Affinage

IRF9

Interferon regulatory factor 9 · UniProt Q00978

Length
393 aa
Mass
43.7 kDa
Annotated
2026-06-10
91 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRF9 is the DNA-binding subunit of the interferon-stimulated gene factor 3 (ISGF3) transcription factor, which it forms with STAT1 and STAT2 to recognize ISRE elements and drive type I and type III interferon-stimulated gene (ISG) expression (PMID:31266943, PMID:30143481). Its IRF-association domain (IAD) engages a divergent surface that specifically binds the STAT2 coiled-coil domain, an interface defined by crystallography and required for ISGF3 function (PMID:29317535), while its bipartite nuclear localization signal drives nuclear transit of the STAT2-bridged complex (PMID:18456457). Rather than assembling in the cytoplasm, the complete ISGF3 trimer assembles on DNA, switching cells from a basal state—maintained by preformed STAT2-IRF9 complexes—to induced ISG expression (PMID:31266943). IRF9 dosage is rate-limiting for the amplitude, timing, and termination of IFNα signaling, including induction of the negative regulator USP18, whose loss in IRF9-deficient cells causes aberrantly prolonged receptor signaling (PMID:20964804, PMID:35182547). Beyond the canonical trimer, IRF9 supports a prolonged second-phase response through unphosphorylated U-ISGF3 acting on distinct ISREs (PMID:24065129), drives a STAT1-independent STAT2/IRF9 antiviral program (PMID:25564224), and cooperates with NF-κB through U-STAT2 bridging to induce IL6 (PMID:29581268). Inherited complete IRF9 deficiency abolishes ISGF3 formation, narrows the IFN-induced transcriptome, and impairs control of influenza A, parainfluenza, and RSV, with the phenotype rescued by wild-type IRF9 (PMID:30143481). IRF9 is targeted by numerous viral antagonists that bind its IAD or DNA-binding domain to block ISGF3 assembly, DNA binding, or nuclear translocation (PMID:31092569, PMID:26342467, PMID:32581091, PMID:28441586), and its activity is tuned by post-translational regulation including S252/S253 phosphorylation (PMID:36662450), AARS1-written L-lactylation that enhances STAT2 interaction (PMID:41481472), and IRF8-NEDD4L-driven proteasomal degradation (PMID:40513519). IRF9 also acts as a sequence-specific transcriptional regulator outside interferon signaling, repressing SIRT1 to modulate p53 acetylation (PMID:29501566) and acting as an anti-fibrotic factor downstream of an MRTF-A–ZEB1 axis (PMID:37121967).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 Medium

    Established that IRF9 has a regulatory role in interferon responses distinct from initiating STAT1 phosphorylation, controlling the timely decline of IRF-1.

    Evidence Genetic epistasis in STAT1/STAT2/IRF9-deficient cells with IRF-1 time-course analysis after IFNτ

    PMID:11804954

    Open questions at the time
    • Mechanism by which IRF9 drives IRF-1 decline not defined
    • Direct target genes not mapped
  2. 2008 Medium

    Defined how the ISGF3 components are physically coupled and routed to the nucleus, showing STAT2 adapts IFNaR2 to IRF9 while IRF9's NLS drives nuclear entry.

    Evidence Co-IP and GFP-ICD nuclear localization assays in STAT2- and IRF9-deficient cells

    PMID:18456457

    Open questions at the time
    • Stoichiometry of the ternary complex unresolved
    • Whether assembly is cytoplasmic vs DNA-templated not addressed here
  3. 2010 Medium

    Showed IRF9 abundance is a rate-limiting determinant of IFNα signaling dynamics, framing IRF9 as a quantitative tuner of the antiviral response.

    Evidence Mathematical modeling with IRF9 overexpression and quantitative gene expression

    PMID:20964804

    Open questions at the time
    • Endogenous IRF9 fluctuations not measured
    • Single cell context
  4. 2013 High

    Revealed non-canonical IRF9 functions: unphosphorylated U-ISGF3 sustains a prolonged second-phase antiviral/DNA-damage-resistance response, and a STAT1-independent STAT2/IRF9 pathway induces DUOX2-driven antiviral H2O2.

    Evidence Manipulated IRF9/STAT expression with reporter and gene-expression analysis; knockdown plus antiviral assays for the DUOX2 pathway

    PMID:23545780 PMID:24065129

    Open questions at the time
    • Distinct ISRE recognition rules for U-ISGF3 vs ISGF3 not defined
    • DUOX2 induction mechanism single-lab
  5. 2015 High

    Demonstrated that STAT2/IRF9 alone can drive a broad, prolonged antiviral ISG program independent of STAT1, and that IRF9/STAT1 mediates a non-IFN proinflammatory program in vivo.

    Evidence Genome-wide transcriptomics and antiviral assays in STAT1-KO cells; DSS colitis with IRF9-KO and IFNAR/IL28R-KO mice

    PMID:25564224 PMID:25918247

    Open questions at the time
    • Determinants selecting STAT2/IRF9 vs full ISGF3 unclear
    • CXCL10 sufficiency not tested in isolation
  6. 2018 High

    Resolved the molecular interface underlying ISGF3 specificity and provided human genetic proof that IRF9 is essential for antiviral immunity.

    Evidence Crystal structures of IRF9-IAD alone and with STAT2-CCD plus mutagenesis; patient with inherited complete IRF9 loss-of-function, transcriptome/viral assays and wild-type rescue

    PMID:29317535 PMID:30143481

    Open questions at the time
    • Structure of full ISGF3 on DNA not solved
    • Spectrum of viruses controlled by IRF9 in patients limited
  7. 2019 High

    Overturned the cytoplasmic-assembly dogma by showing ISGF3 assembles on DNA, with preformed STAT2-IRF9 maintaining basal ISG expression.

    Evidence Integrated transcriptomics, proteomics, ChIP-seq and in vivo BioID proximity labeling in macrophages

    PMID:31266943

    Open questions at the time
    • Kinetics of on-DNA assembly not directly timed
    • Whether all cell types follow this model unknown
  8. 2018 Medium

    Identified IRF9 as a direct transcriptional repressor outside interferon signaling, linking it to the SIRT1-p53 axis in leukemia.

    Evidence ChIP on the SIRT1 promoter with IRF9 knockdown/overexpression and acetyl-p53 readout

    PMID:29501566

    Open questions at the time
    • DNA motif for IRF9 at SIRT1 promoter not defined
    • Cofactor requirements unknown
  9. 2018 Medium

    Showed IRF9/STAT1 is required for IFN-driven TLR7 upregulation and autoantibody production, implicating IRF9 in autoimmunity.

    Evidence Pristane-induced lupus in IRF9-KO and STAT1-KO mice with B cell stimulation assays

    PMID:18340381

    Open questions at the time
    • Direct IRF9 binding at TLR7 locus not shown
    • Human relevance untested
  10. 2022 Medium

    Explained why ISGF3 deficiency causes prolonged IFN signaling, identifying failed induction of the negative regulator USP18.

    Evidence IFN stimulation kinetics and transcriptomics in patient-derived and iPSC-macrophage STAT1/STAT2/IRF9-deficient cells

    PMID:35182547

    Open questions at the time
    • Direct IRF9 occupancy at USP18 not mapped here
    • Therapeutic implications untested
  11. 2023 Medium

    Extended IRF9 regulatory biology with phosphosite mapping, a Twist1-dependent constitutive ISG mechanism, and an anti-fibrotic role downstream of MRTF-A–ZEB1.

    Evidence MS phosphosite identification with S252/S253 mutagenesis; Twist1 Co-IP with ISRE and ZIKV assays; RNA-seq/ChIP and MRTF-A KO mice for fibrosis

    PMID:36662450 PMID:37121967 PMID:37144865

    Open questions at the time
    • Functional effect of S252/S253 modest and target-selective
    • Kinase for IRF9 phosphorylation unknown
    • Twist1-IRF9 interface not structurally defined
  12. 2026 Medium

    Defined post-translational control of IRF9-STAT2 binding by a lactylation-delactylation cycle, opening a metabolic input into antiviral signaling.

    Evidence L-lactylation identification with AARS1 (writer) knockdown, SIRT1 (eraser) delactylation, Co-IP and antiviral/metformin assays

    PMID:41481472

    Open questions at the time
    • Lactylation site(s) on IRF9 not pinpointed
    • In vivo relevance single-lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct IRF9-containing complexes (ISGF3, U-ISGF3, STAT2/IRF9, IRF9/STAT1, IRF9-NF-κB) are selected, targeted to specific genomic elements, and integrated with IRF9's PTM state remains unresolved.
  • No structure of any full complex on DNA
  • Rules distinguishing ISRE subclasses not defined
  • PTM-to-complex-choice logic uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
AKT1IFNAR2NEDD4LPPIARELASTAT1STAT2TWIST1
Complex memberships
ISGF3 (STAT1/STAT2/IRF9)STAT2/IRF9U-ISGF3

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 Crystal structures of IRF9-IAD alone and in complex with STAT2 coiled-coil domain (CCD) were solved, revealing the molecular interface required for ISGF3 function. The IRF9-IAD surface has diverged from paralogs to enable specific interaction with STAT2-CCD, and mutagenesis of this interface abolished ISGF3 function in cells. X-ray crystallography, structure-guided mutagenesis, cell-based ISGF3 functional assay Proceedings of the National Academy of Sciences of the United States of America High 29317535
2019 Under homeostatic (resting) conditions, preformed STAT2-IRF9 complexes control basal expression of IFN-induced genes. Upon type I IFN or IFN-γ stimulation, a complete ISGF3 complex (STAT1/STAT2/IRF9) assembles on DNA (not in the cytoplasm as previously thought), switching macrophages from resting-state to induced ISG expression. Integrated transcriptomics, proteomics, ChIP-seq, in vivo proximity-dependent labeling (BioID) in living cells Nature communications High 31266943
2013 After IFNβ treatment, elevated IRF9 together with unphosphorylated STAT1 and STAT2 (U-ISGF3) drives a prolonged second-phase antiviral and DNA-damage-resistance response distinct from the initial ISGF3-driven response, acting through distinct ISREs. IFNβ treatment of cells with manipulated IRF9/STAT expression levels, reporter assays, gene expression analysis The EMBO journal High 24065129
2018 IRF9 (as DNA-binding subunit of ISGF3) and unphosphorylated STAT2 (U-STAT2) cooperate with NF-κB to drive IL6 expression. U-STAT2 binds tightly to IRF9 and also to the p65 subunit of NF-κB, bridging ISRE and κB elements in the IL6 promoter as shown by ChIP. ChIP analysis, co-immunoprecipitation, reporter assays, exogenous overexpression of U-STAT2 and IRF9 Proceedings of the National Academy of Sciences of the United States of America High 29581268
2008 IFNaR2 intracellular domain (IFNaR2-ICD), STAT2, and IRF9 form a ternary complex. STAT2 serves as an adaptor mediating the interaction between IFNaR2-ICD and IRF9, while the bipartite nuclear localization signal within IRF9 is the primary determinant driving nuclear transit of the complex. Co-immunoprecipitation, GFP-ICD nuclear localization assays in STAT2- and IRF9-deficient cells Cellular signalling Medium 18456457
2015 In STAT1-deficient cells, a STAT2/IRF9 complex (requiring STAT2 phosphorylation and the STAT2 transactivation domain) drives expression of ~120 antiviral ISRE-containing ISGs in a prolonged manner compared to ISGF3, and can trigger an antiviral response against EMCV and VSV. Microarray/genome-wide transcriptomics in STAT1-KO cells stably overexpressing STAT2, antiviral assays, co-immunoprecipitation The Biochemical journal High 25564224
2013 IFNβ + TNFα synergism triggers a non-canonical, STAT1-independent antiviral pathway that requires STAT2 and IRF9 to induce DUOX2 NADPH oxidase expression, which then produces H2O2 as part of an antiviral state in airway epithelial cells. Knockdown of STAT1, STAT2, IRF9 individually, luciferase reporters, antiviral assays, siRNA-mediated DUOX2 knockdown Cell research Medium 23545780
2012 Cyclophilin A (CypA) binds directly to IRF9 via its PPIase pocket, specifically at the C-terminal IRF-association domain (IAD) but not the DNA-binding or linker domains. CypA also associates with the multimeric ISGF3 complex. CypA inhibitors prevent IRF9-CypA complex formation and enhance IFN-induced transcription. HCV NS5A competes with IRF9 for CypA binding. Cellular and recombinant pulldown assays, domain deletion mapping, co-immunoprecipitation, transcriptional reporter assays Journal of hepatology Medium 22902549
2019 PRRSV nonstructural protein nsp11 interacts with the C-terminal IRF-association domain of IRF9 (independently of NendoU endoribonuclease activity), impairing ISGF3 formation and nuclear translocation to antagonize type I IFN signaling. Co-immunoprecipitation, domain-mapping with nsp11 active-site mutants, nuclear translocation assays, ISRE reporter assays in nsp11-overexpressing and PRRSV-infected cells Journal of virology Medium 31092569
2015 Porcine bocavirus NP1 blocks ISGF3 DNA-binding activity by directly interacting with the DNA-binding domain (DBD) of IRF9, without affecting STAT1/STAT2 activation/translocation or ISGF3 complex formation. Co-immunoprecipitation, domain interaction mapping, ISRE reporter assays, ISG expression analysis Virology Medium 26342467
2020 Measles virus V protein displaces IRF9 (IRF-association domain) from preformed STAT2-core/IRF9 complexes, as demonstrated by size-exclusion chromatography with purified recombinant proteins. The MeV V binding site on STAT2 overlaps with that of IRF9, allowing V to inhibit the STAT2/IRF9 interaction and disrupt preassembled ISGF3. Biophysical binding assays with purified proteins, size exclusion chromatography, quantified dissociation constants Journal of virology High 32581091
2002 In response to IFNτ, IRF-9 is required for the timely decline of IRF-1 expression after 6 h: cells lacking IRF-9 showed persistent elevated IRF-1 without the normal sharp decline, whereas IRF-1 induction itself required tyrosine-phosphorylated STAT1 (not IRF-9). Cell lines deficient for specific IFN signaling components (STAT1-deficient, STAT2-deficient, IRF9-deficient), complementation with STAT1 mutants, IRF-1 mRNA/protein time-course analysis Biology of reproduction Medium 11804954
2018 Inherited complete loss-of-function IRF9 deficiency in a child abolishes ISGF3 (STAT1/STAT2/IRF9) trimer formation in response to IFN-α2b, greatly narrows the IFN-α2b-induced transcriptome, and prevents control of influenza A, parainfluenza, and RSV in vitro; the phenotype is rescued by wild-type IRF9. Patient cell studies, IFN stimulation assays, transcriptome analysis, viral replication assays, IRF9 rescue (wild-type re-expression) and knockdown in control cells The Journal of experimental medicine High 30143481
2010 IRF9 concentration is a key rate-limiting determinant of IFNα signaling dynamics: mathematical modeling and IRF9 overexpression experiments demonstrated that increasing IRF9 reduces time-to-peak, increases amplitude, and enhances termination of JAK-STAT pathway activation, forming a positive feedback loop that accelerates early antiviral gene expression. Mathematical modeling combined with IRF9 overexpression studies, quantitative gene expression analysis The FEBS journal Medium 20964804
2009 IRF9 is required for the antiproliferative activity of IFN-α: IRF9 RNAi completely abolished IFN-α antiproliferative effects in OVCAR3 cells (unlike STAT1 RNAi), and IRF9 RNAi specifically inhibited IFN-α-induced TRAIL transcription. ISGF3 binds ISRE-like motifs in the TRAIL promoter after IFN-α treatment. IRF9 overexpression facilitated IFN-α-induced apoptosis in IFN-α-resistant T98G cells. RNAi knockdown, ISRE/TRAIL promoter binding (ChIP/EMSA), overexpression rescue, cell proliferation assays Journal of immunotherapy Medium 19752753
2001 Transcriptional activation of IRF9 (independent of IFN) corresponds with resistance to antimicrotubule agents in breast adenocarcinoma cells. Transient overexpression of IRF9 alone reproduced the drug-resistance phenotype and induced expression of IFN-responsive genes, whereas overexpression of STAT1 or STAT2 did not. Differential display, single-gene overexpression, drug resistance assays, gene expression analysis Cancer research Medium 11522652
2015 IRF9 functions in a noncanonical proinflammatory complex with STAT1 (apart from IFN-I and IFN-III signaling) in intestinal epithelial cells. IRF9 deficiency protects mice from DSS-induced colitis, while combined loss of type I and III IFN receptors worsens colitis. The CXCL10 chemokine gene is an important mediator of this IRF9/STAT1 proinflammatory activity. DSS colitis mouse model, IRF9-KO and IFNAR/IL28R double-KO mice, gene expression analysis, genetic epistasis Molecular and cellular biology Medium 25918247
2018 IRF9 and STAT1 are required for IFN-α-mediated upregulation of TLR7 in B cells and for IgG (but not IgM) autoantibody production in pristane-induced murine lupus. IRF9-KO B cells are incapable of activation through TLR7. IRF9-KO and STAT1-KO mouse model (pristane-induced SLE), B cell stimulation assays through TLR7/TLR9, autoantibody measurement The Journal of clinical investigation Medium 18340381
2008 IFN-β-mediated inhibition of IL-8 expression requires all three ISGF3 components (STAT1, STAT2, and IRF9); however, the transactivation domains of STAT1 and STAT2 are not essential for this inhibitory signaling, distinguishing it from positive ISGF3-driven gene activation. Cell lines deficient for STAT1, STAT2, or IRF9, ISRE reporter assays, IL-8 expression analysis, transactivation domain mutants Journal of interferon & cytokine research Medium 18370868
2010 Expression of IRF9 fused to the transactivation domain of STAT1 (IRF9-S1C) or STAT2 (IRF9-S2C) in IFN-α-resistant HCV replicon cells restored ISRE promoter activity, induced HLA-1 surface expression, and significantly inhibited HCV RNA replication and viral protein expression independently of IFN-α, demonstrating that the IRF9 nuclear translocation is intact in these resistant cells while STAT phosphorylation is defective. Fusion protein expression, ISRE luciferase reporter, HCV replication assays, flow cytometry for HLA-1 Virology journal Medium 20939906
2021 SARS-CoV-2 Spike-transfected cells release exosomes loaded with miR-148a and miR-590; these miRNAs are internalized by human microglia and suppress USP33 expression. USP33 regulates IRF9 turnover via deubiquitylation, so its suppression reduces IRF9 protein levels and alters innate immune gene expression. Exosome isolation, miRNA transfection, knockdown assays, Western blot for IRF9/USP33, inflammatory gene expression Frontiers in immunology Low 33936086
2023 IRF9 is phosphorylated at S252 and S253 under IFNβ-induced conditions and at R242 under non-induced conditions. Site-directed mutagenesis of S252/S253 to alanine or aspartic acid modestly affects USP18 gene expression (a negative regulator of type I IFN) but not Mx1 gene expression. Phosphoprotein enrichment, Phos-tag assay, tandem mass spectrometry on immunoprecipitated IRF9, site-directed mutagenesis, qPCR for ISG expression Molecular biology reports Medium 36662450
2018 IRF9 binds the SIRT1 promoter and represses SIRT1 expression in AML cells; IRF9 knockdown promotes proliferation and survival while overexpression inhibits growth. This IRF9-SIRT1 repression increases p53 acetylation (a SIRT1 deacetylation substrate) and promotes expression of p53 target genes. ChIP for IRF9 on SIRT1 promoter, IRF9 knockdown/overexpression, cell proliferation/colony assays, Western blot for acetylated p53 Experimental cell research Medium 29501566
2023 In renal fibroblasts, the MRTF-A/TEAD1 complex activates ZEB1 transcription; ZEB1 in turn represses IRF9 transcription. IRF9 knockdown promotes fibroblast-myofibroblast transition (FMyT), whereas IRF9 overexpression antagonizes TGF-β-induced FMyT, placing IRF9 downstream of the MRTF-A–ZEB1 axis as an anti-fibrotic factor. RNA-seq, ChIP for MRTF-A/TEAD1 on Zeb1 promoter, IRF9 knockdown/overexpression, myofibroblast differentiation assays, myofibroblast-specific MRTF-A KO mice Experimental & molecular medicine Medium 37121967
2021 IRF9 promotes PASMC proliferation by directly interacting with AKT to inhibit AKT phosphorylation at Thr308, leading to mitochondrial dysfunction. IRF9 also directly restrains PHB1 (Prohibitin 1) expression. Both mechanisms contribute to PASMC proliferation in pulmonary arterial hypertension models. IRF9 overexpression/knockdown, co-immunoprecipitation for IRF9-AKT interaction, AKT inhibitor (MK2206) rescue, EdU proliferation assays, PHB1 expression analysis, PAH rat models Frontiers in pharmacology Low 34925032
2023 SVV 3Cpro antagonizes type I IFN signaling by degrading STAT1, STAT2, and IRF9, and by cleaving STAT2. SVV 3Cpro also degrades karyopherin α1 (KPNA1) to block ISGF3 nuclear translocation. Overexpression assays, Western blot for protein degradation/cleavage, nuclear translocation assays, IFN signaling reporter assays Journal of virology Medium 37819133
2017 Kobuvirus VP3 protein associates with STAT2 and IRF9, interfering with STAT2-IRF9 and STAT2-STAT2 complex formation, thereby impairing nuclear translocation of both STAT2 and IRF9 and suppressing downstream antiviral gene expression. Co-immunoprecipitation, nuclear translocation assays, IFN-β luciferase reporter, qPCR for ISG expression Virology Medium 28441586
2022 STAT3 is activated upstream of IRF9 in multicellular spheroids of colon carcinoma cells and binds the IRF9 promoter, driving IRF9 expression and subsequent IRDS gene upregulation. This occurs via gp130/JAK signaling from a soluble factor in conditioned media. STAT3 ChIP on IRF9 promoter, conditioned media transfer experiments, STAT3 inhibition, IRF9 knockdown, gene expression analysis Scientific reports Medium 30679726
2023 IRF9 interacts with Twist1 in human trophoblast cells; this interaction is required for IRF9 binding to the IFN-stimulated response element (ISRE) and constitutive ISG expression. Twist1 also acts as an upstream regulator controlling basal IRF9 protein levels. Absence of Twist1 renders trophoblasts susceptible to ZIKV infection. Co-immunoprecipitation for IRF9-Twist1 interaction, ISRE reporter assays, knockdown experiments, antiviral (ZIKV) assays Journal of immunology Medium 37144865
2025 IRF8 promotes IRF9 degradation through the ubiquitin-proteasome pathway by upregulating the E3 ubiquitin ligase NEDD4L, thereby suppressing type I IFN signaling and facilitating BEFV replication. Knockdown of NEDD4L reduced IRF8-driven IRF9 degradation. Knockdown/overexpression of IRF8 and NEDD4L, Western blot for IRF9 protein levels, proteasome inhibitor experiments, viral replication assays Veterinary microbiology Medium 40513519
2026 L-lactic acid induces IRF9 L-lactylation mediated by AARS1. IRF9 L-lactylation promotes IRF9-STAT2 interaction, potentiating type I IFN signaling and boosting antiviral immune response. Viruses achieve immune evasion by promoting SIRT1-mediated delactylation of IRF9. Metformin enhances IRF9 L-lactylation by accumulating lactic acid and disrupting virus-induced IRF9-SIRT1 interaction. L-lactylation modification identification, AARS1 knockdown, Co-IP for IRF9-STAT2 interaction, SIRT1 delactylation assay, antiviral assays, metformin treatment Proceedings of the National Academy of Sciences of the United States of America Medium 41481472
2012 Fish IRF9 (CaIRF9) is constitutively present in the nucleus driven by two nuclear localization signals (NLS): one within the DNA-binding domain and one immediately behind the DBD (mammalian IRF9 has only the first NLS). CaIRF9 together with CaSTAT2 activates ISRE-containing promoters, upregulates ISGs, and also activates the IFN promoter itself. GFP-fusion subcellular localization, NLS deletion mutants, co-transfection reporter assays, ISG expression analysis Fish & shellfish immunology Medium 22626811
2022 In STAT2- or IRF9-deficient cells, deficiency of any ISGF3 component suppresses induction of negative regulators such as USP18, leading to abnormally prolonged IFN-I receptor signaling. In cells lacking STAT2 or IRF9, this aberrant late transcriptional response to IFN-α mimics the effect of IFN-γ (GAF-like response), suggesting a negative feedback failure mechanism. IFN stimulation kinetics in patient-derived primary cells and iPSC-derived macrophages from STAT1-, STAT2-, or IRF9-deficient patients, transcriptome analysis, USP18 expression assays The Journal of allergy and clinical immunology Medium 35182547

Source papers

Stage 0 corpus · 91 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. The EMBO journal 289 24065129
2018 Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. The Journal of experimental medicine 175 30143481
2019 A molecular switch from STAT2-IRF9 to ISGF3 underlies interferon-induced gene transcription. Nature communications 174 31266943
2013 STAT2 and IRF9: Beyond ISGF3. JAK-STAT 115 24498542
2018 IRF9 and unphosphorylated STAT2 cooperate with NF-κB to drive IL6 expression. Proceedings of the National Academy of Sciences of the United States of America 96 29581268
2015 STAT2/IRF9 directs a prolonged ISGF3-like transcriptional response and antiviral activity in the absence of STAT1. The Biochemical journal 83 25564224
2008 IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice. The Journal of clinical investigation 82 18340381
2021 SARS-CoV-2 Spike Targets USP33-IRF9 Axis via Exosomal miR-148a to Activate Human Microglia. Frontiers in immunology 75 33936086
2018 Structural basis of STAT2 recognition by IRF9 reveals molecular insights into ISGF3 function. Proceedings of the National Academy of Sciences of the United States of America 70 29317535
2001 Overexpression of IRF9 confers resistance to antimicrotubule agents in breast cancer cells. Cancer research 67 11522652
2018 Interferon-β signal may up-regulate PD-L1 expression through IRF9-dependent and independent pathways in lung cancer cells. Biochemical and biophysical research communications 66 30446226
2013 IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH oxidase-mediated airway antiviral response. Cell research 61 23545780
2015 Noncanonical Effects of IRF9 in Intestinal Inflammation: More than Type I and Type III Interferons. Molecular and cellular biology 58 25918247
2009 IRF9 is a key factor for eliciting the antiproliferative activity of IFN-alpha. Journal of immunotherapy (Hagerstown, Md. : 1997) 54 19752753
2023 PTBP2-Mediated Alternative Splicing of IRF9 Controls Tumor-Associated Monocyte/Macrophage Chemotaxis and Repolarization in Neuroblastoma Progression. Research (Washington, D.C.) 53 37040518
2019 Porcine Reproductive and Respiratory Syndrome Virus nsp11 Antagonizes Type I Interferon Signaling by Targeting IRF9. Journal of virology 47 31092569
2012 Subcellular localization and functional characterization of a fish IRF9 from crucian carp Carassius auratus. Fish & shellfish immunology 47 22626811
2022 Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency. The Journal of allergy and clinical immunology 44 35182547
2012 Mice deficient in STAT1 but not STAT2 or IRF9 develop a lethal CD4+ T-cell-mediated disease following infection with lymphocytic choriomeningitis virus. Journal of virology 42 22496215
2002 Roles of Stat1, Stat2, and interferon regulatory factor-9 (IRF-9) in interferon tau regulation of IRF-1. Biology of reproduction 41 11804954
2017 IRF9 Prevents CD8+ T Cell Exhaustion in an Extrinsic Manner during Acute Lymphocytic Choriomeningitis Virus Infection. Journal of virology 39 28878077
2017 IRF9 as a negative regulator involved in TRIF-mediated NF-κB pathway in a teleost fish, Miichthys miiuy. Molecular immunology 38 28236773
2010 Combining theoretical analysis and experimental data generation reveals IRF9 as a crucial factor for accelerating interferon α-induced early antiviral signalling. The FEBS journal 36 20964804
2021 Monoclonal antibody-mediated neutralization of SARS-CoV-2 in an IRF9-deficient child. Proceedings of the National Academy of Sciences of the United States of America 32 34702736
2020 Specific enhancer selection by IRF3, IRF5 and IRF9 is determined by ISRE half-sites, 5' and 3' flanking bases, collaborating transcription factors and the chromatin environment in a combinatorial fashion. Nucleic acids research 31 31799619
2015 Porcine bocavirus NP1 negatively regulates interferon signaling pathway by targeting the DNA-binding domain of IRF9. Virology 31 26342467
2014 Structural and functional characterization of salmon STAT1, STAT2 and IRF9 homologs sheds light on interferon signaling in teleosts. FEBS open bio 29 25379383
2013 IL6 sensitizes prostate cancer to the antiproliferative effect of IFNα2 through IRF9. Endocrine-related cancer 27 23913484
2022 Butyrate Prevents Induction of CXCL10 and Non-Canonical IRF9 Expression by Activated Human Intestinal Epithelial Cells via HDAC Inhibition. International journal of molecular sciences 26 35409339
2008 IFN-beta-mediated inhibition of IL-8 expression requires the ISGF3 components Stat1, Stat2, and IRF-9. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 26 18370868
2016 Expression and functional characterization of interferon regulatory factors (irf2, irf7 and irf9) in the blunt snout bream (Megalobrama amblycephala). Developmental and comparative immunology 24 27677680
2012 HCV NS5A and IRF9 compete for CypA binding. Journal of hepatology 24 22902549
2020 ADAR1 Suppresses Interferon Signaling in Gastric Cancer Cells by MicroRNA-302a-Mediated IRF9/STAT1 Regulation. International journal of molecular sciences 23 32867271
2018 Increase of viral hemorrhagic septicemia virus growth by knockout of IRF9 gene in Epithelioma papulosum cyprini cells. Fish & shellfish immunology 23 30244086
2022 Increased IRF9-STAT2 Signaling Leads to Adaptive Resistance toward Targeted Therapy in Melanoma by Restraining GSDME-Dependent Pyroptosis. The Journal of investigative dermatology 22 35148998
2018 The IRF9-SIRT1-P53 axis is involved in the growth of human acute myeloid leukemia. Experimental cell research 22 29501566
2014 Differential regulation of Tetraodon nigroviridis Mx gene promoter activity by constitutively-active forms of STAT1, STAT2, and IRF9. Fish & shellfish immunology 21 24680831
2014 Molecular cloning and characterization of interferon regulatory factor 9 (IRF9) in Japanese flounder, Paralichthys olivaceus. Fish & shellfish immunology 21 24837327
2021 MiR-20a-5p Regulates MPP+-Induced Oxidative Stress and Neuroinflammation in HT22 Cells by Targeting IRF9/NF-κB Axis. Evidence-based complementary and alternative medicine : eCAM 20 34249133
2023 Seneca Valley virus 3Cpro antagonizes type I interferon response by targeting STAT1-STAT2-IRF9 and KPNA1 signals. Journal of virology 19 37819133
2020 The Measles Virus V Protein Binding Site to STAT2 Overlaps That of IRF9. Journal of virology 19 32581091
2023 An MRTF-A-ZEB1-IRF9 axis contributes to fibroblast-myofibroblast transition and renal fibrosis. Experimental & molecular medicine 18 37121967
2019 The Combination of IFN β and TNF Induces an Antiviral and Immunoregulatory Program via Non-Canonical Pathways Involving STAT2 and IRF9. Cells 18 31426476
2017 Interaction of IRF9 and STAT2 synergistically up-regulates IFN and PKR transcription in Ctenopharyngodon idella. Molecular immunology 18 28347954
2023 Suppression of IRF9 Promotes Osteoclast Differentiation by Decreased Ferroptosis via STAT3 Activation. Inflammation 17 37804406
2023 ISGF3 and STAT2/IRF9 Control Basal and IFN-Induced Transcription through Genome-Wide Binding of Phosphorylated and Unphosphorylated Complexes to Common ISRE-Containing ISGs. International journal of molecular sciences 17 38139463
2022 The Transcription Factor IRF9 Promotes Colorectal Cancer via Modulating the IL-6/STAT3 Signaling Axis. Cancers 17 35205671
2021 Upregulation of IRF9 Contributes to Pulmonary Artery Smooth Muscle Cell Proliferation During Pulmonary Arterial Hypertension. Frontiers in pharmacology 17 34925032
2022 Pseudorabies Virus EP0 Antagonizes the Type I Interferon Response via Inhibiting IRF9 Transcription. Journal of virology 16 35708311
2010 Intracellular expression of IRF9 Stat fusion protein overcomes the defective Jak-Stat signaling and inhibits HCV RNA replication. Virology journal 14 20939906
2020 IRF9 promotes apoptosis and innate immunity by inhibiting SIRT1-p53 axis in fish. Fish & shellfish immunology 13 32439513
2019 STAT3 is activated in multicellular spheroids of colon carcinoma cells and mediates expression of IRF9 and interferon stimulated genes. Scientific reports 13 30679726
2019 Molecular characterization and functional analysis of interferon regulatory factor 9 (irf9) in common carp Cyprinus carpio: a pivotal molecule in the Ifn response against pathogens. Journal of fish biology 13 31059592
2020 IRF9 Affects the TNF-Induced Phenotype of Rheumatoid-Arthritis Fibroblast-Like Synoviocytes via Regulation of the SIRT-1/NF-κB Signaling Pathway. Cells, tissues, organs 12 32772027
2022 SCD2-mediated cooperative activation of IRF3-IRF9 regulatory circuit controls type I interferon transcriptome in CD4+ T cells. Frontiers in immunology 11 36059459
2019 Identification and characterization of IRF9 from black carp Mylopharyngodon piceus. Developmental and comparative immunology 10 31654647
2017 Kobuvirus VP3 protein restricts the IFN-β-triggered signaling pathway by inhibiting STAT2-IRF9 and STAT2-STAT2 complex formation. Virology 10 28441586
2024 Elevated unphosphorylated STAT1 and IRF9 in T and B cells of primary sjögren's syndrome: Novel biomarkers for disease activity and subsets. Journal of autoimmunity 9 38788537
2022 Long non-coding RNA TTTY15 sponges miR-520a-3p to exacerbate neural apoptosis induced by cerebral ischemia/reperfusion via targeting IRF9 both in vivo and in vitro. Biomedical journal 9 35439640
2008 Nuclear transit of the intracellular domain of the interferon receptor subunit IFNaR2 requires Stat2 and Irf9. Cellular signalling 9 18456457
2023 Twist1-IRF9 Interaction Is Necessary for IFN-Stimulated Gene Anti-Zika Viral Infection. Journal of immunology (Baltimore, Md. : 1950) 8 37144865
2020 Negative Regulation of SIRT1 by IRF9 Involved in Hyperlipidemia Acute Pancreatitis Associated with Kidney Injury. Digestive diseases and sciences 8 32462510
2020 A novel function of IRF9 in acute pancreatitis by modulating cell apoptosis, proliferation, migration, and suppressing SIRT1-p53. Molecular and cellular biochemistry 7 32577948
2025 Avian interferon regulatory factor (IRF) family reunion: IRF3 and IRF9 found. BMC biology 6 40597257
2020 Sustained Inflammatory Signalling through Stat1/Stat2/IRF9 Is Associated with Amoeboid Phenotype of Melanoma Cells. Cancers 6 32872349
2025 FAM210B activates STAT1/IRF9/IFIT3 axis by upregulating IFN-α/β expression to impede the progression of lung adenocarcinoma. Cell death & disease 5 39900908
2025 The critical role of the ZBP1-NINJ1 axis and IRF1/IRF9 in ethanol-induced cell death, PANoptosis, and alcohol-associated liver disease. bioRxiv : the preprint server for biology 5 40161842
2024 The Role of IRF9 Upregulation in Modulating Sensitivity to Olaparib and Platinum-Based Chemotherapies in Breast Cancer. Genes 5 39062738
2024 Role and mechanism of IRF9 in promoting the progression of rheumatoid arthritis by regulating macrophage polarization via PSMA5. Heliyon 5 39170377
2022 Positive selection-driven fixation of a hominin-specific amino acid mutation related to dephosphorylation in IRF9. BMC ecology and evolution 5 36357830
2025 Identification and validation of diagnostic genes IFI44 and IRF9 in insomnia-associated autoimmune uveitis. Frontiers in immunology 4 39958336
2023 Phosphorylation of interferon regulatory factor 9 (IRF9). Molecular biology reports 4 36662450
2023 IRF9 inhibits CyHV-3 replication by regulating the PI3K-AKT signalling pathway in common carp (Cyprinus carpio) epithelial cells. Developmental and comparative immunology 4 37549834
2022 IRF9 and XAF1 as Diagnostic Markers of Primary Sjogren Syndrome. Computational and mathematical methods in medicine 4 36132546
2025 IRF8 facilitates bovine ephemeral fever virus replication by downregulating IRF9. Veterinary microbiology 3 40513519
2024 The Immune Response of OAS1, IRF9, and IFI6 Genes in the Pathogenesis of COVID-19. International journal of molecular sciences 3 38731851
2024 IFNh and IRF9 influence the transcription of MHCII mediated by IFNγ to maintain immune balance in sea perch lateolabrax japonicus. Fish & shellfish immunology 3 39182707
2024 IRF9 and STAT1 as biomarkers involved in T-cell immunity in atherosclerosis. Journal of biosciences 3 39234946
2024 Interferon Regulatory Factors (IRF1, IRF4, IRF5, IRF7 and IRF9) in Sichuan taimen (Hucho bleekeri): Identification and Functional Characterization. Genes 2 39596618
2023 Effect of temperature and IRF-9 gene-knockout on dynamics of vRNA, cRNA, and mRNA of viral hemorrhagic septicemia virus (VHSV). Fish & shellfish immunology 2 36796598
2017 Retraction: IRF9 inhibits human acute myeloid leukemia through the SIRT1-p53 signaling pathway. FEBS letters 2 28213966
2025 Integrative multi-omics analysis identifies a PTM-related immune signature and IRF9 as a driver in ccRCC. Frontiers in immunology 1 41403935
2015 A genomic variant in IRF9 is associated with serum cytokine levels in pig. Immunogenetics 1 26518782
2026 L-lactic acid enhances type I interferon immune response and inhibits virus infection by promoting IRF9 L-lactylation. Proceedings of the National Academy of Sciences of the United States of America 0 41481472
2026 Epigenetic dysregulation of IRF9 drives excessive interferon signaling in COPD. EMBO molecular medicine 0 41731077
2026 CRISPR-based functional analysis of chicken IRF9 reveals distinct modulation of dsRNA stimulated innate immune pathways. Developmental and comparative immunology 0 41759757
2025 Therapeutic Targeting of the IRF9/RTN4/RHOA/ROCK Pathway via RVG29-Modified PLGA Nanoparticles and rTMS for Neural and Vascular Regeneration Post-Cerebral Infarction. Advanced healthcare materials 0 40968528
2025 TAMs-derived exosomes promote breast cancer progression by regulating the IRF9/IFI6 axis. Breast cancer (Tokyo, Japan) 0 41037232
2025 Chromatin remodeling factor CHRAC1 regulates doxorubicin-induced cardiotoxicity via IRF9/GSDMD/CASP-1. Cellular signalling 0 41325875
2024 The lack of either IRF9, or STAT2, has surprisingly little effect on human natural killer cell development and function. Immunology 0 38514903
2024 Two IFNa3s mediate the regulation of IRF9 in the process of infection with Streptococcus iniae in yellowfin seabream, Acanthopagrus latus (Hottuyn, 1782). Developmental and comparative immunology 0 38574830

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