{"gene":"IRF1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1998,"finding":"Functional domain mapping of murine IRF-1 identified: (1) a minimal DNA-binding domain requiring N-terminal 124 amino acids plus a C-terminal extension; (2) a nuclear localization signal (NLS) sufficient for nuclear translocation; (3) a heterodimerization domain (homologous to IRF-2) that mediates interaction with ICSBP in vitro; (4) an acidic C-terminal domain required and sufficient for transcriptional activation.","method":"GFP-fusion mutant live-cell imaging, in vitro heterodimerization assays, mammalian two-hybrid system, epitope mapping","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (in vitro binding, live-cell imaging, two-hybrid, deletion mutagenesis) in one rigorous study defining distinct functional domains","pmids":["9742224"],"is_preprint":false},{"year":2002,"finding":"IRF-1 and IRF-2 induced by IFN-γ bind to three distinct sites in the IL-4 promoter and function as transcriptional repressors of IL-4 gene expression, providing a direct negative feedback mechanism by which IFN-γ attenuates Th2 responses.","method":"Electrophoretic mobility shift assay (EMSA), reporter gene assays, IRF-1/IRF-2 overexpression and knockdown in CD4+ T cells","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct DNA binding demonstrated by EMSA plus functional reporter assays with overexpression/knockdown, single lab but multiple orthogonal methods","pmids":["12479817"],"is_preprint":false},{"year":2002,"finding":"HCV NS5A protein colocalizes with PKR and suppresses dsRNA-mediated activation of PKR, thereby blocking IRF-1 activation and induction of IRF-1-dependent antiviral genes; mutations in the PKR-binding domain of NS5A relieved this blockade and reduced HCV replication efficiency.","method":"Colocalization (subcellular imaging), reporter gene assays with NS5A mutants, HCV subgenomic replicon system, dsRNA stimulation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via NS5A mutagenesis plus reporter assays and colocalization, single lab","pmids":["11904369"],"is_preprint":false},{"year":1996,"finding":"IRF-1 transcriptionally activates PKR expression: IRF-1-deficient mouse embryonic fibroblasts show reduced PKR levels, and transfection of IRF-1 into IRF-1-haploinsufficient U937 cells (which carry a deletion of one IRF-1 allele) is sufficient to induce PKR expression.","method":"IRF-1 knockout fibroblasts, transient transfection overexpression, Western blot/Northern blot for PKR levels","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout cells plus rescue transfection experiment, replicated in both mouse and human cell contexts","pmids":["8622878"],"is_preprint":false},{"year":1999,"finding":"IRF-1 transactivates the 2-5A synthetase and p21 (WAF1/CIP1) gene promoters by directly binding to IRF-binding elements within them; IRF-2 counteracts this activation; and IRF-1 also induces transcription of IRF-2 itself via an IRF-E in the IRF-2 promoter, establishing an autoinhibitory feedback loop.","method":"EMSA (direct promoter binding), CAT reporter transfection assays, IRF-1/IRF-2 ectopic expression and antisense constructs","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct DNA binding by EMSA combined with functional reporter assays and antisense rescue, multiple orthogonal approaches in one study","pmids":["10321737"],"is_preprint":false},{"year":2014,"finding":"DTX3L and ARTD9 (PARP9) form a complex that acts as a transcriptional repressor of IRF1 in metastatic prostate cancer cells; co-immunoprecipitation confirmed physical interaction between DTX3L, ARTD8, and ARTD9.","method":"Co-immunoprecipitation, Western blot, siRNA knockdown, immunofluorescence","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus functional knockdown assays, single lab, multiple methods","pmids":["24886089"],"is_preprint":false},{"year":2015,"finding":"BATF2 physically associates with IRF1 (demonstrated by co-immunoprecipitation), and this Batf2/Irf1 complex drives expression of inflammatory genes (Tnf, Ccl5, Nos2, Il12b) in IFN-γ-activated macrophages and during Mycobacterium tuberculosis infection.","method":"Co-immunoprecipitation, Irf1 knockdown, gene expression profiling","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus IRF1 knockdown demonstrating functional dependence, single lab","pmids":["25957166"],"is_preprint":false},{"year":2019,"finding":"IRF1 enhances recruitment of BRD4 to promoter-enhancer regions of interferon-stimulated genes (ISGs) for rapid transcriptional induction, and maintains histone H3K4me1 levels at ISG loci for constitutive expression; IRF1 also regulates constitutive expression of TLR2 and TLR3, promoting signaling through these pattern recognition receptors.","method":"CRISPR KO cell line, transcriptome analysis, chromatin immunoprecipitation (ChIP) for BRD4 and H3K4me1, IFN/JAK-STAT blockade, viral infection assays","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined phenotype, ChIP for mechanistic chromatin evidence, IFN-independent pathway dissection, multiple orthogonal methods","pmids":["31156620"],"is_preprint":false},{"year":2019,"finding":"GSK3β phosphorylates IRF1 at residue T181, generating a phosphodegron recognized by the SCF-Fbxw7α E3 ubiquitin ligase, which ubiquitinates and degrades DNA-bound IRF1; T181A mutation stabilizes IRF1 at target promoters but blocks RNA Pol II elongation and transcription of target genes, abolishing anti-proliferative activity.","method":"Site-directed mutagenesis (T181A), ChIP, RNA Pol II elongation assay, proteasome inhibition, Fbxw7-deficient cell lines, proliferation assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation, mutagenesis, ChIP, functional readout (transcription and antiproliferative activity) with multiple orthogonal methods in one rigorous study","pmids":["30854564"],"is_preprint":false},{"year":2013,"finding":"E3 ligases CHIP and MDM2 dock to the Mf2 domain of IRF-1 and ubiquitinate lysine residues predominantly in loop structures of the DNA-binding domain; when IRF-1 is bound to cognate DNA, the Mf2 docking site is occluded, suppressing ubiquitination and protecting active DNA-bound IRF-1 from degradation.","method":"In vitro ubiquitination assays, DNA-binding competition assays, site-directed mutagenesis of Mf2 domain","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro ubiquitination with mutagenesis and DNA competition, single lab but multiple orthogonal biochemical methods","pmids":["23134341"],"is_preprint":false},{"year":2023,"finding":"In IFN-γ-stimulated cells, KAT8 undergoes phase separation with IRF1, forming biomolecular condensates; within these condensates KAT8 acetylates IRF1 at K78, which promotes IRF1 binding to the CD274 (PD-L1) promoter and enriches the transcription apparatus to drive PD-L1 transcription; a blocking peptide (2142-R8) disrupts KAT8-IRF1 condensate formation and inhibits PD-L1 expression.","method":"Phase separation assays, co-immunoprecipitation, mass spectrometry, mutagenesis of IRF1 K78, ChIP, in vitro and in vivo tumor models with blocking peptide","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical reconstitution of condensates, identification of acetylation site by mutagenesis, ChIP, in vivo validation; multiple orthogonal methods","pmids":["36894639"],"is_preprint":false},{"year":2022,"finding":"SPOP (E3 ubiquitin ligase adaptor) binds IRF1 and triggers its ubiquitin-proteasomal degradation, thereby suppressing IRF1-mediated transcriptional upregulation of PD-L1; cancer-associated SPOP mutants lose the ability to degrade IRF1, resulting in IRF1 stabilization and elevated PD-L1 expression.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibition, Western blot with SPOP mutants, reporter assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus ubiquitination assay plus functional mutant analysis, multiple orthogonal methods in single lab","pmids":["36481790"],"is_preprint":false},{"year":2020,"finding":"IRF1 directly binds to the promoter region of DRP1 and suppresses its expression; IS (indoxyl sulfate) upregulates IRF1, which in turn reduces DRP1 and inhibits mitophagic flux, causing intestinal barrier injury; IRF1 knockout mice are protected from these effects.","method":"ChIP assay (IRF1 binding to DRP1 promoter), IRF1 knockout mice, DRP1 overexpression rescue, Western blot, transmission electron microscopy","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, genetic KO with rescue experiment, multiple phenotypic readouts","pmids":["32641998"],"is_preprint":false},{"year":2020,"finding":"IRF1 directly binds to the promoter of PGC1α (via histone H3K9 acetylation-dependent upregulation of IRF1 by high phosphate) and transcriptionally represses PGC1α expression, leading to myocardial energy metabolism dysfunction in cardiorenal syndrome type 4.","method":"ChIP assay (IRF1 binding to PGC1α promoter), IRF1 knockdown, IRF1 knockout mice, histone acetylation analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP plus genetic KO in vivo, multiple orthogonal methods, single lab","pmids":["32938919"],"is_preprint":false},{"year":2022,"finding":"IRF-1 is transcriptionally upregulated by RelB/p52 (non-canonical NF-κB) binding to the IRF-1 promoter at −782/−770; IRF-1 in turn binds the GSDMD promoter at −526/−515 and the CASP1 promoter at −11/10 to promote their expression, driving NLRP3 inflammasome-mediated pyroptosis and atherosclerosis.","method":"ChIP assay, RNA-seq, endothelial-specific NIK and IRF-1 KO mice on Apoe-null background, luciferase reporter, Western blot","journal":"Translational research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP for both upstream regulation and downstream targets, genetic KO with in vivo atherosclerosis phenotype, RNA-seq; multiple orthogonal methods","pmids":["36384204"],"is_preprint":false},{"year":2020,"finding":"IRF1 is required for caspase-3 expression in intestinal epithelial cells by directly binding to IRF1-binding sites in the caspase-3 promoter, as confirmed by dual-luciferase reporter and ChIP assays; IRF1−/− mice are completely protected from TNFα-induced IEC shedding.","method":"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), IRF1 and caspase-3 knockout mice, TNFα-injection model","journal":"Journal of Crohn's & colitis","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and reporter, genetic KO phenotype, multiple orthogonal approaches","pmids":["34309645"],"is_preprint":false},{"year":2020,"finding":"IRF1 interacts with IRF3 (via its DNA-binding domain) and augments IRF3 activation by blocking the interaction between IRF3 and protein phosphatase 2A (PP2A), thereby increasing IRF3 phosphorylation and innate immune gene induction during viral infection.","method":"Co-immunoprecipitation, IRF1 DBD deletion mutants, PP2A interaction competition assay, siRNA knockdown, viral infection assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, domain mapping, mechanistic PP2A competition assay, multiple orthogonal methods, single lab","pmids":["32878885"],"is_preprint":false},{"year":2018,"finding":"IRF1 promotes STAT1 phosphorylation at Y701 and JAK1 phosphorylation, enabling STAT1 dimerization and binding to gamma-activated sequence (GAS) elements; the transactivation domain of IRF1 is required for this effect, and IRF1-conditioned medium (containing a secreted factor that is not IFN-β or IFN-γ) can activate STAT1 in recipient cells; loss of IRF1 reduces sustained IFN-γ-induced STAT1 phosphorylation.","method":"IRF1 transient overexpression and CRISPR KO in HEK293 cells, GAS-reporter assays, anti-IFN neutralizing antibodies, Western blot for phospho-STAT1/JAK1, EMSA for STAT1-GAS binding","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KO rescue and reporter assays with domain mapping, single lab, indirect mechanism (secreted factor not fully identified)","pmids":["29893425"],"is_preprint":false},{"year":2000,"finding":"IRF-1 binds to an ISRE/IRF-E candidate sequence in the SMN and SMNc gene promoters in vitro, and overexpression of IRF-1 induces SMN/SMNc mRNA and protein expression in transfection assays; IFN-β and IFN-γ induction of SMN genes is at least partly mediated by IRF-1.","method":"In vitro DNA binding (EMSA), transfection reporter/overexpression assays, primary fibroblasts from SMA patients, Western blot","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA for direct binding plus functional overexpression in multiple cell types, single lab","pmids":["11147573"],"is_preprint":false},{"year":2014,"finding":"Oncogenic Ras/MEK signaling downregulates IRF1 protein expression; MEK inhibition restores IRF1 expression; and re-expression of IRF1 in human cancer cells renders them resistant to oncolytic vesicular stomatitis virus, placing IRF1 downstream of Ras/MEK in suppressing IFN-inducible gene transcription.","method":"Promoter deletion analysis, IRF1−/− MEFs (epistasis), MEK inhibitor treatment, IRF1 re-expression, oncolytic virus infection assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using IRF1 KO MEFs, promoter analysis, pharmacological MEK inhibition, and functional rescue; multiple orthogonal methods replicated in mouse and human cells","pmids":["25347735"],"is_preprint":false},{"year":2019,"finding":"XAF1 stabilizes IRF1 protein by antagonizing CHIP-mediated ubiquitination and degradation of IRF1; this XAF1-IRF1 positive feedback loop induces antiviral IRF1 target genes (DDX58, DDX60, MX1, OAS2) and restricts RNA virus replication.","method":"Co-immunoprecipitation, XAF1 knockout cell lines, CHIP ubiquitination assay, viral infection in vitro and in vivo mouse models","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay plus KO phenotype, single lab, multiple orthogonal methods","pmids":["35972291"],"is_preprint":false},{"year":2017,"finding":"HCFC2 promotes the binding of IRF1 and IRF2 to the Tlr3 promoter; without HCFC2, IRF1/IRF2 binding is impaired, resulting in reduced Tlr3 transcription and diminished poly(I:C)-induced cytokine and type I IFN responses in macrophages.","method":"ENU mutagenesis screen, ChIP for IRF1/IRF2 at Tlr3 promoter, genetic complementation, macrophage poly(I:C) stimulation, viral infection survival assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (ENU screen + complementation), ChIP demonstrating mechanistic link, in vivo infection phenotype; multiple orthogonal methods","pmids":["28970238"],"is_preprint":false},{"year":2019,"finding":"Human cytomegalovirus induces Roquin expression; Roquin binds IRF1 mRNA directly (identified by CLIP-seq) and reduces IRF1 protein expression post-transcriptionally, suppressing IRF1-dependent antiviral gene expression to enable viral replication.","method":"CLIP-seq (cross-linking immunoprecipitation + sequencing), loss-of-function screen, transcriptome profiling, Roquin knockdown/overexpression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CLIP-seq identifying direct mRNA binding site, combined with loss-of-function screen and transcriptome data; multiple orthogonal methods, single lab","pmids":["31451648"],"is_preprint":false},{"year":2016,"finding":"DUSP1 overexpression elevates IRF1 mRNA and protein stability by suppressing MAPKs (which otherwise destabilize IRF1), thereby maintaining expression of IRF1-dependent genes including CXCL10; ChIP showed IRF1 recruitment to the CXCL10 promoter is essentially unaffected by dexamethasone despite DUSP1 induction.","method":"DUSP1 overexpression and siRNA silencing, MAPK inhibitors, mRNA stability assays, ChIP at CXCL10 and other IRF1-dependent promoters","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus overexpression/knockdown demonstrating regulatory mechanism, single lab, multiple methods","pmids":["27551049"],"is_preprint":false},{"year":2021,"finding":"IRF1 governs differential ISG responses in human macrophages vs. monocytes: TLR4 signaling in macrophages uniquely engages IRF1, which facilitates chromatin opening at ISG loci for transcription; this lineage-specific chromatin remodeling function was not observed in monocytes.","method":"ATAC-seq (chromatin accessibility), RNA-seq, IRF1 KO in macrophages, TLR ligand stimulation panel, ChIP","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with genome-wide ATAC-seq and RNA-seq establishing direct chromatin remodeling function; multiple orthogonal methods","pmids":["33761354"],"is_preprint":false},{"year":2017,"finding":"IRF1 and BATF serve as pioneering transcription factors during Tr1 cell differentiation: both are induced early by IL-27 and are required for chromatin accessibility and expression of Tr1 cell functional genes, as shown by epigenetic (ATAC-seq) and transcriptional analyses in IRF1- and BATF-deficient cells.","method":"ATAC-seq, RNA-seq, IRF1-deficient and BATF-deficient T cells, in vitro and in vivo Tr1 differentiation assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide chromatin accessibility + transcriptomics in genetic KO cells, in vivo validation; multiple orthogonal methods in rigorous study","pmids":["28166218"],"is_preprint":false},{"year":2023,"finding":"IRF1-deficient mononuclear phagocytes fail to control mycobacteria and related intramacrophagic pathogens after IFN-γ stimulation; IFN-γ-dependent responses in IRF1-deficient leukocytes and fibroblasts are qualitatively and quantitatively much more impaired than IFN-α/β-dependent responses, demonstrating that IRF1 is essential for IFN-γ-dependent macrophagic immunity but largely redundant for IFN-α/β-dependent antiviral responses.","method":"IRF1-deficient patient cells (natural human genetic experiment), in vitro IFN-γ and IFN-α/β stimulation, mycobacterial killing assays, virus infection assays in fibroblasts","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — human loss-of-function (complete IRF1 deficiency) with mechanistic functional assays across multiple pathogens and IFN types, replicated across unrelated patients","pmids":["36736301"],"is_preprint":false},{"year":2023,"finding":"IRF1 acts as an upstream transcriptional regulator of PANoptosome components: IRF1 contributes to ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosome activation and PANoptosis (inflammatory cell death) in primary murine macrophages, but is dispensable for inflammasomes that form independently of the PANoptosome to drive pyroptosis alone.","method":"Live-cell imaging, Western blotting, ELISA, genetic IRF1 KO primary macrophages, multiple PANoptosome activation stimuli","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary KO macrophages with multiple activation stimuli and orthogonal readouts, single lab","pmids":["37557956"],"is_preprint":false},{"year":2020,"finding":"IRF1 transcriptionally suppresses PGC1α expression by binding to its promoter region (upregulated via H3K9 acetylation induced by high phosphate); restoration of PGC1α or genetic IRF1 knockdown attenuates high-phosphate-induced myocardial energy metabolism dysfunction.","method":"ChIP (IRF1 binding to PGC1α promoter), H3K9 acetylation analysis, IRF1 knockdown in vitro and KO mice in vivo, metabolic assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus in vivo KO rescue plus histone modification analysis; multiple orthogonal methods, replicated in vitro and in vivo","pmids":["32938919"],"is_preprint":false},{"year":2023,"finding":"IRF1 binds to the promoter region of SLC7A11 (xCT) and suppresses its transcription, as confirmed by ChIP and luciferase reporter assays; loss of IRF1 increases SLC7A11, suppressing ferroptosis of hepatic stellate cells; this mechanism mediates GRh2-induced HSC ferroptosis and liver fibrosis attenuation.","method":"ChIP assay, luciferase reporter assay, IRF1 loss-of-function, SLC7A11 expression analysis, ferroptosis markers","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and reporter, functional KO, single lab","pmids":["37441987"],"is_preprint":false},{"year":2023,"finding":"IRF1 directly binds the GBP5 promoter (confirmed by ChIP and dual luciferase assay) to enhance GBP5 expression; the IRF1/GBP5 axis promotes NLRP3 inflammasome-mediated chondrocyte pyroptosis and extracellular matrix degradation in osteoarthritis.","method":"Dual-luciferase reporter assay, ChIP, siRNA knockdown, adenoviral overexpression, NLRP3 inflammasome pathway readouts, DMM mouse model","journal":"Journal of orthopaedic translation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and reporter, in vivo KO phenotype, single lab","pmids":["38229660"],"is_preprint":false},{"year":2024,"finding":"Radiation-induced leakage of mitochondrial DNA (mtDNA) initiates nuclear translocation of IRF1; novel PTM sites in the IRF1 NLS were identified — mutation of an acetylation site and phosphorylation sites in the NLS blocked IRF1 transcriptional activation and reduced radiation-induced cell death. Reciprocal regulation between SSBP1 and IRF1 restrains STING/p300-mediated PTMs of IRF1.","method":"Site-directed mutagenesis of NLS PTM sites, mass spectrometry PTM identification, nuclear fractionation/translocation imaging, SSBP1-IRF1 co-IP, CRISPR KO, radiation and SARS-CoV-2 infection models","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of novel PTM sites combined with nuclear translocation and co-IP data, single lab with multiple orthogonal methods","pmids":["38849539"],"is_preprint":false},{"year":2015,"finding":"IRF1 is required downstream of IRF8 for IL-1β expression in reactive microglia: peripheral nerve injury induces IRF1 gene expression in spinal microglia in an IRF8-dependent manner; IRF8 transduction in cultured microglia induces IRF1 de novo; and IRF1 knockdown in IRF8-transduced microglia prevents IL-1β upregulation.","method":"IRF8 viral transduction, IRF1 siRNA knockdown, in vivo spinal cord IRF1 expression analysis after nerve injury, qPCR/Western blot","journal":"Journal of pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (IRF8 → IRF1 → IL-1β) demonstrated by KD rescue in defined cell type, in vivo validation, single lab","pmids":["26318672"],"is_preprint":false},{"year":2016,"finding":"IRF1 directly regulates IRG1 (immune-responsive gene 1/CAD) transcription: siRNA-mediated knockdown of IRF1 in macrophages significantly decreased IRG1/CAD gene and protein expression and correlated with reduced itaconic acid production.","method":"siRNA knockdown, RT-PCR, Western blot, itaconic acid measurement, gene regulatory network computational + experimental validation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with multiple readouts (mRNA, protein, metabolite), computational network prediction validated experimentally, single lab","pmids":["26872335"],"is_preprint":false},{"year":2012,"finding":"IRF-1 transcriptionally regulates VCAM-1 expression in human aortic endothelial cells: overexpression of IRF-1 recapitulated proatherogenic upregulation of VCAM-1, while silencing of IRF-1 mimicked the antiatherogenic downregulation; IRF-1 and miR-126 were reciprocally modulated by postprandial triglyceride-rich lipoproteins.","method":"IRF-1 overexpression, siRNA silencing, miR-126 modulation, VCAM-1 expression assays in HAEC","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression and knockdown with functional readout, single lab, two orthogonal interventions","pmids":["22874466"],"is_preprint":false},{"year":2021,"finding":"SARS-CoV-2 ORF6 protein suppresses IRF1 gene expression by blocking STAT1 signaling (type II interferon-mediated), which prevents IRF1 upregulation of NLRC5 and MHC class I pathway genes; ORF6 also blocks karyopherin complex-dependent nuclear import of NLRC5.","method":"SARS-CoV-2-infected epithelial cell lines, COVID-19 patient gene expression, ORF6 overexpression, JAK-STAT reporter assays, nuclear import assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ORF6 mechanistic experiments in cell lines plus patient data, pathway confirmed by reporter assays, single lab","pmids":["34782627"],"is_preprint":false},{"year":2023,"finding":"PARP7 is a nuclear, cysteine-specific mono-ADP-ribosyltransferase that modifies FRA1 (AP-1 transcription factor) at C97; loss of FRA1 ADP-ribosylation promotes FRA1 degradation via PSMC3, which de-represses IRF1- and IRF3-dependent proapoptotic and cytokine gene expression, culminating in CASP8-mediated apoptosis.","method":"PARP7 inhibition (RBN-2397), C97 mutation of FRA1, proteasome inhibition, IRF1/IRF3-dependent reporter assays, mass spectrometry for ADP-ribosylation sites","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific mutagenesis + MS identification of modification site + functional IRF1-dependent reporter assays, single lab, multiple methods","pmids":["38011562"],"is_preprint":false},{"year":2023,"finding":"IRF1 regulates ZBP1 transcription in an IRF1-dependent manner downstream of TNF-α; IRF1-driven ZBP1 overexpression is activated by mitochondrial DNA binding to ZBP1; activated ZBP1 interacts with RIPK1 and activates TAK1-NF-κB signaling, leading to chondrocyte inflammation and matrix degradation in osteoarthritis.","method":"IRF1 KD in chondrocytes, ZBP1 KD, DMM mouse model, co-immunoprecipitation (ZBP1-RIPK1), Cyclosporine A (mtDNA release blocker), Western blot","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis (IRF1 → ZBP1) plus co-IP for ZBP1-RIPK1, in vivo KD phenotype, single lab","pmids":["39026271"],"is_preprint":false},{"year":2023,"finding":"IRF1 loss in mouse HSCs significantly impairs self-renewal, increases stress-induced proliferation, and confers resistance to apoptosis, establishing IRF1 as a pivotal regulator of HSC homeostasis.","method":"Conditional IRF1 KO in mouse HSCs, transplantation assays, stress-induced proliferation assays, apoptosis measurement","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined cellular phenotypes in stem cell assays, single lab","pmids":["37889967"],"is_preprint":false},{"year":2024,"finding":"IRF1 binds to the promoter of GPX4 indirectly by interacting with SPI1 (PU.1) and suppressing SPI1's transcriptional activating effect on GPX4 expression, thereby reducing GPX4 levels, increasing lipid ROS accumulation, and enhancing ferroptosis in colon cancer cells.","method":"Co-immunoprecipitation (IRF1-SPI1 interaction), ChIP (SPI1 binding to GPX4 promoter), luciferase reporter assay, IRF1/SPI1 overexpression and knockdown, ferroptosis markers","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus reporter assay, single lab, multiple orthogonal methods","pmids":["37517591"],"is_preprint":false},{"year":2022,"finding":"IFIH1 promotes IRF1 translocation into the nucleus in macrophages during infection; nuclear IRF1 then binds to the STAT1 promoter (confirmed by ChIP-seq) and activates STAT1 transcription, contributing to macrophage M1 polarization and septic lung injury.","method":"ChIP-seq (IRF1 binding to STAT1 promoter), IRF1 KO mice (CLP model), shRNA knockdown, nuclear fractionation, immunohistochemistry","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus IRF1 KO in vivo model, single lab, multiple methods","pmids":["36462334"],"is_preprint":false},{"year":2020,"finding":"iNOS/NO promotes IRF1 nuclear translocation and transcriptional activity through HDAC2-mediated histone H3 deacetylation (H3K9 hypoacetylation) at IRF1 target gene promoters; iNOS KO mice show impaired IRF1 nuclear translocation and reduced PUMA expression after hepatic I/R injury.","method":"iNOS KO mice (I/R model), iNOS overexpression, NO donors, HDAC inhibitor (romidepsin), nuclear fractionation for IRF1, H3AcK9 Western blot, IRF1 reporter assay","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus pharmacological intervention plus histone modification analysis, single lab, multiple orthogonal methods","pmids":["32517688"],"is_preprint":false}],"current_model":"IRF1 is a stimulus-inducible transcription factor that binds IRF-binding elements (ISRE/IRF-E) in target gene promoters through its N-terminal DNA-binding domain; its transcriptional activation requires an acidic C-terminal domain and regulated protein turnover mediated by GSK3β-phosphorylation at T181, which creates a phosphodegron for SCF-Fbxw7α-dependent ubiquitination and proteasomal degradation — a process that is itself required for productive RNA Pol II elongation at target promoters; IRF1 forms heterodimers with ICSBP/IRF2 and physical complexes with partners including BATF2, IRF3 (whose activation it promotes by blocking PP2A-mediated dephosphorylation), and KAT8 (which acetylates IRF1-K78 within phase-separated condensates to drive PD-L1 transcription); IRF1 protein stability is positively regulated by XAF1 (antagonizing CHIP-mediated degradation) and negatively by SPOP-mediated ubiquitination and Roquin-mediated mRNA destabilization, while DUSP1-mediated MAPK suppression prolongs IRF1 mRNA/protein stability; downstream, IRF1 activates diverse target genes (PKR, p21, 2-5A synthetase, TLR3, caspase-3, GSDMD, CASP1, ZBP1, GBP5, DRP1, STAT1, IRG1, SMN) and represses others (PGC1α, SLC7A11, GPX4 via SPI1 interaction), placing IRF1 as a central integrator of IFN-γ-dependent macrophagic immunity, innate antiviral defense, inflammatory cell death (PANoptosis/pyroptosis/ferroptosis), and cell growth control."},"narrative":{"mechanistic_narrative":"IRF1 is a stimulus-inducible transcription factor that integrates interferon and inflammatory signaling into programs of antiviral defense, macrophagic immunity, inflammatory cell death, and cell growth control [PMID:36736301, PMID:36384204]. It engages target promoters through an N-terminal DNA-binding domain that, together with a C-terminal extension, recognizes ISRE/IRF-E elements, while a separable acidic C-terminal domain provides transcriptional activation and a dedicated NLS directs nuclear import; the same protein carries a heterodimerization surface that mediates binding to ICSBP/IRF2 [PMID:9742224]. Through direct promoter binding IRF1 activates antiviral and growth-suppressive genes including PKR, 2-5A synthetase, and the cell-cycle inhibitor p21, and induces IRF2 itself to establish autoinhibitory feedback [PMID:8622878, PMID:10321737], while functioning as a repressor at other loci such as IL-4, PGC1α, and SLC7A11 [PMID:12479817, PMID:32938919, PMID:37441987]. At chromatin, IRF1 acts as a pioneering/remodeling factor that opens ISG and lineage-specific loci, recruits BRD4, and maintains H3K4me1 to enable rapid and constitutive induction of interferon-stimulated and pattern-recognition genes including TLR2/TLR3 [PMID:31156620, PMID:33761354, PMID:28166218]. Human IRF1 deficiency demonstrates that this factor is essential for IFN-γ-dependent control of mycobacteria and intramacrophagic pathogens but largely redundant for IFN-α/β antiviral responses [PMID:36736301]. IRF1 output is gated by tightly controlled protein turnover: GSK3β phosphorylation at T181 creates a phosphodegron recognized by SCF-Fbxw7α, and this ubiquitin-driven degradation of DNA-bound IRF1 is itself required for productive RNA Pol II elongation at target promoters [PMID:30854564], whereas DNA binding occludes the Mf2 docking site used by CHIP and MDM2 to protect active IRF1 [PMID:23134341]. Stability is further tuned by XAF1 (antagonizing CHIP), SPOP-mediated ubiquitination, and Roquin-mediated mRNA destabilization [PMID:35972291, PMID:36481790, PMID:31451648]. IRF1 also acts within IFN-γ-induced KAT8 condensates, where acetylation at K78 drives CD274/PD-L1 transcription [PMID:36894639], cooperates with partners such as BATF2 and IRF3 (whose activation it promotes by blocking PP2A) [PMID:25957166, PMID:32878885], and directs inflammatory cell-death programs by transactivating GSDMD, CASP1, GBP5, and ZBP1 and contributing to PANoptosome activation [PMID:36384204, PMID:38229660, PMID:39026271, PMID:37557956].","teleology":[{"year":1996,"claim":"Established that IRF1 is not merely an interferon-responsive marker but a functional transcriptional activator of an effector gene, linking it directly to antiviral output.","evidence":"IRF-1 knockout fibroblasts and rescue transfection in haploinsufficient cells measuring PKR levels","pmids":["8622878"],"confidence":"High","gaps":["Did not map the IRF-E in the PKR promoter","Did not address other target genes"]},{"year":1998,"claim":"Defined the modular architecture of IRF1, separating DNA binding, nuclear import, heterodimerization, and transactivation into discrete domains.","evidence":"GFP-fusion imaging, in vitro heterodimerization, two-hybrid and deletion mutagenesis of murine IRF-1","pmids":["9742224"],"confidence":"High","gaps":["Domain function defined largely in vitro/ectopic systems","Structural basis of DNA recognition not resolved"]},{"year":1999,"claim":"Showed IRF1 directly binds and transactivates growth-suppressive and antiviral promoters while autoregulating via IRF2, framing it as a bidirectional regulator within a feedback network.","evidence":"EMSA promoter binding plus CAT reporter and antisense assays for 2-5A synthetase, p21, and IRF-2","pmids":["10321737"],"confidence":"High","gaps":["Quantitative contribution of each IRF-E in vivo not established","Cell-type specificity of feedback loop unaddressed"]},{"year":2002,"claim":"Demonstrated IRF1 can act as a transcriptional repressor, providing a direct mechanism for IFN-γ antagonism of Th2 responses.","evidence":"EMSA, reporter assays, and IRF-1/IRF-2 over/knockdown at the IL-4 promoter in CD4+ T cells","pmids":["12479817"],"confidence":"High","gaps":["Co-repressor machinery not identified","Does not explain switch between activation and repression at different promoters"]},{"year":2002,"claim":"Placed IRF1 activation within an antiviral signaling axis targeted by viral immune evasion.","evidence":"HCV NS5A colocalization with PKR, replicon system, and NS5A mutant reporter assays","pmids":["11904369"],"confidence":"Medium","gaps":["IRF1 activation inferred from downstream readouts rather than measured directly","Single lab, indirect link via PKR"]},{"year":2013,"claim":"Resolved how active DNA-bound IRF1 is protected from degradation, coupling its transcriptional state to its stability.","evidence":"In vitro ubiquitination, Mf2 mutagenesis, and DNA-binding competition with CHIP and MDM2","pmids":["23134341"],"confidence":"High","gaps":["In vitro reconstitution only","Relative in vivo contribution of CHIP vs MDM2 unclear"]},{"year":2019,"claim":"Uncovered a phosphodegron mechanism in which regulated IRF1 turnover is paradoxically required for transcription, linking degradation to Pol II elongation.","evidence":"T181A mutagenesis, ChIP, RNA Pol II elongation assays, and Fbxw7-deficient cells","pmids":["30854564"],"confidence":"High","gaps":["Mechanistic coupling of ubiquitination to elongation not fully defined","Generality across all IRF1 targets untested"]},{"year":2019,"claim":"Defined IRF1 as a chromatin-priming factor that recruits BRD4 and maintains active histone marks for rapid and constitutive ISG induction.","evidence":"CRISPR KO, transcriptomics, ChIP for BRD4 and H3K4me1, and IFN/JAK-STAT blockade","pmids":["31156620"],"confidence":"High","gaps":["How IRF1 selects ISG loci genome-wide not fully resolved","Direct vs indirect H3K4me1 maintenance unclear"]},{"year":2017,"claim":"Established IRF1 as a pioneering transcription factor that opens chromatin during lymphoid and myeloid differentiation programs.","evidence":"ATAC-seq and RNA-seq in IRF1- and BATF-deficient cells during IL-27-driven Tr1 differentiation; later extended to macrophage TLR4 responses","pmids":["28166218","33761354"],"confidence":"High","gaps":["Cofactors enabling nucleosome engagement not defined","Lineage selectivity of remodeling mechanism unexplained"]},{"year":2017,"claim":"Showed IRF1 promoter occupancy depends on accessory factors, identifying HCFC2 as a determinant of IRF1/IRF2 binding to the Tlr3 promoter.","evidence":"ENU screen, ChIP for IRF1/IRF2, genetic complementation, and poly(I:C) macrophage responses","pmids":["28970238"],"confidence":"High","gaps":["Molecular basis of HCFC2-IRF1 cooperation unresolved","Generality to other IRF1 targets untested"]},{"year":2020,"claim":"Defined IRF1 as a multi-pathway driver of inflammatory cell death by directly transactivating pyroptotic and apoptotic effector genes.","evidence":"ChIP/reporter assays and IRF1 KO mice for caspase-3, GSDMD, CASP1, and DRP1 across intestinal, vascular, and barrier-injury models","pmids":["34309645","36384204","32641998"],"confidence":"High","gaps":["Context determinants selecting cell-death program not defined","Direct vs indirect promoter effects vary by study"]},{"year":2020,"claim":"Demonstrated IRF1 enhances IRF3 activation by shielding it from PP2A, expanding IRF1 into a post-translational regulator of partner transcription factors.","evidence":"Co-IP, IRF1 DBD deletion mutants, and PP2A interaction competition during viral infection","pmids":["32878885"],"confidence":"High","gaps":["Stoichiometry of the IRF1-IRF3-PP2A interaction unknown","Whether this is DNA-independent unclear"]},{"year":2022,"claim":"Identified SPOP-mediated and Roquin-mediated negative regulation that constrains IRF1-driven immune and PD-L1 expression.","evidence":"Co-IP and ubiquitination assays with SPOP mutants; CLIP-seq mapping of Roquin binding to IRF1 mRNA","pmids":["36481790","31451648"],"confidence":"High","gaps":["Degradation site mapping incomplete","Interplay with stabilizing factors not reconciled"]},{"year":2023,"claim":"Showed IRF1 functions within phase-separated KAT8 condensates where K78 acetylation drives PD-L1 transcription, adding biomolecular condensates and acetylation to IRF1 regulation.","evidence":"Phase separation assays, MS, K78 mutagenesis, ChIP, and in vivo tumor models with a blocking peptide","pmids":["36894639"],"confidence":"High","gaps":["Generality of condensate behavior to non-PD-L1 targets untested","Determinants of condensate composition unclear"]},{"year":2023,"claim":"Human IRF1 deficiency established the non-redundant, pathway-specific role of IRF1 in IFN-γ-dependent macrophagic immunity versus dispensable IFN-α/β antiviral function.","evidence":"IRF1-deficient patient cells with IFN-γ and IFN-α/β stimulation, mycobacterial killing, and viral infection assays","pmids":["36736301"],"confidence":"High","gaps":["Molecular basis of IFN-type selectivity not fully defined","Spectrum of susceptible pathogens incomplete"]},{"year":2024,"claim":"Revealed NLS-localized PTMs and mtDNA/STING-linked signals controlling IRF1 nuclear translocation and activation.","evidence":"MS PTM mapping, NLS site mutagenesis, nuclear translocation imaging, and SSBP1-IRF1 co-IP in radiation and infection models","pmids":["38849539"],"confidence":"Medium","gaps":["Enzymes depositing each NLS PTM only partly defined","In vivo physiological relevance limited to specific stress models"]},{"year":null,"claim":"How IRF1 selects between transcriptional activation and repression, and how its post-translational modifications, condensate behavior, and turnover are integrated to specify divergent cell-fate outcomes (antiviral defense vs PANoptosis vs growth control), remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTM state to activator vs repressor function","Determinants of target-gene selection across tissues unknown","Structural model of DNA-bound IRF1 with cofactors absent from corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,4,8,14]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4,12,14,15]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,31,40,41]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[8,10]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,24,26]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,7,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[14,15,27,29]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,9,11,20]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[7,24,25]}],"complexes":[],"partners":["IRF2","ICSBP","BATF2","IRF3","KAT8","SPOP","XAF1","SPI1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P10914","full_name":"Interferon regulatory factor 1","aliases":[],"length_aa":325,"mass_kda":36.5,"function":"Transcriptional regulator which displays a remarkable functional diversity in the regulation of cellular responses (PubMed:15226432, PubMed:15509808, PubMed:17516545, PubMed:17942705, PubMed:18497060, PubMed:19404407, PubMed:19851330, PubMed:22367195, PubMed:32385160). Regulates transcription of IFN and IFN-inducible genes, host response to viral and bacterial infections, regulation of many genes expressed during hematopoiesis, inflammation, immune responses and cell proliferation and differentiation, regulation of the cell cycle and induction of growth arrest and programmed cell death following DNA damage (PubMed:15226432, PubMed:15509808, PubMed:17516545, PubMed:17942705, PubMed:18497060, PubMed:19404407, PubMed:19851330, PubMed:22367195, PubMed:7687740). Stimulates both innate and acquired immune responses through the activation of specific target genes and can act as a transcriptional activator and repressor regulating target genes by binding to an interferon-stimulated response element (ISRE) in their promoters (PubMed:15226432, PubMed:15509808, PubMed:17516545, PubMed:17942705, PubMed:18497060, PubMed:19404407, PubMed:19851330, PubMed:21389130, PubMed:22367195). Has an essentail role in IFNG-dependent immunity to mycobacteria (PubMed:36736301). Competes with the transcriptional repressor ZBED2 for binding to a common consensus sequence in gene promoters (PubMed:32385160). Its target genes for transcriptional activation activity include: genes involved in anti-viral response, such as IFN-alpha/beta, RIGI, TNFSF10/TRAIL, ZBP1, OAS1/2, PIAS1/GBP, EIF2AK2/PKR and RSAD2/viperin; antibacterial response, such as GBP2, GBP5 and NOS2/INOS; anti-proliferative response, such as p53/TP53, LOX and CDKN1A; apoptosis, such as BBC3/PUMA, CASP1, CASP7 and CASP8; immune response, such as IL7, IL12A/B and IL15, PTGS2/COX2 and CYBB; DNA damage responses and DNA repair, such as POLQ/POLH; MHC class I expression, such as TAP1, PSMB9/LMP2, PSME1/PA28A, PSME2/PA28B and B2M and MHC class II expression, such as CIITA; metabolic enzymes, such as ACOD1/IRG1 (PubMed:15226432, PubMed:15509808, PubMed:17516545, PubMed:17942705, PubMed:18497060, PubMed:19404407, PubMed:19851330, PubMed:22367195). Represses genes involved in anti-proliferative response, such as BIRC5/survivin, CCNB1, CCNE1, CDK1, CDK2 and CDK4 and in immune response, such as FOXP3, IL4, ANXA2 and TLR4 (PubMed:18641303, PubMed:22200613). Stimulates p53/TP53-dependent transcription through enhanced recruitment of EP300 leading to increased acetylation of p53/TP53 (PubMed:15509808, PubMed:18084608). Plays an important role in immune response directly affecting NK maturation and activity, macrophage production of IL12, Th1 development and maturation of CD8+ T-cells (PubMed:11244049, PubMed:11846971, PubMed:11846974, PubMed:16932750). Also implicated in the differentiation and maturation of dendritic cells and in the suppression of regulatory T (Treg) cells development (PubMed:11244049, PubMed:11846971, PubMed:11846974, PubMed:16932750). Acts as a tumor suppressor and plays a role not only in antagonism of tumor cell growth but also in stimulating an immune response against tumor cells (PubMed:20049431)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P10914/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IRF1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IRF1","total_profiled":1310},"omim":[{"mim_id":"620668","title":"IMMUNODEFICIENCY 117; IMD117","url":"https://www.omim.org/entry/620668"},{"mim_id":"616121","title":"GTPase, VERY LARGE INTERFERON-INDUCIBLE, PSEUDOGENE 1; GVINP1","url":"https://www.omim.org/entry/616121"},{"mim_id":"615332","title":"INTERFERON REGULATORY FACTOR 2-BINDING PROTEIN 2; IRF2BP2","url":"https://www.omim.org/entry/615332"},{"mim_id":"615331","title":"INTERFERON REGULATORY FACTOR 2-BINDING PROTEIN 1; IRF2BP1","url":"https://www.omim.org/entry/615331"},{"mim_id":"615326","title":"INTERFERON, KAPPA; IFNK","url":"https://www.omim.org/entry/615326"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":134.1}],"url":"https://www.proteinatlas.org/search/IRF1"},"hgnc":{"alias_symbol":["MAR"],"prev_symbol":[]},"alphafold":{"accession":"P10914","domains":[{"cath_id":"1.10.10.10","chopping":"7-110","consensus_level":"high","plddt":94.0355,"start":7,"end":110}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P10914","model_url":"https://alphafold.ebi.ac.uk/files/AF-P10914-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P10914-F1-predicted_aligned_error_v6.png","plddt_mean":65.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IRF1","jax_strain_url":"https://www.jax.org/strain/search?query=IRF1"},"sequence":{"accession":"P10914","fasta_url":"https://rest.uniprot.org/uniprotkb/P10914.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P10914/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P10914"}},"corpus_meta":[{"pmid":"11846971","id":"PMC_11846971","title":"Activities of 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requiring N-terminal 124 amino acids plus a C-terminal extension; (2) a nuclear localization signal (NLS) sufficient for nuclear translocation; (3) a heterodimerization domain (homologous to IRF-2) that mediates interaction with ICSBP in vitro; (4) an acidic C-terminal domain required and sufficient for transcriptional activation.\",\n      \"method\": \"GFP-fusion mutant live-cell imaging, in vitro heterodimerization assays, mammalian two-hybrid system, epitope mapping\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (in vitro binding, live-cell imaging, two-hybrid, deletion mutagenesis) in one rigorous study defining distinct functional domains\",\n      \"pmids\": [\"9742224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IRF-1 and IRF-2 induced by IFN-γ bind to three distinct sites in the IL-4 promoter and function as transcriptional repressors of IL-4 gene expression, providing a direct negative feedback mechanism by which IFN-γ attenuates Th2 responses.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), reporter gene assays, IRF-1/IRF-2 overexpression and knockdown in CD4+ T cells\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA binding demonstrated by EMSA plus functional reporter assays with overexpression/knockdown, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12479817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HCV NS5A protein colocalizes with PKR and suppresses dsRNA-mediated activation of PKR, thereby blocking IRF-1 activation and induction of IRF-1-dependent antiviral genes; mutations in the PKR-binding domain of NS5A relieved this blockade and reduced HCV replication efficiency.\",\n      \"method\": \"Colocalization (subcellular imaging), reporter gene assays with NS5A mutants, HCV subgenomic replicon system, dsRNA stimulation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via NS5A mutagenesis plus reporter assays and colocalization, single lab\",\n      \"pmids\": [\"11904369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"IRF-1 transcriptionally activates PKR expression: IRF-1-deficient mouse embryonic fibroblasts show reduced PKR levels, and transfection of IRF-1 into IRF-1-haploinsufficient U937 cells (which carry a deletion of one IRF-1 allele) is sufficient to induce PKR expression.\",\n      \"method\": \"IRF-1 knockout fibroblasts, transient transfection overexpression, Western blot/Northern blot for PKR levels\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout cells plus rescue transfection experiment, replicated in both mouse and human cell contexts\",\n      \"pmids\": [\"8622878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"IRF-1 transactivates the 2-5A synthetase and p21 (WAF1/CIP1) gene promoters by directly binding to IRF-binding elements within them; IRF-2 counteracts this activation; and IRF-1 also induces transcription of IRF-2 itself via an IRF-E in the IRF-2 promoter, establishing an autoinhibitory feedback loop.\",\n      \"method\": \"EMSA (direct promoter binding), CAT reporter transfection assays, IRF-1/IRF-2 ectopic expression and antisense constructs\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct DNA binding by EMSA combined with functional reporter assays and antisense rescue, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"10321737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DTX3L and ARTD9 (PARP9) form a complex that acts as a transcriptional repressor of IRF1 in metastatic prostate cancer cells; co-immunoprecipitation confirmed physical interaction between DTX3L, ARTD8, and ARTD9.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, siRNA knockdown, immunofluorescence\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus functional knockdown assays, single lab, multiple methods\",\n      \"pmids\": [\"24886089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BATF2 physically associates with IRF1 (demonstrated by co-immunoprecipitation), and this Batf2/Irf1 complex drives expression of inflammatory genes (Tnf, Ccl5, Nos2, Il12b) in IFN-γ-activated macrophages and during Mycobacterium tuberculosis infection.\",\n      \"method\": \"Co-immunoprecipitation, Irf1 knockdown, gene expression profiling\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus IRF1 knockdown demonstrating functional dependence, single lab\",\n      \"pmids\": [\"25957166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IRF1 enhances recruitment of BRD4 to promoter-enhancer regions of interferon-stimulated genes (ISGs) for rapid transcriptional induction, and maintains histone H3K4me1 levels at ISG loci for constitutive expression; IRF1 also regulates constitutive expression of TLR2 and TLR3, promoting signaling through these pattern recognition receptors.\",\n      \"method\": \"CRISPR KO cell line, transcriptome analysis, chromatin immunoprecipitation (ChIP) for BRD4 and H3K4me1, IFN/JAK-STAT blockade, viral infection assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined phenotype, ChIP for mechanistic chromatin evidence, IFN-independent pathway dissection, multiple orthogonal methods\",\n      \"pmids\": [\"31156620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GSK3β phosphorylates IRF1 at residue T181, generating a phosphodegron recognized by the SCF-Fbxw7α E3 ubiquitin ligase, which ubiquitinates and degrades DNA-bound IRF1; T181A mutation stabilizes IRF1 at target promoters but blocks RNA Pol II elongation and transcription of target genes, abolishing anti-proliferative activity.\",\n      \"method\": \"Site-directed mutagenesis (T181A), ChIP, RNA Pol II elongation assay, proteasome inhibition, Fbxw7-deficient cell lines, proliferation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation, mutagenesis, ChIP, functional readout (transcription and antiproliferative activity) with multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"30854564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"E3 ligases CHIP and MDM2 dock to the Mf2 domain of IRF-1 and ubiquitinate lysine residues predominantly in loop structures of the DNA-binding domain; when IRF-1 is bound to cognate DNA, the Mf2 docking site is occluded, suppressing ubiquitination and protecting active DNA-bound IRF-1 from degradation.\",\n      \"method\": \"In vitro ubiquitination assays, DNA-binding competition assays, site-directed mutagenesis of Mf2 domain\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro ubiquitination with mutagenesis and DNA competition, single lab but multiple orthogonal biochemical methods\",\n      \"pmids\": [\"23134341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In IFN-γ-stimulated cells, KAT8 undergoes phase separation with IRF1, forming biomolecular condensates; within these condensates KAT8 acetylates IRF1 at K78, which promotes IRF1 binding to the CD274 (PD-L1) promoter and enriches the transcription apparatus to drive PD-L1 transcription; a blocking peptide (2142-R8) disrupts KAT8-IRF1 condensate formation and inhibits PD-L1 expression.\",\n      \"method\": \"Phase separation assays, co-immunoprecipitation, mass spectrometry, mutagenesis of IRF1 K78, ChIP, in vitro and in vivo tumor models with blocking peptide\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical reconstitution of condensates, identification of acetylation site by mutagenesis, ChIP, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"36894639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SPOP (E3 ubiquitin ligase adaptor) binds IRF1 and triggers its ubiquitin-proteasomal degradation, thereby suppressing IRF1-mediated transcriptional upregulation of PD-L1; cancer-associated SPOP mutants lose the ability to degrade IRF1, resulting in IRF1 stabilization and elevated PD-L1 expression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibition, Western blot with SPOP mutants, reporter assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus ubiquitination assay plus functional mutant analysis, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"36481790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IRF1 directly binds to the promoter region of DRP1 and suppresses its expression; IS (indoxyl sulfate) upregulates IRF1, which in turn reduces DRP1 and inhibits mitophagic flux, causing intestinal barrier injury; IRF1 knockout mice are protected from these effects.\",\n      \"method\": \"ChIP assay (IRF1 binding to DRP1 promoter), IRF1 knockout mice, DRP1 overexpression rescue, Western blot, transmission electron microscopy\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, genetic KO with rescue experiment, multiple phenotypic readouts\",\n      \"pmids\": [\"32641998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IRF1 directly binds to the promoter of PGC1α (via histone H3K9 acetylation-dependent upregulation of IRF1 by high phosphate) and transcriptionally represses PGC1α expression, leading to myocardial energy metabolism dysfunction in cardiorenal syndrome type 4.\",\n      \"method\": \"ChIP assay (IRF1 binding to PGC1α promoter), IRF1 knockdown, IRF1 knockout mice, histone acetylation analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus genetic KO in vivo, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"32938919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IRF-1 is transcriptionally upregulated by RelB/p52 (non-canonical NF-κB) binding to the IRF-1 promoter at −782/−770; IRF-1 in turn binds the GSDMD promoter at −526/−515 and the CASP1 promoter at −11/10 to promote their expression, driving NLRP3 inflammasome-mediated pyroptosis and atherosclerosis.\",\n      \"method\": \"ChIP assay, RNA-seq, endothelial-specific NIK and IRF-1 KO mice on Apoe-null background, luciferase reporter, Western blot\",\n      \"journal\": \"Translational research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP for both upstream regulation and downstream targets, genetic KO with in vivo atherosclerosis phenotype, RNA-seq; multiple orthogonal methods\",\n      \"pmids\": [\"36384204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IRF1 is required for caspase-3 expression in intestinal epithelial cells by directly binding to IRF1-binding sites in the caspase-3 promoter, as confirmed by dual-luciferase reporter and ChIP assays; IRF1−/− mice are completely protected from TNFα-induced IEC shedding.\",\n      \"method\": \"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), IRF1 and caspase-3 knockout mice, TNFα-injection model\",\n      \"journal\": \"Journal of Crohn's & colitis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and reporter, genetic KO phenotype, multiple orthogonal approaches\",\n      \"pmids\": [\"34309645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IRF1 interacts with IRF3 (via its DNA-binding domain) and augments IRF3 activation by blocking the interaction between IRF3 and protein phosphatase 2A (PP2A), thereby increasing IRF3 phosphorylation and innate immune gene induction during viral infection.\",\n      \"method\": \"Co-immunoprecipitation, IRF1 DBD deletion mutants, PP2A interaction competition assay, siRNA knockdown, viral infection assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, domain mapping, mechanistic PP2A competition assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"32878885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IRF1 promotes STAT1 phosphorylation at Y701 and JAK1 phosphorylation, enabling STAT1 dimerization and binding to gamma-activated sequence (GAS) elements; the transactivation domain of IRF1 is required for this effect, and IRF1-conditioned medium (containing a secreted factor that is not IFN-β or IFN-γ) can activate STAT1 in recipient cells; loss of IRF1 reduces sustained IFN-γ-induced STAT1 phosphorylation.\",\n      \"method\": \"IRF1 transient overexpression and CRISPR KO in HEK293 cells, GAS-reporter assays, anti-IFN neutralizing antibodies, Western blot for phospho-STAT1/JAK1, EMSA for STAT1-GAS binding\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KO rescue and reporter assays with domain mapping, single lab, indirect mechanism (secreted factor not fully identified)\",\n      \"pmids\": [\"29893425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IRF-1 binds to an ISRE/IRF-E candidate sequence in the SMN and SMNc gene promoters in vitro, and overexpression of IRF-1 induces SMN/SMNc mRNA and protein expression in transfection assays; IFN-β and IFN-γ induction of SMN genes is at least partly mediated by IRF-1.\",\n      \"method\": \"In vitro DNA binding (EMSA), transfection reporter/overexpression assays, primary fibroblasts from SMA patients, Western blot\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA for direct binding plus functional overexpression in multiple cell types, single lab\",\n      \"pmids\": [\"11147573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Oncogenic Ras/MEK signaling downregulates IRF1 protein expression; MEK inhibition restores IRF1 expression; and re-expression of IRF1 in human cancer cells renders them resistant to oncolytic vesicular stomatitis virus, placing IRF1 downstream of Ras/MEK in suppressing IFN-inducible gene transcription.\",\n      \"method\": \"Promoter deletion analysis, IRF1−/− MEFs (epistasis), MEK inhibitor treatment, IRF1 re-expression, oncolytic virus infection assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using IRF1 KO MEFs, promoter analysis, pharmacological MEK inhibition, and functional rescue; multiple orthogonal methods replicated in mouse and human cells\",\n      \"pmids\": [\"25347735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"XAF1 stabilizes IRF1 protein by antagonizing CHIP-mediated ubiquitination and degradation of IRF1; this XAF1-IRF1 positive feedback loop induces antiviral IRF1 target genes (DDX58, DDX60, MX1, OAS2) and restricts RNA virus replication.\",\n      \"method\": \"Co-immunoprecipitation, XAF1 knockout cell lines, CHIP ubiquitination assay, viral infection in vitro and in vivo mouse models\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay plus KO phenotype, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35972291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HCFC2 promotes the binding of IRF1 and IRF2 to the Tlr3 promoter; without HCFC2, IRF1/IRF2 binding is impaired, resulting in reduced Tlr3 transcription and diminished poly(I:C)-induced cytokine and type I IFN responses in macrophages.\",\n      \"method\": \"ENU mutagenesis screen, ChIP for IRF1/IRF2 at Tlr3 promoter, genetic complementation, macrophage poly(I:C) stimulation, viral infection survival assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (ENU screen + complementation), ChIP demonstrating mechanistic link, in vivo infection phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"28970238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human cytomegalovirus induces Roquin expression; Roquin binds IRF1 mRNA directly (identified by CLIP-seq) and reduces IRF1 protein expression post-transcriptionally, suppressing IRF1-dependent antiviral gene expression to enable viral replication.\",\n      \"method\": \"CLIP-seq (cross-linking immunoprecipitation + sequencing), loss-of-function screen, transcriptome profiling, Roquin knockdown/overexpression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP-seq identifying direct mRNA binding site, combined with loss-of-function screen and transcriptome data; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31451648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DUSP1 overexpression elevates IRF1 mRNA and protein stability by suppressing MAPKs (which otherwise destabilize IRF1), thereby maintaining expression of IRF1-dependent genes including CXCL10; ChIP showed IRF1 recruitment to the CXCL10 promoter is essentially unaffected by dexamethasone despite DUSP1 induction.\",\n      \"method\": \"DUSP1 overexpression and siRNA silencing, MAPK inhibitors, mRNA stability assays, ChIP at CXCL10 and other IRF1-dependent promoters\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus overexpression/knockdown demonstrating regulatory mechanism, single lab, multiple methods\",\n      \"pmids\": [\"27551049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IRF1 governs differential ISG responses in human macrophages vs. monocytes: TLR4 signaling in macrophages uniquely engages IRF1, which facilitates chromatin opening at ISG loci for transcription; this lineage-specific chromatin remodeling function was not observed in monocytes.\",\n      \"method\": \"ATAC-seq (chromatin accessibility), RNA-seq, IRF1 KO in macrophages, TLR ligand stimulation panel, ChIP\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with genome-wide ATAC-seq and RNA-seq establishing direct chromatin remodeling function; multiple orthogonal methods\",\n      \"pmids\": [\"33761354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IRF1 and BATF serve as pioneering transcription factors during Tr1 cell differentiation: both are induced early by IL-27 and are required for chromatin accessibility and expression of Tr1 cell functional genes, as shown by epigenetic (ATAC-seq) and transcriptional analyses in IRF1- and BATF-deficient cells.\",\n      \"method\": \"ATAC-seq, RNA-seq, IRF1-deficient and BATF-deficient T cells, in vitro and in vivo Tr1 differentiation assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide chromatin accessibility + transcriptomics in genetic KO cells, in vivo validation; multiple orthogonal methods in rigorous study\",\n      \"pmids\": [\"28166218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IRF1-deficient mononuclear phagocytes fail to control mycobacteria and related intramacrophagic pathogens after IFN-γ stimulation; IFN-γ-dependent responses in IRF1-deficient leukocytes and fibroblasts are qualitatively and quantitatively much more impaired than IFN-α/β-dependent responses, demonstrating that IRF1 is essential for IFN-γ-dependent macrophagic immunity but largely redundant for IFN-α/β-dependent antiviral responses.\",\n      \"method\": \"IRF1-deficient patient cells (natural human genetic experiment), in vitro IFN-γ and IFN-α/β stimulation, mycobacterial killing assays, virus infection assays in fibroblasts\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human loss-of-function (complete IRF1 deficiency) with mechanistic functional assays across multiple pathogens and IFN types, replicated across unrelated patients\",\n      \"pmids\": [\"36736301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IRF1 acts as an upstream transcriptional regulator of PANoptosome components: IRF1 contributes to ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosome activation and PANoptosis (inflammatory cell death) in primary murine macrophages, but is dispensable for inflammasomes that form independently of the PANoptosome to drive pyroptosis alone.\",\n      \"method\": \"Live-cell imaging, Western blotting, ELISA, genetic IRF1 KO primary macrophages, multiple PANoptosome activation stimuli\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary KO macrophages with multiple activation stimuli and orthogonal readouts, single lab\",\n      \"pmids\": [\"37557956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IRF1 transcriptionally suppresses PGC1α expression by binding to its promoter region (upregulated via H3K9 acetylation induced by high phosphate); restoration of PGC1α or genetic IRF1 knockdown attenuates high-phosphate-induced myocardial energy metabolism dysfunction.\",\n      \"method\": \"ChIP (IRF1 binding to PGC1α promoter), H3K9 acetylation analysis, IRF1 knockdown in vitro and KO mice in vivo, metabolic assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus in vivo KO rescue plus histone modification analysis; multiple orthogonal methods, replicated in vitro and in vivo\",\n      \"pmids\": [\"32938919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IRF1 binds to the promoter region of SLC7A11 (xCT) and suppresses its transcription, as confirmed by ChIP and luciferase reporter assays; loss of IRF1 increases SLC7A11, suppressing ferroptosis of hepatic stellate cells; this mechanism mediates GRh2-induced HSC ferroptosis and liver fibrosis attenuation.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, IRF1 loss-of-function, SLC7A11 expression analysis, ferroptosis markers\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and reporter, functional KO, single lab\",\n      \"pmids\": [\"37441987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IRF1 directly binds the GBP5 promoter (confirmed by ChIP and dual luciferase assay) to enhance GBP5 expression; the IRF1/GBP5 axis promotes NLRP3 inflammasome-mediated chondrocyte pyroptosis and extracellular matrix degradation in osteoarthritis.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP, siRNA knockdown, adenoviral overexpression, NLRP3 inflammasome pathway readouts, DMM mouse model\",\n      \"journal\": \"Journal of orthopaedic translation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and reporter, in vivo KO phenotype, single lab\",\n      \"pmids\": [\"38229660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Radiation-induced leakage of mitochondrial DNA (mtDNA) initiates nuclear translocation of IRF1; novel PTM sites in the IRF1 NLS were identified — mutation of an acetylation site and phosphorylation sites in the NLS blocked IRF1 transcriptional activation and reduced radiation-induced cell death. Reciprocal regulation between SSBP1 and IRF1 restrains STING/p300-mediated PTMs of IRF1.\",\n      \"method\": \"Site-directed mutagenesis of NLS PTM sites, mass spectrometry PTM identification, nuclear fractionation/translocation imaging, SSBP1-IRF1 co-IP, CRISPR KO, radiation and SARS-CoV-2 infection models\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of novel PTM sites combined with nuclear translocation and co-IP data, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38849539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IRF1 is required downstream of IRF8 for IL-1β expression in reactive microglia: peripheral nerve injury induces IRF1 gene expression in spinal microglia in an IRF8-dependent manner; IRF8 transduction in cultured microglia induces IRF1 de novo; and IRF1 knockdown in IRF8-transduced microglia prevents IL-1β upregulation.\",\n      \"method\": \"IRF8 viral transduction, IRF1 siRNA knockdown, in vivo spinal cord IRF1 expression analysis after nerve injury, qPCR/Western blot\",\n      \"journal\": \"Journal of pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (IRF8 → IRF1 → IL-1β) demonstrated by KD rescue in defined cell type, in vivo validation, single lab\",\n      \"pmids\": [\"26318672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IRF1 directly regulates IRG1 (immune-responsive gene 1/CAD) transcription: siRNA-mediated knockdown of IRF1 in macrophages significantly decreased IRG1/CAD gene and protein expression and correlated with reduced itaconic acid production.\",\n      \"method\": \"siRNA knockdown, RT-PCR, Western blot, itaconic acid measurement, gene regulatory network computational + experimental validation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with multiple readouts (mRNA, protein, metabolite), computational network prediction validated experimentally, single lab\",\n      \"pmids\": [\"26872335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IRF-1 transcriptionally regulates VCAM-1 expression in human aortic endothelial cells: overexpression of IRF-1 recapitulated proatherogenic upregulation of VCAM-1, while silencing of IRF-1 mimicked the antiatherogenic downregulation; IRF-1 and miR-126 were reciprocally modulated by postprandial triglyceride-rich lipoproteins.\",\n      \"method\": \"IRF-1 overexpression, siRNA silencing, miR-126 modulation, VCAM-1 expression assays in HAEC\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression and knockdown with functional readout, single lab, two orthogonal interventions\",\n      \"pmids\": [\"22874466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SARS-CoV-2 ORF6 protein suppresses IRF1 gene expression by blocking STAT1 signaling (type II interferon-mediated), which prevents IRF1 upregulation of NLRC5 and MHC class I pathway genes; ORF6 also blocks karyopherin complex-dependent nuclear import of NLRC5.\",\n      \"method\": \"SARS-CoV-2-infected epithelial cell lines, COVID-19 patient gene expression, ORF6 overexpression, JAK-STAT reporter assays, nuclear import assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ORF6 mechanistic experiments in cell lines plus patient data, pathway confirmed by reporter assays, single lab\",\n      \"pmids\": [\"34782627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PARP7 is a nuclear, cysteine-specific mono-ADP-ribosyltransferase that modifies FRA1 (AP-1 transcription factor) at C97; loss of FRA1 ADP-ribosylation promotes FRA1 degradation via PSMC3, which de-represses IRF1- and IRF3-dependent proapoptotic and cytokine gene expression, culminating in CASP8-mediated apoptosis.\",\n      \"method\": \"PARP7 inhibition (RBN-2397), C97 mutation of FRA1, proteasome inhibition, IRF1/IRF3-dependent reporter assays, mass spectrometry for ADP-ribosylation sites\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific mutagenesis + MS identification of modification site + functional IRF1-dependent reporter assays, single lab, multiple methods\",\n      \"pmids\": [\"38011562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IRF1 regulates ZBP1 transcription in an IRF1-dependent manner downstream of TNF-α; IRF1-driven ZBP1 overexpression is activated by mitochondrial DNA binding to ZBP1; activated ZBP1 interacts with RIPK1 and activates TAK1-NF-κB signaling, leading to chondrocyte inflammation and matrix degradation in osteoarthritis.\",\n      \"method\": \"IRF1 KD in chondrocytes, ZBP1 KD, DMM mouse model, co-immunoprecipitation (ZBP1-RIPK1), Cyclosporine A (mtDNA release blocker), Western blot\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis (IRF1 → ZBP1) plus co-IP for ZBP1-RIPK1, in vivo KD phenotype, single lab\",\n      \"pmids\": [\"39026271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IRF1 loss in mouse HSCs significantly impairs self-renewal, increases stress-induced proliferation, and confers resistance to apoptosis, establishing IRF1 as a pivotal regulator of HSC homeostasis.\",\n      \"method\": \"Conditional IRF1 KO in mouse HSCs, transplantation assays, stress-induced proliferation assays, apoptosis measurement\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined cellular phenotypes in stem cell assays, single lab\",\n      \"pmids\": [\"37889967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IRF1 binds to the promoter of GPX4 indirectly by interacting with SPI1 (PU.1) and suppressing SPI1's transcriptional activating effect on GPX4 expression, thereby reducing GPX4 levels, increasing lipid ROS accumulation, and enhancing ferroptosis in colon cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (IRF1-SPI1 interaction), ChIP (SPI1 binding to GPX4 promoter), luciferase reporter assay, IRF1/SPI1 overexpression and knockdown, ferroptosis markers\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus reporter assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37517591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IFIH1 promotes IRF1 translocation into the nucleus in macrophages during infection; nuclear IRF1 then binds to the STAT1 promoter (confirmed by ChIP-seq) and activates STAT1 transcription, contributing to macrophage M1 polarization and septic lung injury.\",\n      \"method\": \"ChIP-seq (IRF1 binding to STAT1 promoter), IRF1 KO mice (CLP model), shRNA knockdown, nuclear fractionation, immunohistochemistry\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus IRF1 KO in vivo model, single lab, multiple methods\",\n      \"pmids\": [\"36462334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"iNOS/NO promotes IRF1 nuclear translocation and transcriptional activity through HDAC2-mediated histone H3 deacetylation (H3K9 hypoacetylation) at IRF1 target gene promoters; iNOS KO mice show impaired IRF1 nuclear translocation and reduced PUMA expression after hepatic I/R injury.\",\n      \"method\": \"iNOS KO mice (I/R model), iNOS overexpression, NO donors, HDAC inhibitor (romidepsin), nuclear fractionation for IRF1, H3AcK9 Western blot, IRF1 reporter assay\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus pharmacological intervention plus histone modification analysis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32517688\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IRF1 is a stimulus-inducible transcription factor that binds IRF-binding elements (ISRE/IRF-E) in target gene promoters through its N-terminal DNA-binding domain; its transcriptional activation requires an acidic C-terminal domain and regulated protein turnover mediated by GSK3β-phosphorylation at T181, which creates a phosphodegron for SCF-Fbxw7α-dependent ubiquitination and proteasomal degradation — a process that is itself required for productive RNA Pol II elongation at target promoters; IRF1 forms heterodimers with ICSBP/IRF2 and physical complexes with partners including BATF2, IRF3 (whose activation it promotes by blocking PP2A-mediated dephosphorylation), and KAT8 (which acetylates IRF1-K78 within phase-separated condensates to drive PD-L1 transcription); IRF1 protein stability is positively regulated by XAF1 (antagonizing CHIP-mediated degradation) and negatively by SPOP-mediated ubiquitination and Roquin-mediated mRNA destabilization, while DUSP1-mediated MAPK suppression prolongs IRF1 mRNA/protein stability; downstream, IRF1 activates diverse target genes (PKR, p21, 2-5A synthetase, TLR3, caspase-3, GSDMD, CASP1, ZBP1, GBP5, DRP1, STAT1, IRG1, SMN) and represses others (PGC1α, SLC7A11, GPX4 via SPI1 interaction), placing IRF1 as a central integrator of IFN-γ-dependent macrophagic immunity, innate antiviral defense, inflammatory cell death (PANoptosis/pyroptosis/ferroptosis), and cell growth control.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IRF1 is a stimulus-inducible transcription factor that integrates interferon and inflammatory signaling into programs of antiviral defense, macrophagic immunity, inflammatory cell death, and cell growth control [#26, #14]. It engages target promoters through an N-terminal DNA-binding domain that, together with a C-terminal extension, recognizes ISRE/IRF-E elements, while a separable acidic C-terminal domain provides transcriptional activation and a dedicated NLS directs nuclear import; the same protein carries a heterodimerization surface that mediates binding to ICSBP/IRF2 [#0]. Through direct promoter binding IRF1 activates antiviral and growth-suppressive genes including PKR, 2-5A synthetase, and the cell-cycle inhibitor p21, and induces IRF2 itself to establish autoinhibitory feedback [#3, #4], while functioning as a repressor at other loci such as IL-4, PGC1\\u03b1, and SLC7A11 [#1, #28, #29]. At chromatin, IRF1 acts as a pioneering/remodeling factor that opens ISG and lineage-specific loci, recruits BRD4, and maintains H3K4me1 to enable rapid and constitutive induction of interferon-stimulated and pattern-recognition genes including TLR2/TLR3 [#7, #24, #25]. Human IRF1 deficiency demonstrates that this factor is essential for IFN-\\u03b3-dependent control of mycobacteria and intramacrophagic pathogens but largely redundant for IFN-\\u03b1/\\u03b2 antiviral responses [#26]. IRF1 output is gated by tightly controlled protein turnover: GSK3\\u03b2 phosphorylation at T181 creates a phosphodegron recognized by SCF-Fbxw7\\u03b1, and this ubiquitin-driven degradation of DNA-bound IRF1 is itself required for productive RNA Pol II elongation at target promoters [#8], whereas DNA binding occludes the Mf2 docking site used by CHIP and MDM2 to protect active IRF1 [#9]. Stability is further tuned by XAF1 (antagonizing CHIP), SPOP-mediated ubiquitination, and Roquin-mediated mRNA destabilization [#20, #11, #22]. IRF1 also acts within IFN-\\u03b3-induced KAT8 condensates, where acetylation at K78 drives CD274/PD-L1 transcription [#10], cooperates with partners such as BATF2 and IRF3 (whose activation it promotes by blocking PP2A) [#6, #16], and directs inflammatory cell-death programs by transactivating GSDMD, CASP1, GBP5, and ZBP1 and contributing to PANoptosome activation [#14, #30, #37, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that IRF1 is not merely an interferon-responsive marker but a functional transcriptional activator of an effector gene, linking it directly to antiviral output.\",\n      \"evidence\": \"IRF-1 knockout fibroblasts and rescue transfection in haploinsufficient cells measuring PKR levels\",\n      \"pmids\": [\"8622878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the IRF-E in the PKR promoter\", \"Did not address other target genes\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the modular architecture of IRF1, separating DNA binding, nuclear import, heterodimerization, and transactivation into discrete domains.\",\n      \"evidence\": \"GFP-fusion imaging, in vitro heterodimerization, two-hybrid and deletion mutagenesis of murine IRF-1\",\n      \"pmids\": [\"9742224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain function defined largely in vitro/ectopic systems\", \"Structural basis of DNA recognition not resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed IRF1 directly binds and transactivates growth-suppressive and antiviral promoters while autoregulating via IRF2, framing it as a bidirectional regulator within a feedback network.\",\n      \"evidence\": \"EMSA promoter binding plus CAT reporter and antisense assays for 2-5A synthetase, p21, and IRF-2\",\n      \"pmids\": [\"10321737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each IRF-E in vivo not established\", \"Cell-type specificity of feedback loop unaddressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated IRF1 can act as a transcriptional repressor, providing a direct mechanism for IFN-\\u03b3 antagonism of Th2 responses.\",\n      \"evidence\": \"EMSA, reporter assays, and IRF-1/IRF-2 over/knockdown at the IL-4 promoter in CD4+ T cells\",\n      \"pmids\": [\"12479817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-repressor machinery not identified\", \"Does not explain switch between activation and repression at different promoters\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Placed IRF1 activation within an antiviral signaling axis targeted by viral immune evasion.\",\n      \"evidence\": \"HCV NS5A colocalization with PKR, replicon system, and NS5A mutant reporter assays\",\n      \"pmids\": [\"11904369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IRF1 activation inferred from downstream readouts rather than measured directly\", \"Single lab, indirect link via PKR\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved how active DNA-bound IRF1 is protected from degradation, coupling its transcriptional state to its stability.\",\n      \"evidence\": \"In vitro ubiquitination, Mf2 mutagenesis, and DNA-binding competition with CHIP and MDM2\",\n      \"pmids\": [\"23134341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro reconstitution only\", \"Relative in vivo contribution of CHIP vs MDM2 unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Uncovered a phosphodegron mechanism in which regulated IRF1 turnover is paradoxically required for transcription, linking degradation to Pol II elongation.\",\n      \"evidence\": \"T181A mutagenesis, ChIP, RNA Pol II elongation assays, and Fbxw7-deficient cells\",\n      \"pmids\": [\"30854564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic coupling of ubiquitination to elongation not fully defined\", \"Generality across all IRF1 targets untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined IRF1 as a chromatin-priming factor that recruits BRD4 and maintains active histone marks for rapid and constitutive ISG induction.\",\n      \"evidence\": \"CRISPR KO, transcriptomics, ChIP for BRD4 and H3K4me1, and IFN/JAK-STAT blockade\",\n      \"pmids\": [\"31156620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IRF1 selects ISG loci genome-wide not fully resolved\", \"Direct vs indirect H3K4me1 maintenance unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established IRF1 as a pioneering transcription factor that opens chromatin during lymphoid and myeloid differentiation programs.\",\n      \"evidence\": \"ATAC-seq and RNA-seq in IRF1- and BATF-deficient cells during IL-27-driven Tr1 differentiation; later extended to macrophage TLR4 responses\",\n      \"pmids\": [\"28166218\", \"33761354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors enabling nucleosome engagement not defined\", \"Lineage selectivity of remodeling mechanism unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed IRF1 promoter occupancy depends on accessory factors, identifying HCFC2 as a determinant of IRF1/IRF2 binding to the Tlr3 promoter.\",\n      \"evidence\": \"ENU screen, ChIP for IRF1/IRF2, genetic complementation, and poly(I:C) macrophage responses\",\n      \"pmids\": [\"28970238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of HCFC2-IRF1 cooperation unresolved\", \"Generality to other IRF1 targets untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined IRF1 as a multi-pathway driver of inflammatory cell death by directly transactivating pyroptotic and apoptotic effector genes.\",\n      \"evidence\": \"ChIP/reporter assays and IRF1 KO mice for caspase-3, GSDMD, CASP1, and DRP1 across intestinal, vascular, and barrier-injury models\",\n      \"pmids\": [\"34309645\", \"36384204\", \"32641998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context determinants selecting cell-death program not defined\", \"Direct vs indirect promoter effects vary by study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated IRF1 enhances IRF3 activation by shielding it from PP2A, expanding IRF1 into a post-translational regulator of partner transcription factors.\",\n      \"evidence\": \"Co-IP, IRF1 DBD deletion mutants, and PP2A interaction competition during viral infection\",\n      \"pmids\": [\"32878885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the IRF1-IRF3-PP2A interaction unknown\", \"Whether this is DNA-independent unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified SPOP-mediated and Roquin-mediated negative regulation that constrains IRF1-driven immune and PD-L1 expression.\",\n      \"evidence\": \"Co-IP and ubiquitination assays with SPOP mutants; CLIP-seq mapping of Roquin binding to IRF1 mRNA\",\n      \"pmids\": [\"36481790\", \"31451648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation site mapping incomplete\", \"Interplay with stabilizing factors not reconciled\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed IRF1 functions within phase-separated KAT8 condensates where K78 acetylation drives PD-L1 transcription, adding biomolecular condensates and acetylation to IRF1 regulation.\",\n      \"evidence\": \"Phase separation assays, MS, K78 mutagenesis, ChIP, and in vivo tumor models with a blocking peptide\",\n      \"pmids\": [\"36894639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of condensate behavior to non-PD-L1 targets untested\", \"Determinants of condensate composition unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Human IRF1 deficiency established the non-redundant, pathway-specific role of IRF1 in IFN-\\u03b3-dependent macrophagic immunity versus dispensable IFN-\\u03b1/\\u03b2 antiviral function.\",\n      \"evidence\": \"IRF1-deficient patient cells with IFN-\\u03b3 and IFN-\\u03b1/\\u03b2 stimulation, mycobacterial killing, and viral infection assays\",\n      \"pmids\": [\"36736301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of IFN-type selectivity not fully defined\", \"Spectrum of susceptible pathogens incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed NLS-localized PTMs and mtDNA/STING-linked signals controlling IRF1 nuclear translocation and activation.\",\n      \"evidence\": \"MS PTM mapping, NLS site mutagenesis, nuclear translocation imaging, and SSBP1-IRF1 co-IP in radiation and infection models\",\n      \"pmids\": [\"38849539\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymes depositing each NLS PTM only partly defined\", \"In vivo physiological relevance limited to specific stress models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IRF1 selects between transcriptional activation and repression, and how its post-translational modifications, condensate behavior, and turnover are integrated to specify divergent cell-fate outcomes (antiviral defense vs PANoptosis vs growth control), remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTM state to activator vs repressor function\", \"Determinants of target-gene selection across tissues unknown\", \"Structural model of DNA-bound IRF1 with cofactors absent from corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 4, 8, 14]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4, 12, 14, 15]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 31, 40, 41]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [8, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 24, 26]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 7, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [14, 15, 27, 29]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 9, 11, 20]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [7, 24, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IRF2\", \"ICSBP\", \"BATF2\", \"IRF3\", \"KAT8\", \"SPOP\", \"XAF1\", \"SPI1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}