 dimer bound to CBP/p300 and DNA; how the multiple negative regulatory modifications (acetylation, inhibitory phosphorylation, ubiquitination, autophagy) are prioritized in different cell types; and the mechanistic details of IRF3's IFN-independent functions including NF-κB suppression and RB-driven senescence.
  • No full-length IRF3 dimer–CBP–DNA co-crystal structure
  • Cell-type-specific hierarchy of IRF3 degradation pathways unexplored
  • Molecular interface for IRF3–NF-κB inhibitory interaction not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 4
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-5357801 Programmed Cell Death 1
Partners
AKT3CREBBPIKBKEKPNA2MAVSRB1STINGTBK1
Complex memberships
IRF3-CBP/p300 transcription complexMAVS-TBK1-IRF3 signalosomeSTING-TBK1-IRF3 signalosome

Evidence

Reading pass · 49 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 IKKε and TBK1 are essential kinases that phosphorylate and activate IRF3 downstream of TLR3/TLR4 and viral infection, coordinating IRF3 and NF-κB activation in innate immune responses. Genetic knockdown/overexpression, kinase assays, reporter assays Nature immunology High 12692549
2003 X-ray crystal structure of the C-terminal regulatory domain of IRF3 (residues 175-427) at 2.3 Å revealed structural similarity to Smad MH2 domain; phosphorylation-induced dimerization generates an acidic pocket that binds CBP/p300 coactivator. X-ray crystallography, structural and functional mutagenesis Nature structural biology High 14555995
2015 Phosphorylated adaptor proteins MAVS and STING bind a positively charged surface of IRF3 to recruit it for phosphorylation by TBK1; TRIF uses a similar phosphorylation-dependent mechanism to activate IRF3. In vitro reconstitution, mutational analysis, Co-IP, phosphopeptide binding assays Science High 25636800
2012 STING functions as a scaffold protein that recruits both TBK1 and IRF3; a C-terminal region of STING is necessary and sufficient to activate TBK1 and specify IRF3 phosphorylation, and STING mutations that disrupt IRF3 binding abrogate IRF3 phosphorylation without impairing TBK1 activation. In vitro reconstitution system, mutational analysis, Co-IP Science signaling High 22394562
2008 MITA (STING) localizes to the outer mitochondrial membrane, associates with VISA (MAVS), interacts directly with IRF3, and recruits TBK1 to the VISA-associated complex; TBK1-mediated phosphorylation of MITA is required for MITA-mediated IRF3 activation. Expression cloning, Co-IP, knockdown, subcellular fractionation, reporter assays Immunity High 18818105
2000 Virus-induced phosphorylation of IRF3 at Ser385 and Ser386 drives IRF3 homodimerization and subsequent stable complex formation with the coactivator p300/CBP; p300 directly recognizes the structure in the vicinity of the phosphorylated residues. Biochemical analysis, synthetic phosphopeptide competition, Co-IP Journal of biochemistry High 10920266
2021 STING S365A mutation disrupts IRF3 binding and type I IFN induction but not NF-κB activation; TBK1 recruitment to STING (via L373/CTT) is essential for both IRF3 and NF-κB activation, demonstrating that STING-IRF3 binding and TBK1 recruitment are genetically separable steps. CRISPR knock-in mice, genetic epistasis, reporter assays, infection studies PNAS High 33785602
2019 Apoptotic caspase-3 cleaves IRF3 (along with cGAS and MAVS) to prevent cytokine overproduction during viral infection, establishing a negative feedback mechanism linking apoptosis to innate immune suppression. Biochemical cleavage assays, genetic knockout cells (caspase-3/7 KO), in vivo mouse infection Molecular cell High 30878284
2016 Mst1 kinase directly phosphorylates IRF3 at Thr75 and Thr253, abolishing activated IRF3 homodimerization, chromatin occupancy, and transcriptional responses; Mst1 also impedes TBK1 activation. Kinase screen, in vitro kinase assay, mutagenesis, ChIP, Co-IP Genes & development High 27125670
2019 KAT8 acetyltransferase directly interacts with IRF3 via its MYST domain and acetylates IRF3 at Lys359, inhibiting IRF3 recruitment to IFN-I gene promoters and decreasing its transcriptional activity. RNAi screen, Co-IP, acetylation assay, ChIP, KAT8 KO mice Journal of experimental medicine High 30842237
2023 UAP1, a metabolic enzyme, acts as a pyrophosphorylase that catalyzes serine pyrophosphorylation of IRF3 at Ser386, promoting robust type I IFN responses; Uap1 deficiency impairs both DNA- and RNA-virus-induced IFN pathways. In vitro pyrophosphorylation assay, UAP1 KO mice, viral infection studies Molecular cell High 36603579
2024 IRF3 activated during innate DNA sensing forms endogenous nuclear complexes with retinoblastoma protein (RB), attenuating CDK4/6-mediated RB hyperphosphorylation and driving cells into senescence; this STING-IRF3-RB axis limits liver fibrosis by pushing hepatic stellate cells toward senescence. Co-IP, conditional KO mice, CDK4/6 inhibitor rescue, liver fibrosis models Science advances High 38416816
2005 GRIP1 directly interacts with IRF3 via its corepression domain; glucocorticoid receptor (GR) competes with IRF3 for GRIP1 binding, and GR activation disrupts GRIP1-IRF3 interaction to repress IRF3-dependent gene expression. Yeast two-hybrid, Co-IP in mammalian cells, GRIP1 knockdown, IRF3-responsive element reporter assays EMBO journal High 16362036
2016 S6K1 interacts with STING in a cGAS-dependent manner upon DNA virus infection; the kinase domain (but not kinase activity) of S6K1 mediates STING binding; formation of a tripartite S6K1-STING-TBK1 complex is necessary for IRF3 activation. Co-IP, domain mutagenesis, RNAi knockdown, reporter assays, in vivo mucosal antiviral assay Nature immunology High 27043414
2020 USP22 deubiquitinates and stabilizes importin KPNA2, which promotes nuclear translocation of IRF3 after viral infection; USP22-IRF3 association in the cytoplasm is KPNA2-dependent, and loss of USP22 or KPNA2 impairs IRF3 nuclear translocation. Co-IP, KPNA2 KO/USP22 KO cells, nuclear fractionation, reconstitution experiment, conditional KO mice Journal of experimental medicine High 32130408
2022 DUSP4 phosphatase forms a signaling complex with TBK1, ERK1/2, and IRF3; DUSP4 regulates TBK1 and ERK1/2 activation within this complex to control type I IFN production downstream of RIG-I and STING. Co-IP, DUSP4 KO mice, viral infection studies, phosphorylation assays Cell death and differentiation Medium 38383887
2021 lncRNA-ISIR directly binds the DNA-binding domain of IRF3 in the cytoplasm, displaces the suppressor protein Flightless-1 (Fli-1) from IRF3, and promotes IRF3 phosphorylation, dimerization, and nuclear translocation. RNA pull-down, RIP, FRET, lncRNA-ISIR KO mice, viral infection studies Cell reports High 34731629
2023 MAVS SUMOylation (by PIAS3) promotes its K63-linked ubiquitination, aggregation, and phase separation through a newly identified SUMO-interacting motif (SIM); IRF3 contains a SIM that mediates its recruitment to MAVS phase-separated droplets, and IRF3 phosphorylation at key residues disables SIM-SUMO interactions to release activated IRF3. SUMOylation assay, phase separation imaging, SIM mutagenesis, SENP1 KO/overexpression Nature structural & molecular biology High 37188808
2019 7-Dehydrocholesterol (7-DHC) specifically promotes phosphorylation of IRF3 (but not TBK1) by enhancing AKT3 expression; AKT3 directly binds and phosphorylates IRF3 at Ser385, which cooperates with TBK1-induced phosphorylation at Ser386 to achieve IRF3 dimerization. In vitro kinase assay, AKT3 KO/KD, site-specific mutagenesis, viral infection models Immunity High 31882361
2021 MID1 E3 ubiquitin ligase physically interacts with IRF3 and induces K48-linked polyubiquitination at Lys313, leading to proteasomal degradation of IRF3 and restriction of IFN-I production. Co-IP, ubiquitination assay, site-specific mutagenesis (K313R), cycloheximide chase Immunology Medium 33513265
2022 OTUD7B deubiquitinase interacts with IRF3 and removes K63-linked ubiquitin chains from cargo receptor SQSTM1/p62 at Lys7, enhancing p62 oligomerization and promoting selective autophagic degradation of IRF3 to limit type I IFN signaling. Co-IP, deubiquitination assay, autophagic flux assays, OTUD7B KO cells Autophagy Medium 35100065
2016 MAP4-regulated dynein-dependent trafficking of BTN3A1 controls spatial activation of TBK1-IRF3 signaling; stimulation with nucleic acids redistributes BTN3A1-TBK1 complex to perinuclear region where BTN3A1 mediates TBK1-IRF3 interaction and IRF3 phosphorylation. Co-IP, siRNA knockdown, live cell imaging, subcellular fractionation, phosphorylation assays PNAS Medium 27911820
2011 IRF8 constitutively binds the ETS/IRF composite element of the IFN-β promoter together with PU.1 in monocytes, forming a scaffold complex that facilitates rapid recruitment of IRF3 upon stimulation; IRF3-IRF8 interaction is independent of their DNA-binding domains and IADs. ChIP, Co-IP, IRF8 knockdown/reconstitution in IRF8-/- cells, domain mapping Blood Medium 21228327
2018 PRMT6 protein binds IRF3 upon viral infection and sequesters it, blocking TBK1-IRF3 interaction and subsequent IRF3 activation; this inhibitory function is independent of PRMT6 methyltransferase activity. Co-IP, PRMT6 KO mice, IRF3 phosphorylation assays, enzymatic-dead mutant Cellular & molecular immunology Medium 29973649
2022 HDAC10 binds IRF3 in a deacetylase-independent manner in uninfected cells and inhibits TBK1-mediated phosphorylation of IRF3 at Ser396; upon viral infection, HDAC10 is degraded by autophagy via LC3-II interaction, releasing IRF3 for activation. Co-IP, HDAC10 KO cells and mice, autophagy assays, IRF3 phosphorylation assays Science signaling Medium 36538592
2019 CALML6 (EF-hand protein) directly binds the phosphorylated serine-rich region of IRF3 and impairs its dimerization and nuclear translocation, establishing a phosphorylation-dependent negative feedback loop. Co-IP, GST pulldown, CALML6 transgenic mice, IRF3 dimerization assay, nuclear fractionation Cell reports Medium 30699354
2016 cFLIPL binds IRF3 in the nucleus and disrupts IRF3 interaction with the IFN-β promoter and its coactivator CBP/p300; nuclear localization of cFLIPL is necessary and sufficient for this inhibitory function. Co-IP, ChIP, nuclear localization mutants, reporter assays, viral infection Journal of immunology Medium 27342840
2019 lncRNA Malat1 binds TDP43 in the nucleus and prevents caspase-3-mediated cleavage of TDP43 to TDP35; the cleaved TDP35 degrades Rbck1 pre-mRNA to prevent IRF3 proteasomal degradation, increasing nuclear IRF3 protein levels and selectively promoting IFN-I production. RIP, RNA pulldown, lncRNA KO mice, Rbck1 mRNA stability assays, IRF3 protein stability assay PNAS Medium 32907941
2020 lncRNA lncLrrc55-AS binds phosphatase methylesterase 1 (PME-1) and promotes PME-1-mediated demethylation and inactivation of PP2A phosphatase, thereby enhancing IRF3 phosphorylation and IFN-I signaling. RNA pulldown, Co-IP, lncLrrc55-AS KO mice, PP2A activity assay, IRF3 phosphorylation assay Cell research Medium 31213650
2005 Thogoto virus ML protein blocks IRF3 dimerization and association with CBP coactivator without preventing IRF3 nuclear transport, distinguishing its mechanism from influenza NS1 which retains IRF3 in the cytoplasm. IRF3 dimerization assay (native PAGE), CBP Co-IP, nuclear/cytoplasmic fractionation, reporter assays Virology Medium 15582653
2022 HDAC10 binds IRF3 in uninfected cells to inhibit Ser396 phosphorylation by TBK1; viral infection triggers autophagy-mediated HDAC10 degradation via LC3-II, releasing IRF3 for TBK1-mediated activation. Co-IP, KO cells/mice, autophagy flux assay, phospho-IRF3 analysis Science signaling Medium 36538592
2021 NBR1 cargo receptor binds both unphosphorylated and phosphorylated IRF3 through its ubiquitin-associated domain and targets IRF3 for autophagic degradation, forming a negative feedback loop upon viral infection. Co-IP, autophagy inhibitor experiments, ATG KO cells, IRF3 stability assays Biochemical and biophysical research communications Low 35914352
2014 Heat shock protein HSPD1 (HSP60) interacts with IRF3 and facilitates its phosphorylation and dimerization; HSPD1 overexpression enhances IFN-β induction by acting upstream of IRF3 phosphorylation (no effect when constitutively active IRF3/5D is used). Co-IP, overexpression/knockdown, reporter assays, IRF3 dimerization assay PloS one Low 25506707
2016 Vimentin interacts with TBK1 and IKKε to disrupt their interactions with IRF3, resulting in inhibition of IRF3 phosphorylation and nuclear translocation; vimentin KO mice showed enhanced IFN-I production and reduced virus replication. Co-IP, vimentin KO cells and mice, IRF3 phosphorylation/nuclear translocation assays Cell reports Medium 36223739
2024 AXIN1 maintains IRF3 stability by recruiting USP35 to remove K48-linked ubiquitination at IRF3 K366, preventing p62-mediated autophagic degradation; upon virus infection, phospho-TBK1 triggers AXIN1 phase separation, increasing IRF3 phosphorylation and IFN-I production. Co-IP, ubiquitination assay, phase separation imaging, USP35 deubiquitination assay, site-specific mutagenesis (K366) Signal transduction and targeted therapy Medium 39384753
2024 IRF3 in macrophages interacts with and inhibits NF-κB activity, suppressing inflammatory gene expression; conditional Irf3 deletion in macrophages causes enhanced NF-κB-dependent and MAPK-dependent inflammatory signaling, lung inflammation, and increased mortality during respiratory virus infection. Conditional KO mice (macrophage-specific Irf3Δ/Δ), RNA-seq, MAPK pathway analysis, viral infection model Science advances Medium 39121222
2022 ZBP1 constitutively expressed in myeloma cells interacts with TBK1 and IRF3, resulting in IRF3 phosphorylation; phosphorylated IRF3 directly binds and activates cell cycle genes in cooperation with IRF4, promoting myeloma cell proliferation. Co-IP, ChIP-seq, IRF3 phosphorylation assays, KO studies Haematologica Medium 33596642
2015 Casein kinase II (CK2) controls TBK1 and IRF3 activation in IFN-inducing signaling pathways through PP2A as an intermediate phosphatase; CK2 knockdown or inhibition results in elevated TBK1 and IRF3 phosphorylation and elevated IFN-αβ response. CK2 knockdown/genetic ablation, PP2A phosphatase assays, TBK1/IRF3 phosphorylation assays, viral infection studies Journal of immunology Medium 25810395
2023 SARS-CoV-2 NSP13 specifically interacts with IRF3 through its 1B domain binding to the IRF3 IAD domain in a TBK1-independent manner, blocking IRF3-directed signal transduction and antiviral gene expression. Co-IP, domain mutagenesis, IRF3/5D constitutively active construct, reporter assays Journal of medical virology Medium 37314155
2021 Pim1 kinase promotes IRF3 phosphorylation and nuclear translocation in a kinase-activity-independent manner by enhancing the formation of TRIF-TRAF3-TBK1-IRF3 signaling complexes. Co-IP, Pim1 KO mice, kinase-dead mutant, IRF3 phosphorylation/nuclear translocation assays, reporter assays Experimental & molecular medicine Medium 36446848
2021 PGAM5 directly interacts with MAVS and supports TBK1 and IRF3 phosphorylation; PGAM5-deficient cells and mouse embryonic fibroblasts show decreased IRF3 phosphorylation and impaired IFN-β production. Co-IP, PGAM5 KO MEFs, IRF3/TBK1 phosphorylation assays, viral replication assay Scientific reports Low 32433485
2021 TG2 (transglutaminase 2) interacts with TBK1, alters its interactome composition, and prevents TBK1-IRF3 interaction, thereby impairing IRF3 phosphorylation; TG2 KO macrophages show increased IFN-β production. Co-IP, proteomic analysis, TG2 KO macrophages, IRF3 phosphorylation assay Journal of immunology Medium 33941660
2023 PRMT2-mediated arginine methylation of IRF3 at R285 mediates the interaction between TLR4 and IRF3, induces IRF3 dimerization, and promotes IRF3 nuclear translocation after LPS stimulation. Methylation assay, site-specific mutagenesis (R285K), Co-IP, nuclear fractionation, IRF3 dimerization assay Molecular immunology Medium 34583098
2006 Cytosolic DNA activates a TLR-independent innate immune response that requires IRF3 but occurs without detectable NF-κB and MAP kinase activation, defining a distinct pathway linking cytosolic DNA sensing to type I IFN production. IRF3 KO mice, NF-κB reporter assays, MAPK phosphorylation assays, TLR-independent bacterial infection model Immunity High 16413926
2002 IRF3 confers specificity to TLR3/TLR4 signaling to induce a distinct antiviral gene program; IRF3 activation requires signal-dependent phosphorylation downstream of TLR3/TLR4 but not TLR2 or TLR9. IRF3 KO cells, dominant-negative IRF3, gene expression analysis, reporter assays Immunity High 12354379
2015 ChIP-seq revealed a distinct IRF3 consensus DNA-binding sequence different from ISGF3; functional analyses in ifnar-/- vs ifnar-/-irf3-/- macrophages showed IRF3 has particularly pronounced specificity for cytokine/chemokine regulation. ChIP-seq, transcriptomics in WT/ifnar-/-/ifnar-/-irf3-/- macrophages, mathematical modeling Journal of leukocyte biology High 25896227
2020 Rotavirus NSP1 targets IRF3 for proteasomal degradation in a host-cell-dependent manner; NSP1 can also inhibit IRF3 transcriptional activity without causing IRF3 degradation; IRF3 is identified as the minimal host factor constraining NSP1 IRF3-degradative ability. Heterologous IRF3 expression in complementary host cells, IRF3 reporter assays, constitutively active IRF3-5D construct Journal of virology Medium 19656876
2020 HDAC10 (deacetylase-independent) and NBR1 (via UBA domain) each bind IRF3 and mediate its autophagic degradation; viral infection reduces HDAC10 via autophagy (LC3-II interaction) to relieve IRF3 inhibition. Co-IP, KO cells, autophagy flux assay, phospho-IRF3 analysis, LC3-II interaction Science signaling Medium 36538592
2024 Ebola virus nucleoprotein/VP35-induced inclusion bodies (IBs) sequester IRF3 (but not TBK1/IKKε) through interaction with STING, blocking TBK1-IRF3 association and preventing IRF3 phosphorylation and nuclear translocation. Transcription/replication-competent VLP system, Co-IP, STING knockdown, IRF3 nuclear translocation assay eLife Medium 38285487

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 2219 12692549
2015 Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science (New York, N.Y.) 1587 25636800
2008 The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 1275 18818105
2012 STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Science signaling 1068 22394562
2006 Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 818 16413926
2002 IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 680 12354379
2019 STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3. Redox biology 507 31121492
2017 IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nature medicine 464 29106401
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 457 33785602
2019 Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3. Molecular cell 266 30878284
2009 Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: a critical role for IRF3. The Journal of neuroscience : the official journal of the Society for Neuroscience 186 19657036
2017 STING-associated vasculopathy develops independently of IRF3 in mice. The Journal of experimental medicine 168 28951494
2016 IRF3 promotes adipose inflammation and insulin resistance and represses browning. The Journal of clinical investigation 150 27400129
2022 mtDNA-STING Axis Mediates Microglial Polarization via IRF3/NF-κB Signaling After Ischemic Stroke. Frontiers in immunology 146 35450066
2003 X-ray crystal structure of IRF-3 and its functional implications. Nature structural biology 144 14555995
2019 Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection. Immunity 128 31882361
2005 The GRIP1:IRF3 interaction as a target for glucocorticoid receptor-mediated immunosuppression. The EMBO journal 123 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 119 32907941
2022 Regulation of IRF3 activation in human antiviral signaling pathways. Biochemical pharmacology 101 35367198
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2000 Analyses of virus-induced homomeric and heteromeric protein associations between IRF-3 and coactivator CBP/p300. Journal of biochemistry 63 10920266
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2005 Thogoto virus ML protein suppresses IRF3 function. Virology 60 15582653
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2009 IRF3 inhibition by rotavirus NSP1 is host cell and virus strain dependent but independent of NSP1 proteasomal degradation. Journal of virology 53 19656876
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2015 Casein kinase II controls TBK1/IRF3 activation in IFN response against viral infection. Journal of immunology (Baltimore, Md. : 1950) 38 25810395
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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
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 36 38011562
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2016 MAP4-regulated dynein-dependent trafficking of BTN3A1 controls the TBK1-IRF3 signaling axis. Proceedings of the National Academy of Sciences of the United States of America 29 27911820
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2015 Limited specificity of IRF3 and ISGF3 in the transcriptional innate-immune response to double-stranded RNA. Journal of leukocyte biology 27 25896227
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2018 Differential and Overlapping Immune Programs Regulated by IRF3 and IRF5 in Plasmacytoid Dendritic Cells. Journal of immunology (Baltimore, Md. : 1950) 20 30297339
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2021 Zebrafish Uba1 Degrades IRF3 through K48-Linked Ubiquitination to Inhibit IFN Production. Journal of immunology (Baltimore, Md. : 1950) 14 34193603
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