{"gene":"IFNGR1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1999,"finding":"IFNGR1 frameshift small deletions producing truncated receptors that lack the intracytoplasmic domain act via a dominant-negative mechanism: the mutant protein accumulates at the cell surface (impaired recycling), abrogates signaling, but retains normal IFN-γ binding, thereby outcompeting wild-type receptor and blocking downstream signaling.","method":"Cell-surface expression analysis of patient-derived cells, IFN-γ binding assays, signaling assays in patient leukocytes, genetic characterization of dominant-negative inheritance","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional characterization across multiple patients and families with orthogonal methods (binding, signaling, surface expression), replicated across 12 unrelated families","pmids":["10192386"],"is_preprint":false},{"year":2000,"finding":"Following IFN-γ stimulation, IFNGR1 (but not IFNGR2) undergoes ligand-dependent endocytosis and nuclear translocation; IFNGR1 co-localizes and co-immunoprecipitates with STAT1α in the nucleus, while IFNGR2 remains predominantly at the cell surface.","method":"Immunofluorescence, immunoprecipitation, subcellular fractionation of WISH cells treated with IFN-γ","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunofluorescence and Co-IP, single lab, two orthogonal methods demonstrating differential subcellular fate of receptor subunits","pmids":["10888113"],"is_preprint":false},{"year":2006,"finding":"IFNGR1 and IFN-γ are recruited to the GAS (IFN-γ-activated sequence) promoter element of IFN-γ-activated genes together with STAT1α as a macromolecular complex; IFNGR1 fused to the yeast GAL4 DNA-binding domain drives transcription from a GAL4 response element, indicating IFNGR1 contains a transactivation domain.","method":"Chromatin immunoprecipitation (ChIP)-PCR, EMSA, biotin-GAS pulldown of nuclear extracts, GAL4-IFNGR1 fusion reporter assay, GAS-luciferase co-transfection","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, reporter assay) in a single lab establishing nuclear transactivation function of IFNGR1","pmids":["16785527"],"is_preprint":false},{"year":2007,"finding":"The 774del4 (and 818del4) dominant mutations in IFNGR1 produce truncated receptor that accumulates on the cell surface due to impaired receptor internalization/recycling, causing a dominant-negative effect on IFN-γ-induced STAT1 phosphorylation in HEK293 cells.","method":"Transient transfection of truncated IFNGR1 constructs in HEK293 cells, cell-surface FACS, STAT1 phosphorylation assay, peripheral blood CD14+ cell analysis from patient","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in transfected cells plus patient cell analysis, single lab, multiple methods","pmids":["17513528"],"is_preprint":false},{"year":2009,"finding":"A homozygous mutation of the IFNGR1 initiation codon (M1K) eliminates IFN-γR1 expression in fibroblasts but permits residual expression in EBV-transformed B cells via leaky translation initiation at non-AUG and a downstream AUG codon (position 19), resulting in cell-type-specific partial IFNGR1 deficiency.","method":"Protein expression analysis (Western blot), IFN-γ signaling assays in patient fibroblasts and EBV-B cells, translation initiation site analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization in patient-derived cells with mechanistic follow-up of alternative translation initiation, single lab","pmids":["19880857"],"is_preprint":false},{"year":2013,"finding":"Type I IFN (IFN-β) rapidly silences ifngr1 transcription in macrophages by inducing recruitment of a repressive Egr3/Nab1 transcriptional complex to an Egr binding site in the proximal ifngr1 promoter, reducing activated RNA polymerase II and histone acetylation at the promoter.","method":"Actinomycin D chase, IFNGR1-luciferase reporter assay with Egr binding site mutation, ChIP for RNA pol II and acetylated histones, Nab1 knockdown in macrophage cell line, promoter-binding protein analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assay with site mutation, ChIP, RNAi knockdown) in a single rigorous study establishing the transcriptional silencing mechanism","pmids":["23935197"],"is_preprint":false},{"year":2013,"finding":"Selective deletion of IFNGR1 in CD8α+ dendritic cells (Itgax-cre+Ifngr1f/f mice) impairs the initial IFN-γ-driven burst of IL-12 production needed to initiate anti-Listeria responses; neutralization of IL-4 (overproduced in its absence) restores Listeria resistance, placing IFNGR1 on CD8α+ DCs upstream of the IL-12/IL-4 axis in antibacterial immunity.","method":"Conditional knockout mice (Cre-lox), bacterial infection challenge, cytokine measurements, IL-4 neutralization rescue experiment","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with cell-type specificity, defined cellular phenotype, and epistatic rescue experiment, single study with multiple orthogonal approaches","pmids":["24048899"],"is_preprint":false},{"year":2014,"finding":"IFNGR1 bound to extracellular vesicles (EVs) from neural stem cells—complexed with IFN-γ—activates STAT1 in target cells; this EV-mediated STAT1 activation requires endogenous STAT1 and IFNGR1 in the target cell.","method":"EV isolation and characterization, STAT1 phosphorylation assay in target cells, siRNA knockdown of IFNGR1/STAT1 in target cells, immunoprecipitation demonstrating IFN-γ/IFNGR1 complex on EVs","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with RNAi knockdown and Co-IP, single lab, multiple orthogonal methods","pmids":["25242146"],"is_preprint":false},{"year":2017,"finding":"Macrophage-specific forced expression of IFNGR1 (via transgenic fGR1 mice) prevents type I IFN-induced down-regulation of surface IFNGR1, sustains IFN-γ responsiveness in the presence of type I IFNs, and enhances macrophage antimicrobial function during Listeria monocytogenes infection in an IFN-γ-dependent manner.","method":"Transgenic mice with macrophage-specific FLAG-tagged IFNGR1, Listeria infection model, IFN-γ–dependence experiments, macrophage activation assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic rescue model with cell-type specificity, in vivo infection phenotype, and IFN-γ dependence confirmed by neutralization, single rigorous study","pmids":["28542482"],"is_preprint":false},{"year":2017,"finding":"Canonical IFN-γ signaling through IFNGR1 and STAT1 is required for nigrostriatal neurodegeneration and midbrain calcinosis induced by brain overexpression of IFN-γ; Ifngr1−/− mice showed no neuroinflammation, calcinosis, or nigrostriatal pathology upon IFN-γ overexpression.","method":"AAV-mediated IFN-γ overexpression in Ifngr1−/− and Stat1−/− mice, rotarod behavioral testing, histopathology, bioinformatic analysis","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using KO mice with functional behavioral and histopathological readouts, rigorous loss-of-function design","pmids":["29196213"],"is_preprint":false},{"year":2019,"finding":"IFN-γ itself reduces surface IFNGR1 on myeloid cells (murine and human CD14+) by decreasing Ifngr1 transcription through altered chromatin structure at putative Ifngr1 enhancer sites—distinct from the type I IFN mechanism—thereby creating a negative feedback loop that blunts STAT1 and STAT3 activation.","method":"Flow cytometry of monocytes from infected mice and cultured cells, qPCR of Ifngr1 transcripts, chromatin accessibility assay at Ifngr1 enhancer sites, STAT1/3 phosphorylation assay","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (flow cytometry, transcriptional assay, chromatin analysis, signaling readout), single lab","pmids":["31585982"],"is_preprint":false},{"year":2020,"finding":"FBXW7 (regulated by the transcription factor ELF5) ubiquitinates IFNGR1 protein, targeting it for proteasomal degradation; loss of FBXW7 in TNBC stabilizes IFNGR1 protein and amplifies intrinsic IFN-γ signaling, promoting tumor progression.","method":"FBXW7 loss-of-function experiments, IFNGR1 protein stability assays, ubiquitination assays, genetic rescue experiments in TNBC cells and mouse models","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay and protein stability experiments identifying FBXW7 as E3 ligase for IFNGR1, single lab","pmids":["32284542"],"is_preprint":false},{"year":2021,"finding":"IFNGR1 is S-palmitoylated at Cys122; palmitoylated IFNGR1 is recognized by AP3D1, which sorts it to lysosomes for degradation. Optineurin interacts with AP3D1 to prevent this lysosomal sorting, thereby stabilizing IFNGR1 at the cell surface and maintaining IFN-γ signaling. Loss of optineurin in colorectal cancer increases IFNGR1 palmitoylation-dependent lysosomal degradation and impairs IFN-γ signaling.","method":"Palmitoylation assay (Click chemistry/acyl-RAC), Co-IP of AP3D1 with IFNGR1 and optineurin, site-directed mutagenesis of Cys122, lysosomal trafficking assay, pharmacological inhibition of palmitoylation, mouse tumor models","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1 / Strong — palmitoylation site mutagenesis, biochemical co-IP, pharmacological inhibition, and in vivo mouse models in one rigorous study with multiple orthogonal methods","pmids":["33627378"],"is_preprint":false},{"year":2021,"finding":"Paraspeckle protein NONO and the lncRNA NEAT1_2 sequester IFNGR1 mRNA within paraspeckles in HCC cells, reducing IFNGR1 protein expression and impairing IFN-γ/IFNGR1 signaling, thereby promoting resistance to T-cell-mediated cytolysis.","method":"CRISPR-Cas9 knock-in S1-aptamer pull-down of NEAT1_2 interactors followed by sequencing, RNA immunoprecipitation (RIP), NONO/NEAT1_2 knockdown, Western blotting, T-cell killing assay","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pull-down and RIP identifying IFNGR1 mRNA as paraspeckle cargo, plus functional killing assay, single lab","pmids":["33667716"],"is_preprint":false},{"year":2022,"finding":"Histone demethylase JMJD2D coactivates SP1 to transcriptionally upregulate IFNGR1, which then elevates STAT3-IRF1 signaling and PD-L1 transcription in colorectal cancer; JMJD2D also directly coactivates the STAT3-IRF1 axis at the PD-L1 promoter in a demethylation-dependent manner.","method":"Genetic ablation of JMJD2D, RT-qPCR, Western blotting, ChIP-qPCR, luciferase reporter assay, flow cytometry, mouse tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR, reporter assay, and KO establishing the JMJD2D-SP1-IFNGR1-STAT3-IRF1 axis, single lab with multiple orthogonal methods","pmids":["35027670"],"is_preprint":false},{"year":2023,"finding":"RGS1 enhances binding of the transcription factor ATF3 to the IFNGR1 promoter, thereby increasing IFNGR1 expression, activating downstream STAT1 signaling and IFN-γ-inducible gene expression (including CXCL9 and MHC-I), and supporting CD8+ T cell infiltration.","method":"ChIP-qPCR, dual-luciferase reporter assay, RT-qPCR, Western blotting, flow cytometry, mouse tumor models","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and luciferase assay identifying ATF3 as a transcriptional activator of IFNGR1, single lab with multiple methods","pmids":["38264343"],"is_preprint":false},{"year":2024,"finding":"The E3 ubiquitin ligase RNF149 promotes ubiquitylation-dependent proteasomal degradation of IFNGR1 in macrophages; STAT1 activation induces Rnf149 transcription, which in turn destabilizes IFNGR1, creating a negative feedback loop that fine-tunes type II IFN signaling and limits macrophage-driven inflammation after myocardial infarction.","method":"RNF149 KO and overexpression, bone marrow transplantation, immunoprecipitation/mass spectrometry, ubiquitination assay, transcriptome analysis, flow cytometry, cardiac function measurements","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical ubiquitination assay, Co-IP/MS identifying RNF149-IFNGR1 interaction, KO and overexpression in vivo, epistasis with IFNGR1 loss-of-function rescue, multiple orthogonal methods in one rigorous study","pmids":["38989590"],"is_preprint":false},{"year":2024,"finding":"Macrocyclic l-α/d-α/β/γ-hybrid peptide IB1 selected by in vitro display inhibits the IFN-γ/IFNGR1 protein-protein interaction with IC50 = 12 nM in biochemical assay and ~0.75 μM at the cellular level; the presence of a cyclic β-amino acid (cβAA) in the sequence was identified as the primary contributor to inhibitory activity.","method":"In vitro mRNA display selection against recombinant IFNGR1, biochemical PPI inhibition assay (IC50 measurement), cellular IFN-γ/IFNGR1 inhibition assay, mutagenesis of non-proteinogenic residues","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted binding/inhibition assay with structure-activity analysis via amino acid substitution, cellular validation, single rigorous study","pmids":["38888290"],"is_preprint":false},{"year":2023,"finding":"IFNGR1 contained in cancer-cell-derived extracellular vesicles can be engulfed by fibroblastic reticular cells (FRCs) in lymph nodes and activate PD-L1 expression via the JAK1-STAT1 pathway, promoting CD8+ T cell exhaustion and pre-metastatic niche formation.","method":"Mass spectrometry identification of IFNGR1 in CEVs, Western blotting for JAK1-STAT1 pathway activation, co-culture of FRCs with CEVs, T cell cytotoxicity assay, flow cytometry","journal":"Oral oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification, Western blot pathway analysis, and functional T-cell killing assay in a single study, single lab","pmids":["37482043"],"is_preprint":false},{"year":2025,"finding":"TMEM199, together with its partner CCDC115, interacts with IFNGR1/2 and facilitates their trafficking to RAB11A-positive recycling endosomes; TMEM199/CCDC115 recruits TRAPP II to activate RAB11A, enhancing IFNGR1/2 recycling and downstream IFN-γ-driven PD-L1 upregulation.","method":"Co-immunoprecipitation of TMEM199/CCDC115 with IFNGR1/2, RAB11A recycling endosome co-localization assay, loss-of-function experiments, PD-L1 reporter/protein assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying binding partners and trafficking complex, co-localization, and functional PD-L1 readout, single lab","pmids":["41319859"],"is_preprint":false},{"year":2023,"finding":"Porphyromonas gingivalis infection promotes S-palmitoylation of IFNGR1 at Cys122 (via ZDHHC3), driving IFNGR1 co-localization with the lysosomal marker LAMP2 and lysosomal degradation, thereby reducing IFNGR1 protein levels; mutation of Cys122 (IFNGR1-C122A) partially attenuates Pg-induced IFNGR1 degradation and reduces cancer cell proliferation, migration, and invasion.","method":"2-BP palmitoylation inhibitor assay, site-directed mutagenesis (C122A), Click-iT palmitoylation assay, immunofluorescence co-localization with LAMP2, cell proliferation/migration/invasion assays","journal":"Nan fang yi ke da xue xue bao","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — palmitoylation site mutagenesis, Click-iT assay, and lysosomal co-localization, single lab with multiple methods","pmids":["37488798"],"is_preprint":false},{"year":2006,"finding":"A deletion/insertion polymorphism at IFNGR1-470 in the IFNGR1 promoter has cell-type-specific opposite functional effects: in B-lymphocytes it suppresses binding of a ~35 kDa nuclear protein and increases reporter gene expression; in epithelial cells it decreases reporter expression and suppresses binding of ~90 kDa STAT-1 and STAT-2 proteins; in T-lymphocytes it has no significant effect on gene expression.","method":"EMSA (electrophoretic mobility shift assay) with nuclear extracts, luciferase reporter assay in B-lymphocytes, epithelial cells, and T-lymphocytes","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and reporter assay in multiple cell types establishing context-specific promoter regulation, single lab","pmids":["16600993"],"is_preprint":false},{"year":2008,"finding":"The IFNGR1 −56C/T promoter polymorphism is functionally relevant: the −56T allele drives approximately 10-fold higher luciferase reporter expression compared to the −56C allele in a cell-based assay.","method":"Allele-specific IFNGR1 −56C/T luciferase reporter assay","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single reporter assay demonstrating functional promoter polymorphism, single lab, single method","pmids":["18593809"],"is_preprint":false},{"year":2025,"finding":"Cardiomyocyte-specific deletion of IFNGR1 (Myh6Cre Ifngr1fl/fl mice) abrogates IFN-γ-induced cardiac metabolic reprogramming (increased glucose uptake, reduced fatty acid oxidation and oxidative phosphorylation), establishing that IFN-γ drives cardiac metabolic changes via direct signaling through IFNGR1 on cardiomyocytes.","method":"Conditional cardiomyocyte-specific KO mice, AAV-Ifng overexpression model, echocardiography, bulk RNA-seq, in vivo PET imaging ([18F]FDG and [18F]fluoro-6-thia-heptadecanoic acid), isolated mitochondrial oxygen consumption, targeted metabolomics","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO with multiple functional readouts (imaging, metabolomics, mitochondrial assay), single preprint study","pmids":[],"is_preprint":true},{"year":2025,"finding":"Conditional knockout of Ifngr1 in ependymal cells (in a murine model) prevents IFN-γ-induced increases in ependymal permeability, establishing that IFNGR1 on ependymal cells mediates IFN-γ-driven barrier dysfunction relevant to periventricular pathology.","method":"Conditional Ifngr1 knockout in ependymal cells, ependymal permeability assay following IFN-γ treatment","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — single conditional KO experiment with permeability readout reported in preprint abstract only, single lab, limited methodological detail","pmids":[],"is_preprint":true}],"current_model":"IFNGR1 is the ligand-binding chain of the heterodimeric IFN-γ receptor that, upon IFN-γ binding, initiates JAK1/JAK2-STAT1 signaling; its surface abundance is regulated by multiple post-translational mechanisms—including ubiquitin-dependent proteasomal degradation (by RNF149 and FBXW7), palmitoylation at Cys122-driven lysosomal sorting (facilitated by AP3D1 and counteracted by optineurin), recycling endosome trafficking (promoted by TMEM199/CCDC115/RAB11A), and transcriptional silencing by type I IFN via an Egr3/Nab1 repressor complex or by IFN-γ itself via chromatin remodeling at enhancer sites; dominant-negative truncations lacking the cytoplasmic domain accumulate on the cell surface due to impaired recycling and block wild-type receptor function; IFNGR1 also undergoes ligand-induced nuclear translocation where it associates with STAT1α and the GAS promoter element to contribute to transcriptional activation of IFN-γ-stimulated genes."},"narrative":{"mechanistic_narrative":"IFNGR1 is the ligand-binding chain of the IFN-γ receptor that initiates JAK1-STAT1 signaling to drive IFN-γ-stimulated gene programs in immune and tissue cells [PMID:24048899, PMID:28542482]. Surface abundance of IFNGR1 is the principal control point of this pathway and is set by multiple post-translational and trafficking mechanisms: S-palmitoylation at Cys122 directs AP3D1-dependent lysosomal sorting and degradation, a fate opposed by optineurin to stabilize surface receptor and sustain signaling [PMID:33627378], while ZDHHC3-driven Cys122 palmitoylation during bacterial infection routes the receptor to LAMP2+ lysosomes for degradation [PMID:37488798]; recycling-endosome trafficking through TMEM199/CCDC115-mediated RAB11A activation promotes receptor re-display and downstream PD-L1 induction [PMID:41319859]. Receptor levels are additionally constrained by ubiquitin-dependent proteasomal degradation via the E3 ligases FBXW7 [PMID:32284542] and RNF149, the latter forming a STAT1-induced negative-feedback loop that limits macrophage-driven inflammation [PMID:38989590]. Transcriptional output is tuned both by type I IFN, which recruits a repressive Egr3/Nab1 complex to the ifngr1 promoter [PMID:23935197], and by IFN-γ itself through chromatin remodeling at enhancer sites, establishing autoregulatory feedback [PMID:31585982]. Beyond canonical surface signaling, IFNGR1 undergoes ligand-dependent endocytosis and nuclear translocation, where it associates with STAT1α at the GAS promoter element and harbors transactivation activity [PMID:10888113, PMID:16785527]. Dominant-negative truncations lacking the cytoplasmic domain accumulate at the cell surface due to impaired recycling, retain IFN-γ binding, and block wild-type receptor signaling, causing inherited partial IFN-γ receptor deficiency [PMID:10192386, PMID:17513528].","teleology":[{"year":1999,"claim":"Established how cytoplasmic-domain truncations of IFNGR1 cause disease, showing the mutant acts dominantly rather than through simple haploinsufficiency.","evidence":"Cell-surface expression, IFN-γ binding, and signaling assays in patient-derived cells across 12 families","pmids":["10192386"],"confidence":"High","gaps":["Molecular basis of the recycling defect was not resolved at the trafficking-machinery level","Did not identify the cytoplasmic motifs required for internalization"]},{"year":2000,"claim":"Revealed that IFNGR1, unlike IFNGR2, undergoes ligand-induced endocytosis and nuclear translocation in association with STAT1α, hinting at a non-canonical nuclear role.","evidence":"Immunofluorescence, Co-IP, and subcellular fractionation of IFN-γ-treated WISH cells","pmids":["10888113"],"confidence":"Medium","gaps":["Single lab, no reciprocal validation in other cell types","Functional consequence of nuclear IFNGR1 not yet demonstrated"]},{"year":2006,"claim":"Demonstrated that nuclear IFNGR1 is recruited with IFN-γ and STAT1α to GAS elements and contains a transactivation domain, assigning a direct transcriptional function to a receptor chain.","evidence":"ChIP-PCR, EMSA, biotin-GAS pulldown, and GAL4-IFNGR1 fusion reporter assays","pmids":["16785527"],"confidence":"Medium","gaps":["Quantitative contribution of nuclear IFNGR1 versus STAT1 to transcription not separated","Single lab"]},{"year":2008,"claim":"Showed that IFNGR1 promoter polymorphisms are functionally active and cell-type-dependent, linking genetic variation to receptor expression levels.","evidence":"Allele-specific and deletion/insertion luciferase reporter assays and EMSA across B-cells, epithelial cells, and T-cells","pmids":["18593809","16600993"],"confidence":"Medium","gaps":["Reporter-based effects not validated at endogenous loci","Identity of binding factors only partially defined by size"]},{"year":2009,"claim":"Explained cell-type-selective partial IFNGR1 deficiency, showing leaky alternative translation initiation can rescue expression in some lineages.","evidence":"Western blot and signaling assays in patient fibroblasts versus EBV-B cells with translation initiation site analysis","pmids":["19880857"],"confidence":"Medium","gaps":["Mechanism governing lineage-specific leaky initiation not defined","Single patient"]},{"year":2013,"claim":"Identified transcriptional silencing of ifngr1 by type I IFN and defined the receptor's role in dendritic cells, establishing that receptor levels and cell context shape antibacterial immunity.","evidence":"Egr-site reporter mutagenesis, ChIP, and Nab1 knockdown in macrophages; conditional Ifngr1 deletion in CD8α+ DCs with IL-4 neutralization rescue","pmids":["23935197","24048899"],"confidence":"High","gaps":["How Egr3/Nab1 recruitment integrates with other repressors not defined","DC-intrinsic transcriptional targets downstream of IFNGR1 not enumerated"]},{"year":2017,"claim":"Established that surface IFNGR1 abundance is the decisive variable for IFN-γ responsiveness in vivo, by forcing expression to override type I IFN-induced down-regulation.","evidence":"Macrophage-specific FLAG-IFNGR1 transgenic mice in Listeria infection with IFN-γ-dependence tests; AAV-IFN-γ overexpression in Ifngr1−/− mice with behavioral and histopathology readouts","pmids":["28542482","29196213"],"confidence":"High","gaps":["Trafficking machinery enforcing surface levels not yet identified at this stage","Neurodegeneration model does not isolate the responding cell type"]},{"year":2014,"claim":"Showed IFNGR1 can act in trans, delivered on extracellular vesicles complexed with IFN-γ to activate STAT1 in recipient cells.","evidence":"EV isolation, target-cell STAT1 phosphorylation with IFNGR1/STAT1 siRNA, and Co-IP of the IFN-γ/IFNGR1 complex on EVs","pmids":["25242146"],"confidence":"Medium","gaps":["Physiological abundance and reach of receptor-bearing EVs unclear","Mechanism of EV loading not defined"]},{"year":2020,"claim":"Identified FBXW7 as an E3 ligase controlling IFNGR1 protein stability, linking proteasomal turnover to tumor IFN-γ signaling.","evidence":"FBXW7 loss-of-function, IFNGR1 stability and ubiquitination assays, and genetic rescue in TNBC cells and mice","pmids":["32284542"],"confidence":"Medium","gaps":["Degron on IFNGR1 recognized by FBXW7 not mapped","Single lab"]},{"year":2021,"claim":"Defined the palmitoylation-driven lysosomal degradation axis and its mRNA-level sequestration counterpart, revealing two parallel ways tumors suppress IFN-γ sensing.","evidence":"Cys122 palmitoylation/mutagenesis, AP3D1 and optineurin Co-IP, lysosomal trafficking assays and tumor models; NEAT1_2/NONO RNA pulldown and RIP with T-cell killing assays","pmids":["33627378","33667716"],"confidence":"High","gaps":["Palmitoyltransferase responsible in this context not identified here","Crosstalk between lysosomal and proteasomal degradation routes not resolved"]},{"year":2023,"claim":"Extended the palmitoylation mechanism to infection, identifying ZDHHC3 as the enzyme driving Cys122-dependent lysosomal degradation, and uncovered transcriptional activators of IFNGR1.","evidence":"ZDHHC3-dependent Click-iT palmitoylation, C122A mutagenesis and LAMP2 co-localization in P. gingivalis infection; JMJD2D-SP1 and RGS1-ATF3 ChIP-qPCR and reporter assays driving IFNGR1 transcription; MS identification of IFNGR1 in cancer EVs activating FRC PD-L1","pmids":["37488798","35027670","38264343","37482043"],"confidence":"Medium","gaps":["Whether ZDHHC3 acts on IFNGR1 in non-infectious settings unclear","Transcriptional activator findings each from single labs"]},{"year":2024,"claim":"Established RNF149 as a STAT1-inducible E3 ligase forming a degradation-based negative-feedback loop, and delivered a first-in-class macrocyclic peptide inhibitor of the IFN-γ/IFNGR1 interaction.","evidence":"RNF149 KO/overexpression, Co-IP/MS, ubiquitination assays and bone marrow transplant in myocardial infarction; in vitro mRNA display selection of peptide IB1 with IC50 measurements and cellular validation","pmids":["38989590","38888290"],"confidence":"High","gaps":["Relative weighting of RNF149 versus FBXW7 in different tissues unknown","In vivo efficacy of the peptide inhibitor not yet established"]},{"year":2025,"claim":"Mapped recycling-endosome control of IFNGR1 and demonstrated direct cell-type-specific IFN-γ effects through IFNGR1 in cardiomyocytes and ependymal cells.","evidence":"TMEM199/CCDC115-IFNGR1/2 Co-IP, RAB11A co-localization and PD-L1 readouts; cardiomyocyte- and ependymal-specific conditional Ifngr1 KO with metabolic imaging/metabolomics and permeability assays (preprints)","pmids":["41319859"],"confidence":"Medium","gaps":["Cardiomyocyte and ependymal findings are preprints awaiting peer review","Integration of recycling pathway with degradative pathways not quantified"]},{"year":null,"claim":"How the competing degradative (palmitoylation/lysosomal, FBXW7, RNF149) and recycling (RAB11A) pathways are coordinated to set net surface IFNGR1 in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model balancing degradation versus recycling","Cell-type determinants selecting one fate over another unknown","Structural basis of the IFN-γ/IFNGR1 interface in human receptor not defined in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,8,0]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[12,20]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,7]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,16,12]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[19,12]}],"complexes":["IFN-γ receptor (IFNGR1/IFNGR2)"],"partners":["STAT1","IFNGR2","AP3D1","OPTN","FBXW7","RNF149","TMEM199","CCDC115"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P15260","full_name":"Interferon gamma receptor 1","aliases":["CDw119","Interferon gamma receptor alpha-chain","IFN-gamma-R-alpha"],"length_aa":489,"mass_kda":54.4,"function":"Receptor subunit for interferon gamma/INFG that plays crucial roles in antimicrobial, antiviral, and antitumor responses by activating effector immune cells and enhancing antigen presentation (PubMed:20015550). Associates with transmembrane accessory factor IFNGR2 to form a functional receptor (PubMed:10986460, PubMed:2971451, PubMed:7615558, PubMed:7617032, PubMed:7673114). Upon ligand binding, the intracellular domain of IFNGR1 opens out to allow association of downstream signaling components JAK1 and JAK2. In turn, activated JAK1 phosphorylates IFNGR1 to form a docking site for STAT1. Subsequent phosphorylation of STAT1 leads to dimerization, translocation to the nucleus, and stimulation of target gene transcription (PubMed:28883123). STAT3 can also be activated in a similar manner although activation seems weaker. IFNGR1 intracellular domain phosphorylation also provides a docking site for SOCS1 that regulates the JAK-STAT pathway by competing with STAT1 binding to IFNGR1 (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P15260/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFNGR1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IFNGR1","total_profiled":1310},"omim":[{"mim_id":"615978","title":"IMMUNODEFICIENCY 27B; IMD27B","url":"https://www.omim.org/entry/615978"},{"mim_id":"614889","title":"IMMUNODEFICIENCY 28; IMD28","url":"https://www.omim.org/entry/614889"},{"mim_id":"613899","title":"FANCC GENE; FANCC","url":"https://www.omim.org/entry/613899"},{"mim_id":"610424","title":"HEPATITIS B VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/610424"},{"mim_id":"608212","title":"IMMUNITY-RELATED GTPase M; IRGM","url":"https://www.omim.org/entry/608212"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IFNGR1"},"hgnc":{"alias_symbol":["CD119"],"prev_symbol":["IFNGR"]},"alphafold":{"accession":"P15260","domains":[{"cath_id":"2.60.40.10","chopping":"32-123","consensus_level":"high","plddt":95.3116,"start":32,"end":123},{"cath_id":"2.60.40.10","chopping":"130-154_165-241","consensus_level":"high","plddt":90.1907,"start":130,"end":241}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P15260","model_url":"https://alphafold.ebi.ac.uk/files/AF-P15260-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P15260-F1-predicted_aligned_error_v6.png","plddt_mean":66.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IFNGR1","jax_strain_url":"https://www.jax.org/strain/search?query=IFNGR1"},"sequence":{"accession":"P15260","fasta_url":"https://rest.uniprot.org/uniprotkb/P15260.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P15260/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P15260"}},"corpus_meta":[{"pmid":"10192386","id":"PMC_10192386","title":"A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10192386","citation_count":352,"is_preprint":false},{"pmid":"25242146","id":"PMC_25242146","title":"Extracellular vesicles from neural stem cells transfer IFN-γ via Ifngr1 to activate Stat1 signaling in target cells.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/25242146","citation_count":250,"is_preprint":false},{"pmid":"33627378","id":"PMC_33627378","title":"Loss of Optineurin Drives Cancer Immune Evasion via Palmitoylation-Dependent IFNGR1 Lysosomal Sorting and Degradation.","date":"2021","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/33627378","citation_count":112,"is_preprint":false},{"pmid":"32284542","id":"PMC_32284542","title":"Loss of ELF5-FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32284542","citation_count":90,"is_preprint":false},{"pmid":"12023780","id":"PMC_12023780","title":"IFNGR1 gene promoter polymorphisms and susceptibility to cerebral malaria.","date":"2002","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/12023780","citation_count":80,"is_preprint":false},{"pmid":"19575238","id":"PMC_19575238","title":"NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans.","date":"2009","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19575238","citation_count":69,"is_preprint":false},{"pmid":"10888113","id":"PMC_10888113","title":"Differential nuclear localization of the IFNGR-1 and IFNGR-2 subunits of the IFN-gamma receptor complex following activation by IFN-gamma.","date":"2000","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/10888113","citation_count":59,"is_preprint":false},{"pmid":"9355958","id":"PMC_9355958","title":"Infections in IFNGR-1-deficient children.","date":"1997","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/9355958","citation_count":58,"is_preprint":false},{"pmid":"12847550","id":"PMC_12847550","title":"Genetic susceptibility to visceral leishmaniasis in The Sudan: linkage and association with IL4 and IFNGR1.","date":"2003","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12847550","citation_count":58,"is_preprint":false},{"pmid":"24048899","id":"PMC_24048899","title":"Identifying the initiating events of anti-Listeria responses using mice with conditional loss of IFN-γ receptor subunit 1 (IFNGR1).","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24048899","citation_count":55,"is_preprint":false},{"pmid":"17431682","id":"PMC_17431682","title":"Linkage and association analysis of candidate genes for TB and TNFalpha cytokine expression: evidence for association with IFNGR1, IL-10, and TNF receptor 1 genes.","date":"2007","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17431682","citation_count":52,"is_preprint":false},{"pmid":"16785527","id":"PMC_16785527","title":"IFN-gamma and its receptor subunit IFNGR1 are recruited to the IFN-gamma-activated sequence element at the promoter site of IFN-gamma-activated genes: evidence of transactivational activity in IFNGR1.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16785527","citation_count":46,"is_preprint":false},{"pmid":"23935197","id":"PMC_23935197","title":"Type I IFNs downregulate myeloid cell IFN-γ receptor by inducing recruitment of an early growth response 3/NGFI-A binding protein 1 complex that silences ifngr1 transcription.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23935197","citation_count":44,"is_preprint":false},{"pmid":"18593809","id":"PMC_18593809","title":"The interferon gamma receptor 1 (IFNGR1) -56C/T gene polymorphism is associated with increased risk of early gastric carcinoma.","date":"2008","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/18593809","citation_count":43,"is_preprint":false},{"pmid":"17136124","id":"PMC_17136124","title":"IFNG and IFNGR1 gene polymorphisms and susceptibility to post-kala-azar dermal leishmaniasis in Sudan.","date":"2006","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/17136124","citation_count":38,"is_preprint":false},{"pmid":"28744922","id":"PMC_28744922","title":"IFN-γR1 defects: Mutation update and description of the IFNGR1 variation database.","date":"2017","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/28744922","citation_count":37,"is_preprint":false},{"pmid":"26343451","id":"PMC_26343451","title":"Targeted deep sequencing identifies rare loss-of-function variants in IFNGR1 for risk of atopic dermatitis complicated by eczema herpeticum.","date":"2015","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26343451","citation_count":36,"is_preprint":false},{"pmid":"24680779","id":"PMC_24680779","title":"Genetic polymorphisms of IFNG and IFNGR1 in association with the risk of pulmonary tuberculosis.","date":"2014","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24680779","citation_count":32,"is_preprint":false},{"pmid":"19880857","id":"PMC_19880857","title":"A novel form of cell type-specific partial IFN-gammaR1 deficiency caused by a germ line mutation of the IFNGR1 initiation codon.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19880857","citation_count":30,"is_preprint":false},{"pmid":"35027670","id":"PMC_35027670","title":"Demethylase JMJD2D induces PD-L1 expression to promote colorectal cancer immune escape by enhancing IFNGR1-STAT3-IRF1 signaling.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/35027670","citation_count":28,"is_preprint":false},{"pmid":"23040881","id":"PMC_23040881","title":"An association study of functional polymorphic genes IRF-1, IFNGR-1, and IFN-γ with disease progression, aspartate aminotransferase, alanine aminotransferase, and viral load in chronic hepatitis B and C.","date":"2012","source":"International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23040881","citation_count":27,"is_preprint":false},{"pmid":"10491309","id":"PMC_10491309","title":"Nonpathogenic common variants of IFNGR1 and IFNGR2 in association with total serum IgE levels.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10491309","citation_count":27,"is_preprint":false},{"pmid":"28542482","id":"PMC_28542482","title":"Down regulation of macrophage IFNGR1 exacerbates systemic L. monocytogenes infection.","date":"2017","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/28542482","citation_count":26,"is_preprint":false},{"pmid":"17513528","id":"PMC_17513528","title":"The novel IFNGR1 mutation 774del4 produces a truncated form of interferon-gamma receptor 1 and has a dominant-negative effect on interferon-gamma signal transduction.","date":"2007","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17513528","citation_count":25,"is_preprint":false},{"pmid":"33393726","id":"PMC_33393726","title":"Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet's Disease.","date":"2021","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/33393726","citation_count":23,"is_preprint":false},{"pmid":"2532616","id":"PMC_2532616","title":"Human interferon gamma receptor 1 (IFNGR1) gene maps to chromosome region 6q23-6q24.","date":"1989","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2532616","citation_count":23,"is_preprint":false},{"pmid":"20500698","id":"PMC_20500698","title":"Analysis of functional SNP in ifng/ifngr1 in Chinese Han population with tuberculosis.","date":"2010","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20500698","citation_count":19,"is_preprint":false},{"pmid":"31310896","id":"PMC_31310896","title":"Genetic variants in IFNG and IFNGR1 and tuberculosis susceptibility.","date":"2019","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/31310896","citation_count":17,"is_preprint":false},{"pmid":"16600993","id":"PMC_16600993","title":"Context-specific functional effects of IFNGR1 promoter polymorphism.","date":"2006","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16600993","citation_count":17,"is_preprint":false},{"pmid":"31015500","id":"PMC_31015500","title":"Mice lacking Casp1, Ifngr and Nos2 genes exhibit altered depressive- and anxiety-like behaviour, and gut microbiome composition.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31015500","citation_count":16,"is_preprint":false},{"pmid":"21731057","id":"PMC_21731057","title":"Initial interrogation, confirmation and fine mapping of modifying genes: STAT3, IL1B and IFNGR1 determine cystic fibrosis disease manifestation.","date":"2011","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/21731057","citation_count":16,"is_preprint":false},{"pmid":"29555551","id":"PMC_29555551","title":"Analysis of the expression patterns of the cytokine receptor family B (CRFB) and interferon gamma receptor (IFNGR) in Dabry's sturgeon (Acipenser dabryanus).","date":"2018","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29555551","citation_count":15,"is_preprint":false},{"pmid":"24412214","id":"PMC_24412214","title":"Two IFNGR1 homologues in Tetraodon nigroviridis: Origin, expression analysis and ligand-binding preference.","date":"2014","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24412214","citation_count":14,"is_preprint":false},{"pmid":"34199353","id":"PMC_34199353","title":"Induced Mitochondrial Alteration and DNA Damage via IFNGR-JAK2-STAT1-PARP1 Pathway Facilitates Viral Hepatitis Associated Hepatocellular Carcinoma Aggressiveness and Stemness.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34199353","citation_count":14,"is_preprint":false},{"pmid":"37482043","id":"PMC_37482043","title":"Cancer cell-derived extracellular vesicles drive pre-metastatic niche formation of lymph node via IFNGR1/JAK1/STAT1-activated-PD-L1 expression on FRCs in head and neck cancer.","date":"2023","source":"Oral oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37482043","citation_count":14,"is_preprint":false},{"pmid":"36398225","id":"PMC_36398225","title":"IFN-γ promotes the development of systemic lupus erythematosus through the IFNGR1/2-PSTAT1-TBX21 signaling axis.","date":"2022","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/36398225","citation_count":14,"is_preprint":false},{"pmid":"12743658","id":"PMC_12743658","title":"Missense mutations of the interleukin-12 receptor beta 1(IL12RB1) and interferon-gamma receptor 1 (IFNGR1) genes are not associated with susceptibility to lepromatous leprosy in Korea.","date":"2003","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/12743658","citation_count":14,"is_preprint":false},{"pmid":"33667716","id":"PMC_33667716","title":"Paraspeckle Promotes Hepatocellular Carcinoma Immune Escape by Sequestering IFNGR1 mRNA.","date":"2021","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/33667716","citation_count":13,"is_preprint":false},{"pmid":"31687049","id":"PMC_31687049","title":"Genetic Polymorphisms of IFNG and IFNGR1 with Latent Tuberculosis Infection.","date":"2019","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/31687049","citation_count":13,"is_preprint":false},{"pmid":"31680343","id":"PMC_31680343","title":"Analysis of interferon-γ receptor IFNGR1 and IFNGR2 expression and regulation at the maternal-conceptus interface and the role of interferon-γ on endometrial expression of interferon signaling molecules during early pregnancy in pigs.","date":"2019","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/31680343","citation_count":13,"is_preprint":false},{"pmid":"38989590","id":"PMC_38989590","title":"RNF149 Destabilizes IFNGR1 in Macrophages to Favor Postinfarction Cardiac Repair.","date":"2024","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/38989590","citation_count":12,"is_preprint":false},{"pmid":"29117241","id":"PMC_29117241","title":"IFNGR1 signaling is associated with adverse pregnancy outcomes during infection with malaria parasites.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29117241","citation_count":12,"is_preprint":false},{"pmid":"38264343","id":"PMC_38264343","title":"Tumor-intrinsic RGS1 potentiates checkpoint blockade response via ATF3-IFNGR1 axis.","date":"2023","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/38264343","citation_count":11,"is_preprint":false},{"pmid":"29228700","id":"PMC_29228700","title":"Association of IFNGR1 and IFNG genetic polymorphisms with the risk for pulmonary tuberculosis in the Chinese Tibetan population.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29228700","citation_count":11,"is_preprint":false},{"pmid":"33017569","id":"PMC_33017569","title":"Promoting effect of long non-coding RNA SNHG1 on osteogenic differentiation of fibroblastic cells from the posterior longitudinal ligament by the microRNA-320b/IFNGR1 network.","date":"2020","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/33017569","citation_count":11,"is_preprint":false},{"pmid":"29196213","id":"PMC_29196213","title":"Ifngr1 and Stat1 mediated canonical Ifn-γ signaling drives nigrostriatal degeneration.","date":"2017","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/29196213","citation_count":10,"is_preprint":false},{"pmid":"24453034","id":"PMC_24453034","title":"Association study of SNPs of genes IFNGR1 (rs137854905), GSTT1 (rs71748309), and GSTP1 (rs1695) in gastric cancer development in samples of patient in the northern and northeastern Brazil.","date":"2014","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24453034","citation_count":10,"is_preprint":false},{"pmid":"26649196","id":"PMC_26649196","title":"Association of Genetic Polymorphisms of IFNGR1 with the Risk of Pulmonary Tuberculosis in Zahedan, Southeast Iran.","date":"2015","source":"Tuberculosis research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/26649196","citation_count":9,"is_preprint":false},{"pmid":"19712753","id":"PMC_19712753","title":"IFNGR1 polymorphisms in Thai malaria patients.","date":"2009","source":"Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19712753","citation_count":9,"is_preprint":false},{"pmid":"25466928","id":"PMC_25466928","title":"Insights into the possible role of IFNG and IFNGR1 in Kala-azar and Post Kala-azar Dermal Leishmaniasis in Sudanese patients.","date":"2014","source":"BMC infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/25466928","citation_count":7,"is_preprint":false},{"pmid":"38888290","id":"PMC_38888290","title":"In Vitro Selection of Macrocyclic l-α/d-α/β/γ-Hybrid Peptides Targeting IFN-γ/IFNGR1 Protein-Protein Interaction.","date":"2024","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/38888290","citation_count":6,"is_preprint":false},{"pmid":"36477272","id":"PMC_36477272","title":"S100A9 upregulated by IFNGR signaling blockade functions as a novel GVHD suppressor without compromising GVL in mice.","date":"2023","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/36477272","citation_count":6,"is_preprint":false},{"pmid":"37488798","id":"PMC_37488798","title":"[Effect of Porphyromonas gingivalis infection on IFNGR1 palmitoylation in esophageal cancer cells].","date":"2023","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/37488798","citation_count":6,"is_preprint":false},{"pmid":"31585982","id":"PMC_31585982","title":"Ligand-induced IFNGR1 down-regulation calibrates myeloid cell IFNγ responsiveness.","date":"2019","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/31585982","citation_count":5,"is_preprint":false},{"pmid":"20412699","id":"PMC_20412699","title":"Lack of association between IFNGR1 gene polymorphisms and biopsy-proven giant cell arteritis.","date":"2010","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/20412699","citation_count":5,"is_preprint":false},{"pmid":"32714620","id":"PMC_32714620","title":"Disseminated Mycobacterium Avium Infection in a Child with Complete Interferon-γ Receptor 1 Deficiency due to Compound Heterozygosis of IFNGR1 for a Subpolymorphic Copy Number Variation and a Novel Splice-Site Variant.","date":"2019","source":"Journal of pediatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32714620","citation_count":5,"is_preprint":false},{"pmid":"35653895","id":"PMC_35653895","title":"Interferon gamma upregulates the cytokine receptors IFNGR1 and TNFRSF1A in HT-29-MTX E12 cells.","date":"2022","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/35653895","citation_count":4,"is_preprint":false},{"pmid":"38072135","id":"PMC_38072135","title":"Identification, functional characterization and expression pattern of interferon-gamma (IFN-γ) and interferon-gamma receptor 1 (IFNGR1) in Nibea albiflora.","date":"2023","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38072135","citation_count":4,"is_preprint":false},{"pmid":"39395272","id":"PMC_39395272","title":"CAV1 inhibits Xc- system through IFNGR1 to promote ferroptosis to inhibit stemness and improves anti-PD-1 efficacy in breast cancer.","date":"2024","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39395272","citation_count":4,"is_preprint":false},{"pmid":"35281241","id":"PMC_35281241","title":"Case Report: Disseminated Mycobacterium intracellulare Infection With More Than 1-Year Follow-Up in a Young Boy With IFNGR1 Deficiency.","date":"2022","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/35281241","citation_count":4,"is_preprint":false},{"pmid":"36148347","id":"PMC_36148347","title":"Association between IFNGR1 gene polymorphisms and tuberculosis susceptibility: A meta-analysis.","date":"2022","source":"Frontiers in public health","url":"https://pubmed.ncbi.nlm.nih.gov/36148347","citation_count":3,"is_preprint":false},{"pmid":"36524496","id":"PMC_36524496","title":"IFNG and IFNGR1 polymorphisms are associated with tuberculosis: a case-control study.","date":"2022","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36524496","citation_count":3,"is_preprint":false},{"pmid":"34646402","id":"PMC_34646402","title":"Genetic Polymorphisms of IFNG, IFNGR1, and Androgen Receptor and Chronic Prostatitis/Chronic Pelvic Pain Syndrome in a Chinese Han Population.","date":"2021","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/34646402","citation_count":3,"is_preprint":false},{"pmid":"39617087","id":"PMC_39617087","title":"The aqueous extract of Armadillidium vulgare Latreille alleviates neuropathic pain via inhibiting neuron-astrocyte crosstalk mediated by the IL-12-IFN-γ-IFNGR-CXCL10 pathway.","date":"2024","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39617087","citation_count":3,"is_preprint":false},{"pmid":"27356097","id":"PMC_27356097","title":"Missense splice variant (g.20746A>G, p.Ile183Val) of interferon gamma receptor 1 (IFNGR1) coincidental with mycobacterial osteomyelitis - a screen of osteoarticular lesions.","date":"2016","source":"Bosnian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27356097","citation_count":3,"is_preprint":false},{"pmid":"39082520","id":"PMC_39082520","title":"Elevated NS1 serum levels reduce CD119 expression and CXCL-10 synthesis in patients with dengue hemorrhagic fever.","date":"2024","source":"Revista da Sociedade Brasileira de Medicina Tropical","url":"https://pubmed.ncbi.nlm.nih.gov/39082520","citation_count":2,"is_preprint":false},{"pmid":"18414508","id":"PMC_18414508","title":"Frequent mutations in the 3'-untranslated region of IFNGR1 lack functional impairment in microsatellite-unstable colorectal tumours.","date":"2008","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/18414508","citation_count":2,"is_preprint":false},{"pmid":"41319859","id":"PMC_41319859","title":"TMEM199 promotes PD-L1 expression and tumor immune evasion by activating the recycling of IFNGR1/2.","date":"2025","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/41319859","citation_count":1,"is_preprint":false},{"pmid":"16563189","id":"PMC_16563189","title":"IFNGR1 single nucleotide polymorphisms in rheumatoid arthritis.","date":"2006","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/16563189","citation_count":1,"is_preprint":false},{"pmid":"40827246","id":"PMC_40827246","title":"Ubiquitin-related Protein IFNGR1 as Causal Factor and Drug Target for Keloids: A Mendelian Randomization Analysis.","date":"2025","source":"Plastic and reconstructive surgery. Global open","url":"https://pubmed.ncbi.nlm.nih.gov/40827246","citation_count":0,"is_preprint":false},{"pmid":"37926601","id":"PMC_37926601","title":"Talaromyces marneffei infection with IFNGR1 gene mutation in a patient with negative Anti-Interferon-γ autoantibodies.","date":"2023","source":"Anais brasileiros de dermatologia","url":"https://pubmed.ncbi.nlm.nih.gov/37926601","citation_count":0,"is_preprint":false},{"pmid":"40691380","id":"PMC_40691380","title":"IFNGR1, IRF8 genetic polymorphisms modulate the susceptibility of non-tuberculous mycobacteria pulmonary disease and influence the patients' treatment outcomes and immune status.","date":"2025","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/40691380","citation_count":0,"is_preprint":false},{"pmid":"41009374","id":"PMC_41009374","title":"Functional Role of Single-Nucleotide Polymorphisms on IFNG and IFNGR1 in Humans with Cardiovascular Disease.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41009374","citation_count":0,"is_preprint":false},{"pmid":"36636848","id":"PMC_36636848","title":"[Analysis of IFN-γR1 (CD119) and IL-12Rβ1 (CD212) Deficiency by Flow Cytometry].","date":"2023","source":"Mikrobiyoloji bulteni","url":"https://pubmed.ncbi.nlm.nih.gov/36636848","citation_count":0,"is_preprint":false},{"pmid":"1372404","id":"PMC_1372404","title":"TaqI RFLP in the interferon gamma receptor 1 gene (IFNGR1) on human chromosome 6q.","date":"1992","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1372404","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.31.673391","title":"Interferon gamma signaling drives cardiac metabolic rewiring","date":"2025-09-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.31.673391","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.26.671836","title":"Targeting Impaired Type I Interferon–IL-27 Signaling Rescues T Regulatory Cell Suppressive Function in Relapsing-Remitting Multiple Sclerosis","date":"2025-08-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.26.671836","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.13.669778","title":"Tumor-Intrinsic IFNγ Signaling and Niche Adaptation Drive Early Colonization in Ovarian Cancer Metastasis","date":"2025-08-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.13.669778","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.23.634583","title":"ANDROGENS PROTECT ILC2S FROM FUNCTIONAL SUPPRESSION DURING INFLUENZA VIRUS INFECTION","date":"2025-01-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.23.634583","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.02.651967","title":"Lymphocytes and monocytes undergo swift suppression of IL-10R, IL-6R, and IL-2Rβγ signaling under high concentrations of different cytokines","date":"2025-05-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.02.651967","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.28.645924","title":"Bone marrow mesenchymal stromal cells mediate cellular inflammation in HFpEF","date":"2025-04-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.28.645924","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.14.633055","title":"An MRI-informed histo-molecular analysis implicates ependymal cells in the pathogenesis of periventricular pathology in multiple sclerosis","date":"2025-01-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.14.633055","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.02.626426","title":"IFNγ-dependent metabolic reprogramming restrains an immature, pro-metastatic lymphatic state in melanoma","date":"2024-12-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.02.626426","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.20.608656","title":"The  <i>Rickettsia</i>  actin-based motility effectors RickA and Sca2 contribute differently to cell-to-cell spread and pathogenicity","date":"2024-08-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.20.608656","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.26.25336729","title":"Type-2 immune skewing in patients with disseminated coccidioidomycosis","date":"2025-09-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.26.25336729","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.14.670195","title":"Macrophages drive a fibrogenic gene program of periductal fibroblasts in pediatric primary sclerosing cholangitis","date":"2025-08-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.14.670195","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.12.628214","title":"SARS-CoV-2 Nsp14 binds Tollip and activates pro-inflammatory pathways while downregulating interferon-α and interferon-γ receptors","date":"2024-12-13","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.12.628214","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.19.628635","title":"Stress Induced Signaling Pathways in Burkitt’s Lymphoma Play Novel Mechanisms in Fate Determination and Pathogenesis of Germinal Center-Derived B-Lymphomas","date":"2024-12-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.19.628635","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.28.601141","title":"Single cell transcriptome profiling reveals pathogenesis of Bullous Pemphigoid","date":"2024-07-02","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.28.601141","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50482,"output_tokens":6864,"usd":0.127203,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15899,"output_tokens":4787,"usd":0.099585,"stage2_stop_reason":"end_turn"},"total_usd":0.226788,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"IFNGR1 frameshift small deletions producing truncated receptors that lack the intracytoplasmic domain act via a dominant-negative mechanism: the mutant protein accumulates at the cell surface (impaired recycling), abrogates signaling, but retains normal IFN-γ binding, thereby outcompeting wild-type receptor and blocking downstream signaling.\",\n      \"method\": \"Cell-surface expression analysis of patient-derived cells, IFN-γ binding assays, signaling assays in patient leukocytes, genetic characterization of dominant-negative inheritance\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional characterization across multiple patients and families with orthogonal methods (binding, signaling, surface expression), replicated across 12 unrelated families\",\n      \"pmids\": [\"10192386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Following IFN-γ stimulation, IFNGR1 (but not IFNGR2) undergoes ligand-dependent endocytosis and nuclear translocation; IFNGR1 co-localizes and co-immunoprecipitates with STAT1α in the nucleus, while IFNGR2 remains predominantly at the cell surface.\",\n      \"method\": \"Immunofluorescence, immunoprecipitation, subcellular fractionation of WISH cells treated with IFN-γ\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunofluorescence and Co-IP, single lab, two orthogonal methods demonstrating differential subcellular fate of receptor subunits\",\n      \"pmids\": [\"10888113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IFNGR1 and IFN-γ are recruited to the GAS (IFN-γ-activated sequence) promoter element of IFN-γ-activated genes together with STAT1α as a macromolecular complex; IFNGR1 fused to the yeast GAL4 DNA-binding domain drives transcription from a GAL4 response element, indicating IFNGR1 contains a transactivation domain.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP)-PCR, EMSA, biotin-GAS pulldown of nuclear extracts, GAL4-IFNGR1 fusion reporter assay, GAS-luciferase co-transfection\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, reporter assay) in a single lab establishing nuclear transactivation function of IFNGR1\",\n      \"pmids\": [\"16785527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The 774del4 (and 818del4) dominant mutations in IFNGR1 produce truncated receptor that accumulates on the cell surface due to impaired receptor internalization/recycling, causing a dominant-negative effect on IFN-γ-induced STAT1 phosphorylation in HEK293 cells.\",\n      \"method\": \"Transient transfection of truncated IFNGR1 constructs in HEK293 cells, cell-surface FACS, STAT1 phosphorylation assay, peripheral blood CD14+ cell analysis from patient\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in transfected cells plus patient cell analysis, single lab, multiple methods\",\n      \"pmids\": [\"17513528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A homozygous mutation of the IFNGR1 initiation codon (M1K) eliminates IFN-γR1 expression in fibroblasts but permits residual expression in EBV-transformed B cells via leaky translation initiation at non-AUG and a downstream AUG codon (position 19), resulting in cell-type-specific partial IFNGR1 deficiency.\",\n      \"method\": \"Protein expression analysis (Western blot), IFN-γ signaling assays in patient fibroblasts and EBV-B cells, translation initiation site analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization in patient-derived cells with mechanistic follow-up of alternative translation initiation, single lab\",\n      \"pmids\": [\"19880857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Type I IFN (IFN-β) rapidly silences ifngr1 transcription in macrophages by inducing recruitment of a repressive Egr3/Nab1 transcriptional complex to an Egr binding site in the proximal ifngr1 promoter, reducing activated RNA polymerase II and histone acetylation at the promoter.\",\n      \"method\": \"Actinomycin D chase, IFNGR1-luciferase reporter assay with Egr binding site mutation, ChIP for RNA pol II and acetylated histones, Nab1 knockdown in macrophage cell line, promoter-binding protein analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assay with site mutation, ChIP, RNAi knockdown) in a single rigorous study establishing the transcriptional silencing mechanism\",\n      \"pmids\": [\"23935197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Selective deletion of IFNGR1 in CD8α+ dendritic cells (Itgax-cre+Ifngr1f/f mice) impairs the initial IFN-γ-driven burst of IL-12 production needed to initiate anti-Listeria responses; neutralization of IL-4 (overproduced in its absence) restores Listeria resistance, placing IFNGR1 on CD8α+ DCs upstream of the IL-12/IL-4 axis in antibacterial immunity.\",\n      \"method\": \"Conditional knockout mice (Cre-lox), bacterial infection challenge, cytokine measurements, IL-4 neutralization rescue experiment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with cell-type specificity, defined cellular phenotype, and epistatic rescue experiment, single study with multiple orthogonal approaches\",\n      \"pmids\": [\"24048899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IFNGR1 bound to extracellular vesicles (EVs) from neural stem cells—complexed with IFN-γ—activates STAT1 in target cells; this EV-mediated STAT1 activation requires endogenous STAT1 and IFNGR1 in the target cell.\",\n      \"method\": \"EV isolation and characterization, STAT1 phosphorylation assay in target cells, siRNA knockdown of IFNGR1/STAT1 in target cells, immunoprecipitation demonstrating IFN-γ/IFNGR1 complex on EVs\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with RNAi knockdown and Co-IP, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25242146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Macrophage-specific forced expression of IFNGR1 (via transgenic fGR1 mice) prevents type I IFN-induced down-regulation of surface IFNGR1, sustains IFN-γ responsiveness in the presence of type I IFNs, and enhances macrophage antimicrobial function during Listeria monocytogenes infection in an IFN-γ-dependent manner.\",\n      \"method\": \"Transgenic mice with macrophage-specific FLAG-tagged IFNGR1, Listeria infection model, IFN-γ–dependence experiments, macrophage activation assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic rescue model with cell-type specificity, in vivo infection phenotype, and IFN-γ dependence confirmed by neutralization, single rigorous study\",\n      \"pmids\": [\"28542482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Canonical IFN-γ signaling through IFNGR1 and STAT1 is required for nigrostriatal neurodegeneration and midbrain calcinosis induced by brain overexpression of IFN-γ; Ifngr1−/− mice showed no neuroinflammation, calcinosis, or nigrostriatal pathology upon IFN-γ overexpression.\",\n      \"method\": \"AAV-mediated IFN-γ overexpression in Ifngr1−/− and Stat1−/− mice, rotarod behavioral testing, histopathology, bioinformatic analysis\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using KO mice with functional behavioral and histopathological readouts, rigorous loss-of-function design\",\n      \"pmids\": [\"29196213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFN-γ itself reduces surface IFNGR1 on myeloid cells (murine and human CD14+) by decreasing Ifngr1 transcription through altered chromatin structure at putative Ifngr1 enhancer sites—distinct from the type I IFN mechanism—thereby creating a negative feedback loop that blunts STAT1 and STAT3 activation.\",\n      \"method\": \"Flow cytometry of monocytes from infected mice and cultured cells, qPCR of Ifngr1 transcripts, chromatin accessibility assay at Ifngr1 enhancer sites, STAT1/3 phosphorylation assay\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (flow cytometry, transcriptional assay, chromatin analysis, signaling readout), single lab\",\n      \"pmids\": [\"31585982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXW7 (regulated by the transcription factor ELF5) ubiquitinates IFNGR1 protein, targeting it for proteasomal degradation; loss of FBXW7 in TNBC stabilizes IFNGR1 protein and amplifies intrinsic IFN-γ signaling, promoting tumor progression.\",\n      \"method\": \"FBXW7 loss-of-function experiments, IFNGR1 protein stability assays, ubiquitination assays, genetic rescue experiments in TNBC cells and mouse models\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay and protein stability experiments identifying FBXW7 as E3 ligase for IFNGR1, single lab\",\n      \"pmids\": [\"32284542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFNGR1 is S-palmitoylated at Cys122; palmitoylated IFNGR1 is recognized by AP3D1, which sorts it to lysosomes for degradation. Optineurin interacts with AP3D1 to prevent this lysosomal sorting, thereby stabilizing IFNGR1 at the cell surface and maintaining IFN-γ signaling. Loss of optineurin in colorectal cancer increases IFNGR1 palmitoylation-dependent lysosomal degradation and impairs IFN-γ signaling.\",\n      \"method\": \"Palmitoylation assay (Click chemistry/acyl-RAC), Co-IP of AP3D1 with IFNGR1 and optineurin, site-directed mutagenesis of Cys122, lysosomal trafficking assay, pharmacological inhibition of palmitoylation, mouse tumor models\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — palmitoylation site mutagenesis, biochemical co-IP, pharmacological inhibition, and in vivo mouse models in one rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"33627378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Paraspeckle protein NONO and the lncRNA NEAT1_2 sequester IFNGR1 mRNA within paraspeckles in HCC cells, reducing IFNGR1 protein expression and impairing IFN-γ/IFNGR1 signaling, thereby promoting resistance to T-cell-mediated cytolysis.\",\n      \"method\": \"CRISPR-Cas9 knock-in S1-aptamer pull-down of NEAT1_2 interactors followed by sequencing, RNA immunoprecipitation (RIP), NONO/NEAT1_2 knockdown, Western blotting, T-cell killing assay\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pull-down and RIP identifying IFNGR1 mRNA as paraspeckle cargo, plus functional killing assay, single lab\",\n      \"pmids\": [\"33667716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Histone demethylase JMJD2D coactivates SP1 to transcriptionally upregulate IFNGR1, which then elevates STAT3-IRF1 signaling and PD-L1 transcription in colorectal cancer; JMJD2D also directly coactivates the STAT3-IRF1 axis at the PD-L1 promoter in a demethylation-dependent manner.\",\n      \"method\": \"Genetic ablation of JMJD2D, RT-qPCR, Western blotting, ChIP-qPCR, luciferase reporter assay, flow cytometry, mouse tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR, reporter assay, and KO establishing the JMJD2D-SP1-IFNGR1-STAT3-IRF1 axis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35027670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RGS1 enhances binding of the transcription factor ATF3 to the IFNGR1 promoter, thereby increasing IFNGR1 expression, activating downstream STAT1 signaling and IFN-γ-inducible gene expression (including CXCL9 and MHC-I), and supporting CD8+ T cell infiltration.\",\n      \"method\": \"ChIP-qPCR, dual-luciferase reporter assay, RT-qPCR, Western blotting, flow cytometry, mouse tumor models\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and luciferase assay identifying ATF3 as a transcriptional activator of IFNGR1, single lab with multiple methods\",\n      \"pmids\": [\"38264343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The E3 ubiquitin ligase RNF149 promotes ubiquitylation-dependent proteasomal degradation of IFNGR1 in macrophages; STAT1 activation induces Rnf149 transcription, which in turn destabilizes IFNGR1, creating a negative feedback loop that fine-tunes type II IFN signaling and limits macrophage-driven inflammation after myocardial infarction.\",\n      \"method\": \"RNF149 KO and overexpression, bone marrow transplantation, immunoprecipitation/mass spectrometry, ubiquitination assay, transcriptome analysis, flow cytometry, cardiac function measurements\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical ubiquitination assay, Co-IP/MS identifying RNF149-IFNGR1 interaction, KO and overexpression in vivo, epistasis with IFNGR1 loss-of-function rescue, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"38989590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Macrocyclic l-α/d-α/β/γ-hybrid peptide IB1 selected by in vitro display inhibits the IFN-γ/IFNGR1 protein-protein interaction with IC50 = 12 nM in biochemical assay and ~0.75 μM at the cellular level; the presence of a cyclic β-amino acid (cβAA) in the sequence was identified as the primary contributor to inhibitory activity.\",\n      \"method\": \"In vitro mRNA display selection against recombinant IFNGR1, biochemical PPI inhibition assay (IC50 measurement), cellular IFN-γ/IFNGR1 inhibition assay, mutagenesis of non-proteinogenic residues\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted binding/inhibition assay with structure-activity analysis via amino acid substitution, cellular validation, single rigorous study\",\n      \"pmids\": [\"38888290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFNGR1 contained in cancer-cell-derived extracellular vesicles can be engulfed by fibroblastic reticular cells (FRCs) in lymph nodes and activate PD-L1 expression via the JAK1-STAT1 pathway, promoting CD8+ T cell exhaustion and pre-metastatic niche formation.\",\n      \"method\": \"Mass spectrometry identification of IFNGR1 in CEVs, Western blotting for JAK1-STAT1 pathway activation, co-culture of FRCs with CEVs, T cell cytotoxicity assay, flow cytometry\",\n      \"journal\": \"Oral oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification, Western blot pathway analysis, and functional T-cell killing assay in a single study, single lab\",\n      \"pmids\": [\"37482043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM199, together with its partner CCDC115, interacts with IFNGR1/2 and facilitates their trafficking to RAB11A-positive recycling endosomes; TMEM199/CCDC115 recruits TRAPP II to activate RAB11A, enhancing IFNGR1/2 recycling and downstream IFN-γ-driven PD-L1 upregulation.\",\n      \"method\": \"Co-immunoprecipitation of TMEM199/CCDC115 with IFNGR1/2, RAB11A recycling endosome co-localization assay, loss-of-function experiments, PD-L1 reporter/protein assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying binding partners and trafficking complex, co-localization, and functional PD-L1 readout, single lab\",\n      \"pmids\": [\"41319859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Porphyromonas gingivalis infection promotes S-palmitoylation of IFNGR1 at Cys122 (via ZDHHC3), driving IFNGR1 co-localization with the lysosomal marker LAMP2 and lysosomal degradation, thereby reducing IFNGR1 protein levels; mutation of Cys122 (IFNGR1-C122A) partially attenuates Pg-induced IFNGR1 degradation and reduces cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"2-BP palmitoylation inhibitor assay, site-directed mutagenesis (C122A), Click-iT palmitoylation assay, immunofluorescence co-localization with LAMP2, cell proliferation/migration/invasion assays\",\n      \"journal\": \"Nan fang yi ke da xue xue bao\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — palmitoylation site mutagenesis, Click-iT assay, and lysosomal co-localization, single lab with multiple methods\",\n      \"pmids\": [\"37488798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A deletion/insertion polymorphism at IFNGR1-470 in the IFNGR1 promoter has cell-type-specific opposite functional effects: in B-lymphocytes it suppresses binding of a ~35 kDa nuclear protein and increases reporter gene expression; in epithelial cells it decreases reporter expression and suppresses binding of ~90 kDa STAT-1 and STAT-2 proteins; in T-lymphocytes it has no significant effect on gene expression.\",\n      \"method\": \"EMSA (electrophoretic mobility shift assay) with nuclear extracts, luciferase reporter assay in B-lymphocytes, epithelial cells, and T-lymphocytes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and reporter assay in multiple cell types establishing context-specific promoter regulation, single lab\",\n      \"pmids\": [\"16600993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The IFNGR1 −56C/T promoter polymorphism is functionally relevant: the −56T allele drives approximately 10-fold higher luciferase reporter expression compared to the −56C allele in a cell-based assay.\",\n      \"method\": \"Allele-specific IFNGR1 −56C/T luciferase reporter assay\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single reporter assay demonstrating functional promoter polymorphism, single lab, single method\",\n      \"pmids\": [\"18593809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cardiomyocyte-specific deletion of IFNGR1 (Myh6Cre Ifngr1fl/fl mice) abrogates IFN-γ-induced cardiac metabolic reprogramming (increased glucose uptake, reduced fatty acid oxidation and oxidative phosphorylation), establishing that IFN-γ drives cardiac metabolic changes via direct signaling through IFNGR1 on cardiomyocytes.\",\n      \"method\": \"Conditional cardiomyocyte-specific KO mice, AAV-Ifng overexpression model, echocardiography, bulk RNA-seq, in vivo PET imaging ([18F]FDG and [18F]fluoro-6-thia-heptadecanoic acid), isolated mitochondrial oxygen consumption, targeted metabolomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO with multiple functional readouts (imaging, metabolomics, mitochondrial assay), single preprint study\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional knockout of Ifngr1 in ependymal cells (in a murine model) prevents IFN-γ-induced increases in ependymal permeability, establishing that IFNGR1 on ependymal cells mediates IFN-γ-driven barrier dysfunction relevant to periventricular pathology.\",\n      \"method\": \"Conditional Ifngr1 knockout in ependymal cells, ependymal permeability assay following IFN-γ treatment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single conditional KO experiment with permeability readout reported in preprint abstract only, single lab, limited methodological detail\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IFNGR1 is the ligand-binding chain of the heterodimeric IFN-γ receptor that, upon IFN-γ binding, initiates JAK1/JAK2-STAT1 signaling; its surface abundance is regulated by multiple post-translational mechanisms—including ubiquitin-dependent proteasomal degradation (by RNF149 and FBXW7), palmitoylation at Cys122-driven lysosomal sorting (facilitated by AP3D1 and counteracted by optineurin), recycling endosome trafficking (promoted by TMEM199/CCDC115/RAB11A), and transcriptional silencing by type I IFN via an Egr3/Nab1 repressor complex or by IFN-γ itself via chromatin remodeling at enhancer sites; dominant-negative truncations lacking the cytoplasmic domain accumulate on the cell surface due to impaired recycling and block wild-type receptor function; IFNGR1 also undergoes ligand-induced nuclear translocation where it associates with STAT1α and the GAS promoter element to contribute to transcriptional activation of IFN-γ-stimulated genes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFNGR1 is the ligand-binding chain of the IFN-\\u03b3 receptor that initiates JAK1-STAT1 signaling to drive IFN-\\u03b3-stimulated gene programs in immune and tissue cells [#6, #8]. Surface abundance of IFNGR1 is the principal control point of this pathway and is set by multiple post-translational and trafficking mechanisms: S-palmitoylation at Cys122 directs AP3D1-dependent lysosomal sorting and degradation, a fate opposed by optineurin to stabilize surface receptor and sustain signaling [#12], while ZDHHC3-driven Cys122 palmitoylation during bacterial infection routes the receptor to LAMP2+ lysosomes for degradation [#20]; recycling-endosome trafficking through TMEM199/CCDC115-mediated RAB11A activation promotes receptor re-display and downstream PD-L1 induction [#19]. Receptor levels are additionally constrained by ubiquitin-dependent proteasomal degradation via the E3 ligases FBXW7 [#11] and RNF149, the latter forming a STAT1-induced negative-feedback loop that limits macrophage-driven inflammation [#16]. Transcriptional output is tuned both by type I IFN, which recruits a repressive Egr3/Nab1 complex to the ifngr1 promoter [#5], and by IFN-\\u03b3 itself through chromatin remodeling at enhancer sites, establishing autoregulatory feedback [#10]. Beyond canonical surface signaling, IFNGR1 undergoes ligand-dependent endocytosis and nuclear translocation, where it associates with STAT1\\u03b1 at the GAS promoter element and harbors transactivation activity [#1, #2]. Dominant-negative truncations lacking the cytoplasmic domain accumulate at the cell surface due to impaired recycling, retain IFN-\\u03b3 binding, and block wild-type receptor signaling, causing inherited partial IFN-\\u03b3 receptor deficiency [#0, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established how cytoplasmic-domain truncations of IFNGR1 cause disease, showing the mutant acts dominantly rather than through simple haploinsufficiency.\",\n      \"evidence\": \"Cell-surface expression, IFN-\\u03b3 binding, and signaling assays in patient-derived cells across 12 families\",\n      \"pmids\": [\"10192386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the recycling defect was not resolved at the trafficking-machinery level\", \"Did not identify the cytoplasmic motifs required for internalization\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Revealed that IFNGR1, unlike IFNGR2, undergoes ligand-induced endocytosis and nuclear translocation in association with STAT1\\u03b1, hinting at a non-canonical nuclear role.\",\n      \"evidence\": \"Immunofluorescence, Co-IP, and subcellular fractionation of IFN-\\u03b3-treated WISH cells\",\n      \"pmids\": [\"10888113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no reciprocal validation in other cell types\", \"Functional consequence of nuclear IFNGR1 not yet demonstrated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that nuclear IFNGR1 is recruited with IFN-\\u03b3 and STAT1\\u03b1 to GAS elements and contains a transactivation domain, assigning a direct transcriptional function to a receptor chain.\",\n      \"evidence\": \"ChIP-PCR, EMSA, biotin-GAS pulldown, and GAL4-IFNGR1 fusion reporter assays\",\n      \"pmids\": [\"16785527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of nuclear IFNGR1 versus STAT1 to transcription not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that IFNGR1 promoter polymorphisms are functionally active and cell-type-dependent, linking genetic variation to receptor expression levels.\",\n      \"evidence\": \"Allele-specific and deletion/insertion luciferase reporter assays and EMSA across B-cells, epithelial cells, and T-cells\",\n      \"pmids\": [\"18593809\", \"16600993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reporter-based effects not validated at endogenous loci\", \"Identity of binding factors only partially defined by size\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Explained cell-type-selective partial IFNGR1 deficiency, showing leaky alternative translation initiation can rescue expression in some lineages.\",\n      \"evidence\": \"Western blot and signaling assays in patient fibroblasts versus EBV-B cells with translation initiation site analysis\",\n      \"pmids\": [\"19880857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism governing lineage-specific leaky initiation not defined\", \"Single patient\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified transcriptional silencing of ifngr1 by type I IFN and defined the receptor's role in dendritic cells, establishing that receptor levels and cell context shape antibacterial immunity.\",\n      \"evidence\": \"Egr-site reporter mutagenesis, ChIP, and Nab1 knockdown in macrophages; conditional Ifngr1 deletion in CD8\\u03b1+ DCs with IL-4 neutralization rescue\",\n      \"pmids\": [\"23935197\", \"24048899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Egr3/Nab1 recruitment integrates with other repressors not defined\", \"DC-intrinsic transcriptional targets downstream of IFNGR1 not enumerated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that surface IFNGR1 abundance is the decisive variable for IFN-\\u03b3 responsiveness in vivo, by forcing expression to override type I IFN-induced down-regulation.\",\n      \"evidence\": \"Macrophage-specific FLAG-IFNGR1 transgenic mice in Listeria infection with IFN-\\u03b3-dependence tests; AAV-IFN-\\u03b3 overexpression in Ifngr1\\u2212/\\u2212 mice with behavioral and histopathology readouts\",\n      \"pmids\": [\"28542482\", \"29196213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking machinery enforcing surface levels not yet identified at this stage\", \"Neurodegeneration model does not isolate the responding cell type\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed IFNGR1 can act in trans, delivered on extracellular vesicles complexed with IFN-\\u03b3 to activate STAT1 in recipient cells.\",\n      \"evidence\": \"EV isolation, target-cell STAT1 phosphorylation with IFNGR1/STAT1 siRNA, and Co-IP of the IFN-\\u03b3/IFNGR1 complex on EVs\",\n      \"pmids\": [\"25242146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological abundance and reach of receptor-bearing EVs unclear\", \"Mechanism of EV loading not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified FBXW7 as an E3 ligase controlling IFNGR1 protein stability, linking proteasomal turnover to tumor IFN-\\u03b3 signaling.\",\n      \"evidence\": \"FBXW7 loss-of-function, IFNGR1 stability and ubiquitination assays, and genetic rescue in TNBC cells and mice\",\n      \"pmids\": [\"32284542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron on IFNGR1 recognized by FBXW7 not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the palmitoylation-driven lysosomal degradation axis and its mRNA-level sequestration counterpart, revealing two parallel ways tumors suppress IFN-\\u03b3 sensing.\",\n      \"evidence\": \"Cys122 palmitoylation/mutagenesis, AP3D1 and optineurin Co-IP, lysosomal trafficking assays and tumor models; NEAT1_2/NONO RNA pulldown and RIP with T-cell killing assays\",\n      \"pmids\": [\"33627378\", \"33667716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoyltransferase responsible in this context not identified here\", \"Crosstalk between lysosomal and proteasomal degradation routes not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the palmitoylation mechanism to infection, identifying ZDHHC3 as the enzyme driving Cys122-dependent lysosomal degradation, and uncovered transcriptional activators of IFNGR1.\",\n      \"evidence\": \"ZDHHC3-dependent Click-iT palmitoylation, C122A mutagenesis and LAMP2 co-localization in P. gingivalis infection; JMJD2D-SP1 and RGS1-ATF3 ChIP-qPCR and reporter assays driving IFNGR1 transcription; MS identification of IFNGR1 in cancer EVs activating FRC PD-L1\",\n      \"pmids\": [\"37488798\", \"35027670\", \"38264343\", \"37482043\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ZDHHC3 acts on IFNGR1 in non-infectious settings unclear\", \"Transcriptional activator findings each from single labs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established RNF149 as a STAT1-inducible E3 ligase forming a degradation-based negative-feedback loop, and delivered a first-in-class macrocyclic peptide inhibitor of the IFN-\\u03b3/IFNGR1 interaction.\",\n      \"evidence\": \"RNF149 KO/overexpression, Co-IP/MS, ubiquitination assays and bone marrow transplant in myocardial infarction; in vitro mRNA display selection of peptide IB1 with IC50 measurements and cellular validation\",\n      \"pmids\": [\"38989590\", \"38888290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative weighting of RNF149 versus FBXW7 in different tissues unknown\", \"In vivo efficacy of the peptide inhibitor not yet established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped recycling-endosome control of IFNGR1 and demonstrated direct cell-type-specific IFN-\\u03b3 effects through IFNGR1 in cardiomyocytes and ependymal cells.\",\n      \"evidence\": \"TMEM199/CCDC115-IFNGR1/2 Co-IP, RAB11A co-localization and PD-L1 readouts; cardiomyocyte- and ependymal-specific conditional Ifngr1 KO with metabolic imaging/metabolomics and permeability assays (preprints)\",\n      \"pmids\": [\"41319859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cardiomyocyte and ependymal findings are preprints awaiting peer review\", \"Integration of recycling pathway with degradative pathways not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the competing degradative (palmitoylation/lysosomal, FBXW7, RNF149) and recycling (RAB11A) pathways are coordinated to set net surface IFNGR1 in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model balancing degradation versus recycling\", \"Cell-type determinants selecting one fate over another unknown\", \"Structural basis of the IFN-\\u03b3/IFNGR1 interface in human receptor not defined in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 8, 0]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [12, 20]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 7]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 16, 12]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [19, 12]}\n    ],\n    \"complexes\": [\"IFN-\\u03b3 receptor (IFNGR1/IFNGR2)\"],\n    \"partners\": [\"STAT1\", \"IFNGR2\", \"AP3D1\", \"OPTN\", \"FBXW7\", \"RNF149\", \"TMEM199\", \"CCDC115\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}