{"gene":"IFNGR2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2000,"finding":"Following IFN-γ stimulation, IFNGR-1 (but not IFNGR-2) is endocytosed and translocated to the nucleus, where it colocalizes and co-immunoprecipitates with activated STAT1α; IFNGR-2 remains predominantly at the cell surface after ligand stimulation.","method":"Immunoprecipitation, immunofluorescence, ligand stimulation of WISH cells","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal immunoprecipitation and immunofluorescence in the same study, single lab, two orthogonal methods","pmids":["10888113"],"is_preprint":false},{"year":2008,"finding":"An in-frame microinsertion mutation in IFNGR2 causes protein misfolding and retention within the cell, with abnormally high molecular weight surface-expressed mutant protein; the mutant allele is functionally null (cells do not respond to IFN-γ). Treatment with compounds modifying N-glycosylation in the secretory pathway reduced the MW of surface mutant IFN-γR2 and restored cellular IFN-γ responsiveness, demonstrating that N-glycosylation quality control governs IFNGR2 trafficking.","method":"Cell transfection, surface expression analysis, MW analysis, IFN-γ response assays, pharmacological complementation with 29 N-glycosylation-modifying compounds","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transfection, functional assay, pharmacological rescue) in a single rigorous study with clear mechanistic conclusion","pmids":["18625743"],"is_preprint":false},{"year":2017,"finding":"A homozygous frameshift deletion in IFNGR2 results in minimal protein expression and abolished downstream IFN-γ signaling, establishing IFNGR2 as the signal-transducing chain of the IFN-γ receptor whose loss prevents IFN-γ-mediated immune responses.","method":"Whole-exome sequencing, protein expression analysis, downstream signaling assays in patient fibroblasts","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mutation with defined signaling phenotype in patient cells, single study","pmids":["29106381"],"is_preprint":false},{"year":2012,"finding":"Heterozygous frameshift IFNGR2 mutations cause haploinsufficiency, with the mutant allele being loss-of-function and non-dominant-negative; IFN-γ responses are more impaired in lymphoid cells than myeloid cells, consistent with lower IFNGR2 expression in lymphoid versus myeloid cells.","method":"Whole-exome sequencing, Sanger sequencing, IFN-γ response assays in EBV-transformed B cells, naive CD4+ T cells, memory T cells, monocytes, and MDMs from heterozygous relatives","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays across multiple cell types establishing cell-type-specific signaling, single lab","pmids":["23161749"],"is_preprint":false},{"year":2013,"finding":"IFN-γR2-deficient monocytes induce a higher percentage of IL-17+ (Th17) cells from both healthy and IFN-γR2-deficient CD4+ T cells, demonstrating that IFN-γ signaling through IFNGR2 in APCs suppresses Th17 cell generation from memory T cells.","method":"Isolation of T cells and monocytes from a patient with IFNGR2 mutation, co-culture assays measuring IL-17 production","journal":"Human immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single patient-derived cells, single method, single lab","pmids":["23459074"],"is_preprint":false},{"year":2019,"finding":"A novel homozygous splice acceptor site variant in intron 2 of IFNGR2 leads to use of a cryptic splice site in exon 3, resulting in an in-frame deletion of three amino acids (Thr70-Ser72) in the fibronectin type III domain of the extracellular region of IFNGR2, causing primary immunodeficiency with susceptibility to mycobacterial disease.","method":"Whole exome sequencing, Sanger sequencing, RT-PCR and cDNA sequencing in patient fibroblasts and blood","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular characterization of splice defect with cDNA-level confirmation in patient fibroblasts, single lab","pmids":["31497017"],"is_preprint":false},{"year":2022,"finding":"Melatonin acts via MT1 membrane receptor to increase HSF1 expression (through lowering inactive GSK3β), which transcriptionally inhibits IFNGR2, leading to defective JAK1/2-STAT1-IRF7 canonical IFN-γ signaling and lower IL-1β production in macrophages.","method":"RNA-seq, metabolomics, genetic manipulation (MT1/HSF1/GSK3β), macrophage stimulation assays, in vivo infection model","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNA-seq, genetic manipulation, metabolomics) in single lab establishing regulatory pathway","pmids":["35184395"],"is_preprint":false},{"year":2025,"finding":"ACOT11-mediated accumulation of intracellular fatty acids (eicosatetraenoic acid and stearic acid) inhibits JAK-STAT signaling through palmitoylation of IFNGR2 at C261, thereby suppressing IL-1β maturation in inflammatory macrophages.","method":"GWAS, ACOT11 overexpression, palmitoylation assay with site-directed mutagenesis (C261 site), JAK-STAT signaling assays, in vivo LPS-induced sepsis model","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific mutagenesis identifying palmitoylation site, functional signaling readout, single lab with multiple methods","pmids":["40715698"],"is_preprint":false},{"year":1996,"finding":"The mouse IFNGR2 gene is encoded by 7 exons spanning ~17 kb; its 5'-flanking region lacks TATA and CAAT boxes but contains Sp1, AP-2, NF1, EGR, and NF-κB binding sites and exhibits promoter activity in transfected cells.","method":"Genomic cloning, sequence analysis, luciferase reporter assays in transiently transfected CHO cells","journal":"Scandinavian journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter assay with multiple deletion constructs, single lab","pmids":["8972742"],"is_preprint":false},{"year":2024,"finding":"A coding SNP in IFNGR2 (rs9808753) selectively promotes downstream STAT1 phosphorylation in response to IFN-γ, particularly in transitional B cells, amplifying IFN-γ signaling independently of EBV infection.","method":"SNP genotyping, STAT1 phosphorylation assays in cell lines and primary B cells (transitional B cell subset analysis)","journal":"Journal of autoimmunity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single SNP functional analysis in cell lines and primary cells, single lab, limited mechanistic depth","pmids":["38972102"],"is_preprint":false}],"current_model":"IFNGR2 is the signal-transducing subunit of the heterodimeric IFN-γ receptor that remains at the cell surface following ligand stimulation (while IFNGR-1 is internalized and translocated to the nucleus); its proper folding and surface trafficking depend on N-glycosylation quality control in the secretory pathway, its expression is transcriptionally regulated by a GC-rich, TATA-less promoter responsive to Sp1/NF-κB, and its signaling activity through the JAK1/2–STAT1 axis is modulated post-translationally by palmitoylation at C261 (downstream of ACOT11-mediated fatty acid accumulation) and transcriptionally suppressed by melatonin–MT1–HSF1 signaling, with loss-of-function mutations causing Mendelian susceptibility to mycobacterial disease and haploinsufficiency selectively impairing IFN-γ responses in lymphoid cells."},"narrative":{"mechanistic_narrative":"IFNGR2 is the signal-transducing chain of the heterodimeric IFN-γ receptor, required to couple IFN-γ engagement to downstream JAK1/2–STAT1 signaling and the cellular IFN-γ response [PMID:29106381]. In contrast to IFNGR-1, which is endocytosed and translocated to the nucleus where it associates with activated STAT1α after ligand stimulation, IFNGR-2 remains predominantly at the cell surface [PMID:10888113]. Productive surface expression depends on N-glycosylation quality control in the secretory pathway: a misfolding microinsertion mutation produces an abnormally high-molecular-weight, retained protein, and pharmacological modification of N-glycosylation restores both normal MW and IFN-γ responsiveness [PMID:18625743]. Loss-of-function mutations in IFNGR2 cause Mendelian susceptibility to mycobacterial disease, and the gene is also subject to dosage effects: heterozygous frameshift alleles are non-dominant-negative but produce haploinsufficiency that more severely impairs IFN-γ responses in lymphoid than myeloid cells, tracking with lower lymphoid IFNGR2 expression [PMID:29106381, PMID:23161749, PMID:31497017]. Receptor output is further tuned post-translationally and transcriptionally — palmitoylation at C261, driven by ACOT11-mediated fatty acid accumulation, inhibits JAK-STAT signaling and dampens IL-1β maturation in inflammatory macrophages [PMID:40715698], and melatonin–MT1–HSF1 signaling transcriptionally represses IFNGR2 to suppress canonical IFN-γ signaling [PMID:35184395]. Transcription of the gene is directed by a TATA- and CAAT-less promoter containing Sp1, AP-2, NF1, EGR, and NF-κB elements [PMID:8972742].","teleology":[{"year":1996,"claim":"Before the regulation of IFNGR2 was understood, its promoter architecture was defined, establishing how the gene is transcribed and which factors could control its expression.","evidence":"Genomic cloning and luciferase reporter deletion assays of the mouse gene in transfected CHO cells","pmids":["8972742"],"confidence":"Medium","gaps":["Functional contribution of individual Sp1/NF-κB sites not dissected","Human promoter not directly characterized","No link to cell-type-specific expression differences"]},{"year":2000,"claim":"It was unknown how the two receptor chains behave after ligand binding; this showed an asymmetric fate in which IFNGR-1 internalizes and reaches the nucleus with STAT1α while IFNGR-2 stays at the surface, framing IFNGR2 as a stably surface-resident signaling chain.","evidence":"Reciprocal immunoprecipitation and immunofluorescence after IFN-γ stimulation of WISH cells","pmids":["10888113"],"confidence":"Medium","gaps":["Functional consequence of differential trafficking not established","Mechanism retaining IFNGR-2 at the surface unknown","Single lab, single cell type"]},{"year":2008,"claim":"The question of what controls IFNGR2 surface delivery was answered by showing that N-glycosylation quality control governs trafficking — a misfolding mutant is retained, and chemically altering glycosylation rescues surface expression and IFN-γ responsiveness.","evidence":"Transfection, surface MW analysis, IFN-γ response assays, and pharmacological complementation with N-glycosylation-modifying compounds","pmids":["18625743"],"confidence":"High","gaps":["Specific glycosylation sites and chaperones not mapped","Generality across other IFNGR2 mutations untested"]},{"year":2012,"claim":"Whether partial IFNGR2 loss matters was addressed by showing heterozygous frameshift alleles cause non-dominant-negative haploinsufficiency that selectively impairs lymphoid IFN-γ responses, linking gene dosage to cell-type-specific immunity.","evidence":"Exome/Sanger sequencing and IFN-γ response assays across B cells, CD4+ T cells, monocytes, and MDMs from heterozygous relatives","pmids":["23161749"],"confidence":"Medium","gaps":["Mechanism of cell-type expression differences not resolved","Clinical penetrance of haploinsufficiency unclear"]},{"year":2013,"claim":"The role of IFNGR2-dependent IFN-γ signaling in shaping T helper differentiation was probed, indicating that signaling in antigen-presenting cells suppresses Th17 generation.","evidence":"Co-culture of patient monocytes and CD4+ T cells measuring IL-17 production","pmids":["23459074"],"confidence":"Low","gaps":["Single patient-derived cells, single method","Molecular mediator of Th17 suppression not identified","Not independently confirmed"]},{"year":2017,"claim":"The signal-transducing identity of IFNGR2 was confirmed by a homozygous frameshift that abolishes protein and downstream IFN-γ signaling, cementing its requirement for IFN-γ-mediated immunity.","evidence":"Whole-exome sequencing and downstream signaling assays in patient fibroblasts","pmids":["29106381"],"confidence":"Medium","gaps":["Structural basis of signal transduction not addressed","Single family"]},{"year":2019,"claim":"The allelic spectrum of disease-causing variants was extended by a splice variant producing an in-frame three-residue deletion in the extracellular fibronectin type III domain, linking the ligand-binding region to mycobacterial susceptibility.","evidence":"Exome sequencing with RT-PCR/cDNA confirmation in patient fibroblasts and blood","pmids":["31497017"],"confidence":"Medium","gaps":["Effect of the deletion on ligand binding not biochemically measured","Single patient"]},{"year":2022,"claim":"How environmental/hormonal signals modulate IFN-γ responsiveness was addressed by showing melatonin acts through MT1–HSF1 to transcriptionally repress IFNGR2, dampening canonical JAK1/2–STAT1–IRF7 signaling and IL-1β.","evidence":"RNA-seq, metabolomics, genetic manipulation of MT1/HSF1/GSK3β, and an in vivo infection model in macrophages","pmids":["35184395"],"confidence":"Medium","gaps":["Direct HSF1 binding at the IFNGR2 promoter not shown","Physiological relevance of melatonin levels uncertain"]},{"year":2024,"claim":"A naturally occurring coding variant was shown to amplify rather than impair signaling, selectively enhancing IFN-γ-driven STAT1 phosphorylation in transitional B cells.","evidence":"SNP genotyping and STAT1 phosphorylation assays in cell lines and primary B cells","pmids":["38972102"],"confidence":"Low","gaps":["Single SNP, limited mechanistic depth","Biochemical basis of enhanced phosphorylation unknown","Not independently confirmed"]},{"year":2025,"claim":"A post-translational brake on receptor output was defined, with ACOT11-driven fatty acid accumulation promoting palmitoylation of IFNGR2 at C261 to inhibit JAK-STAT signaling and IL-1β maturation.","evidence":"GWAS, ACOT11 overexpression, site-directed C261 palmitoylation mutagenesis, signaling assays, and LPS sepsis model","pmids":["40715698"],"confidence":"Medium","gaps":["Palmitoyltransferase responsible not identified","How palmitoylation mechanistically disrupts JAK engagement unresolved"]},{"year":null,"claim":"How surface-resident IFNGR2 structurally couples ligand engagement to JAK1/2 activation, and how its glycosylation, palmitoylation, and transcriptional controls are integrated in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the active receptor complex in the corpus","Direct JAK1/2 contact sites on IFNGR2 not mapped","Integration of competing regulatory inputs untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[2,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6,7]}],"complexes":["IFN-γ receptor"],"partners":["IFNGR1","STAT1","JAK1","JAK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P38484","full_name":"Interferon gamma receptor 2","aliases":["Interferon gamma receptor accessory factor 1","AF-1","Interferon gamma receptor beta-chain","IFN-gamma-R-beta","Interferon gamma transducer 1"],"length_aa":337,"mass_kda":37.8,"function":"Associates with IFNGR1 to form a receptor for the cytokine interferon gamma (IFNG) (PubMed:7615558, PubMed:7673114, PubMed:8124716). Ligand binding stimulates activation of the JAK/STAT signaling pathway (PubMed:15356148, PubMed:7673114, PubMed:8124716). Required for signal transduction in contrast to other receptor subunit responsible for ligand binding (PubMed:7673114)","subcellular_location":"Cell membrane; Cytoplasmic vesicle membrane; Golgi apparatus membrane; Endoplasmic reticulum membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P38484/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFNGR2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IFNGR2","total_profiled":1310},"omim":[{"mim_id":"614889","title":"IMMUNODEFICIENCY 28; IMD28","url":"https://www.omim.org/entry/614889"},{"mim_id":"608382","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY A, MEMBER 3; DNAJA3","url":"https://www.omim.org/entry/608382"},{"mim_id":"607948","title":"MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/607948"},{"mim_id":"601604","title":"INTERLEUKIN 12 RECEPTOR, BETA-1; IL12RB1","url":"https://www.omim.org/entry/601604"},{"mim_id":"600555","title":"SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1; STAT1","url":"https://www.omim.org/entry/600555"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IFNGR2"},"hgnc":{"alias_symbol":["AF-1"],"prev_symbol":["IFNGT1"]},"alphafold":{"accession":"P38484","domains":[{"cath_id":"2.60.40.10","chopping":"33-135","consensus_level":"high","plddt":94.0064,"start":33,"end":135},{"cath_id":"2.60.40.10","chopping":"143-239","consensus_level":"high","plddt":95.4545,"start":143,"end":239},{"cath_id":"1.20.5","chopping":"241-283","consensus_level":"medium","plddt":83.5788,"start":241,"end":283}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P38484","model_url":"https://alphafold.ebi.ac.uk/files/AF-P38484-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P38484-F1-predicted_aligned_error_v6.png","plddt_mean":83.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IFNGR2","jax_strain_url":"https://www.jax.org/strain/search?query=IFNGR2"},"sequence":{"accession":"P38484","fasta_url":"https://rest.uniprot.org/uniprotkb/P38484.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P38484/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P38484"}},"corpus_meta":[{"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":"18625743","id":"PMC_18625743","title":"Complementation of a pathogenic IFNGR2 misfolding mutation with modifiers of N-glycosylation.","date":"2008","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18625743","citation_count":52,"is_preprint":false},{"pmid":"29106381","id":"PMC_29106381","title":"A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations.","date":"2017","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/29106381","citation_count":48,"is_preprint":false},{"pmid":"23161749","id":"PMC_23161749","title":"Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23161749","citation_count":46,"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":"35184395","id":"PMC_35184395","title":"Melatonergic signalling instructs transcriptional inhibition of IFNGR2 to lessen interleukin-1β-dependent inflammation.","date":"2022","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35184395","citation_count":26,"is_preprint":false},{"pmid":"22057826","id":"PMC_22057826","title":"Association of IFNGR2 gene polymorphisms with pulmonary tuberculosis among the Vietnamese.","date":"2011","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22057826","citation_count":26,"is_preprint":false},{"pmid":"25994869","id":"PMC_25994869","title":"Genetic association of key Th1/Th2 pathway candidate genes, IRF2, IL6, IFNGR2, STAT4 and IL4RA, with atopic asthma in the Indian population.","date":"2015","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25994869","citation_count":22,"is_preprint":false},{"pmid":"21597988","id":"PMC_21597988","title":"Bovine IFNGR2, IL12RB1, IL12RB2, and IL23R polymorphisms and MAP infection status.","date":"2011","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/21597988","citation_count":18,"is_preprint":false},{"pmid":"31497017","id":"PMC_31497017","title":"A Novel Splice Site Mutation in IFNGR2 in Patients With Primary Immunodeficiency Exhibiting Susceptibility to Mycobacterial Diseases.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31497017","citation_count":18,"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":"23459074","id":"PMC_23459074","title":"Influence of a mutation in IFN-γ receptor 2 (IFNGR2) in human cells on the generation of Th17 cells in memory T cells.","date":"2013","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23459074","citation_count":13,"is_preprint":false},{"pmid":"40715698","id":"PMC_40715698","title":"Porcine GWAS identifies ACOT11 as regulator for macrophage IL-1β maturation via IFNGR2 palmitoylation.","date":"2025","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40715698","citation_count":12,"is_preprint":false},{"pmid":"8972742","id":"PMC_8972742","title":"Genomic organization and promoter analysis of the gene ifngr2 encoding the second chain of the mouse interferon-gamma receptor.","date":"1996","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8972742","citation_count":12,"is_preprint":false},{"pmid":"27563937","id":"PMC_27563937","title":"IFNGR2 genetic polymorphism associated with sex-specific paranoid schizophrenia risk.","date":"2016","source":"Nordic journal of psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/27563937","citation_count":9,"is_preprint":false},{"pmid":"36634655","id":"PMC_36634655","title":"Exosome-mediated delivery of gga-miR-20a-5p regulates immune response of chicken macrophages by targeting IFNGR2, MAPK1, MAP3K5, and MAP3K14.","date":"2023","source":"Animal bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/36634655","citation_count":5,"is_preprint":false},{"pmid":"37441189","id":"PMC_37441189","title":"Association Between HTRA1, GAS6 and IFNGR2 Gene Polymorphisms and Stroke Susceptibility in the Chinese Han Population.","date":"2023","source":"Pharmacogenomics and personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37441189","citation_count":0,"is_preprint":false},{"pmid":"38972102","id":"PMC_38972102","title":"Impact of coding risk variant IFNGR2 on the B cell-intrinsic IFN-γ signaling pathway in multiple sclerosis.","date":"2024","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/38972102","citation_count":0,"is_preprint":false},{"pmid":"40056764","id":"PMC_40056764","title":"Genetic variants in the IFNGR2 locus associated with severe chronic Q fever.","date":"2025","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40056764","citation_count":0,"is_preprint":false},{"pmid":"17065794","id":"PMC_17065794","title":"Sequence analysis of the porcine IFNAR1 and IFNGR2 genes.","date":"2006","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/17065794","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.26.655341","title":"Marker genes for predicting cytokine release syndrome in vitro before CAR T cell infusion","date":"2025-05-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.26.655341","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12762,"output_tokens":2521,"usd":0.038051,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9764,"output_tokens":3466,"usd":0.067735,"stage2_stop_reason":"end_turn"},"total_usd":0.105786,"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\": 2000,\n      \"finding\": \"Following IFN-γ stimulation, IFNGR-1 (but not IFNGR-2) is endocytosed and translocated to the nucleus, where it colocalizes and co-immunoprecipitates with activated STAT1α; IFNGR-2 remains predominantly at the cell surface after ligand stimulation.\",\n      \"method\": \"Immunoprecipitation, immunofluorescence, ligand stimulation of WISH cells\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal immunoprecipitation and immunofluorescence in the same study, single lab, two orthogonal methods\",\n      \"pmids\": [\"10888113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"An in-frame microinsertion mutation in IFNGR2 causes protein misfolding and retention within the cell, with abnormally high molecular weight surface-expressed mutant protein; the mutant allele is functionally null (cells do not respond to IFN-γ). Treatment with compounds modifying N-glycosylation in the secretory pathway reduced the MW of surface mutant IFN-γR2 and restored cellular IFN-γ responsiveness, demonstrating that N-glycosylation quality control governs IFNGR2 trafficking.\",\n      \"method\": \"Cell transfection, surface expression analysis, MW analysis, IFN-γ response assays, pharmacological complementation with 29 N-glycosylation-modifying compounds\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transfection, functional assay, pharmacological rescue) in a single rigorous study with clear mechanistic conclusion\",\n      \"pmids\": [\"18625743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A homozygous frameshift deletion in IFNGR2 results in minimal protein expression and abolished downstream IFN-γ signaling, establishing IFNGR2 as the signal-transducing chain of the IFN-γ receptor whose loss prevents IFN-γ-mediated immune responses.\",\n      \"method\": \"Whole-exome sequencing, protein expression analysis, downstream signaling assays in patient fibroblasts\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mutation with defined signaling phenotype in patient cells, single study\",\n      \"pmids\": [\"29106381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Heterozygous frameshift IFNGR2 mutations cause haploinsufficiency, with the mutant allele being loss-of-function and non-dominant-negative; IFN-γ responses are more impaired in lymphoid cells than myeloid cells, consistent with lower IFNGR2 expression in lymphoid versus myeloid cells.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, IFN-γ response assays in EBV-transformed B cells, naive CD4+ T cells, memory T cells, monocytes, and MDMs from heterozygous relatives\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays across multiple cell types establishing cell-type-specific signaling, single lab\",\n      \"pmids\": [\"23161749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IFN-γR2-deficient monocytes induce a higher percentage of IL-17+ (Th17) cells from both healthy and IFN-γR2-deficient CD4+ T cells, demonstrating that IFN-γ signaling through IFNGR2 in APCs suppresses Th17 cell generation from memory T cells.\",\n      \"method\": \"Isolation of T cells and monocytes from a patient with IFNGR2 mutation, co-culture assays measuring IL-17 production\",\n      \"journal\": \"Human immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single patient-derived cells, single method, single lab\",\n      \"pmids\": [\"23459074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A novel homozygous splice acceptor site variant in intron 2 of IFNGR2 leads to use of a cryptic splice site in exon 3, resulting in an in-frame deletion of three amino acids (Thr70-Ser72) in the fibronectin type III domain of the extracellular region of IFNGR2, causing primary immunodeficiency with susceptibility to mycobacterial disease.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, RT-PCR and cDNA sequencing in patient fibroblasts and blood\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular characterization of splice defect with cDNA-level confirmation in patient fibroblasts, single lab\",\n      \"pmids\": [\"31497017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Melatonin acts via MT1 membrane receptor to increase HSF1 expression (through lowering inactive GSK3β), which transcriptionally inhibits IFNGR2, leading to defective JAK1/2-STAT1-IRF7 canonical IFN-γ signaling and lower IL-1β production in macrophages.\",\n      \"method\": \"RNA-seq, metabolomics, genetic manipulation (MT1/HSF1/GSK3β), macrophage stimulation assays, in vivo infection model\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNA-seq, genetic manipulation, metabolomics) in single lab establishing regulatory pathway\",\n      \"pmids\": [\"35184395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACOT11-mediated accumulation of intracellular fatty acids (eicosatetraenoic acid and stearic acid) inhibits JAK-STAT signaling through palmitoylation of IFNGR2 at C261, thereby suppressing IL-1β maturation in inflammatory macrophages.\",\n      \"method\": \"GWAS, ACOT11 overexpression, palmitoylation assay with site-directed mutagenesis (C261 site), JAK-STAT signaling assays, in vivo LPS-induced sepsis model\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific mutagenesis identifying palmitoylation site, functional signaling readout, single lab with multiple methods\",\n      \"pmids\": [\"40715698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The mouse IFNGR2 gene is encoded by 7 exons spanning ~17 kb; its 5'-flanking region lacks TATA and CAAT boxes but contains Sp1, AP-2, NF1, EGR, and NF-κB binding sites and exhibits promoter activity in transfected cells.\",\n      \"method\": \"Genomic cloning, sequence analysis, luciferase reporter assays in transiently transfected CHO cells\",\n      \"journal\": \"Scandinavian journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter assay with multiple deletion constructs, single lab\",\n      \"pmids\": [\"8972742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A coding SNP in IFNGR2 (rs9808753) selectively promotes downstream STAT1 phosphorylation in response to IFN-γ, particularly in transitional B cells, amplifying IFN-γ signaling independently of EBV infection.\",\n      \"method\": \"SNP genotyping, STAT1 phosphorylation assays in cell lines and primary B cells (transitional B cell subset analysis)\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single SNP functional analysis in cell lines and primary cells, single lab, limited mechanistic depth\",\n      \"pmids\": [\"38972102\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFNGR2 is the signal-transducing subunit of the heterodimeric IFN-γ receptor that remains at the cell surface following ligand stimulation (while IFNGR-1 is internalized and translocated to the nucleus); its proper folding and surface trafficking depend on N-glycosylation quality control in the secretory pathway, its expression is transcriptionally regulated by a GC-rich, TATA-less promoter responsive to Sp1/NF-κB, and its signaling activity through the JAK1/2–STAT1 axis is modulated post-translationally by palmitoylation at C261 (downstream of ACOT11-mediated fatty acid accumulation) and transcriptionally suppressed by melatonin–MT1–HSF1 signaling, with loss-of-function mutations causing Mendelian susceptibility to mycobacterial disease and haploinsufficiency selectively impairing IFN-γ responses in lymphoid cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFNGR2 is the signal-transducing chain of the heterodimeric IFN-γ receptor, required to couple IFN-γ engagement to downstream JAK1/2–STAT1 signaling and the cellular IFN-γ response [#2]. In contrast to IFNGR-1, which is endocytosed and translocated to the nucleus where it associates with activated STAT1α after ligand stimulation, IFNGR-2 remains predominantly at the cell surface [#0]. Productive surface expression depends on N-glycosylation quality control in the secretory pathway: a misfolding microinsertion mutation produces an abnormally high-molecular-weight, retained protein, and pharmacological modification of N-glycosylation restores both normal MW and IFN-γ responsiveness [#1]. Loss-of-function mutations in IFNGR2 cause Mendelian susceptibility to mycobacterial disease, and the gene is also subject to dosage effects: heterozygous frameshift alleles are non-dominant-negative but produce haploinsufficiency that more severely impairs IFN-γ responses in lymphoid than myeloid cells, tracking with lower lymphoid IFNGR2 expression [#2, #3, #5]. Receptor output is further tuned post-translationally and transcriptionally — palmitoylation at C261, driven by ACOT11-mediated fatty acid accumulation, inhibits JAK-STAT signaling and dampens IL-1β maturation in inflammatory macrophages [#7], and melatonin–MT1–HSF1 signaling transcriptionally represses IFNGR2 to suppress canonical IFN-γ signaling [#6]. Transcription of the gene is directed by a TATA- and CAAT-less promoter containing Sp1, AP-2, NF1, EGR, and NF-κB elements [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Before the regulation of IFNGR2 was understood, its promoter architecture was defined, establishing how the gene is transcribed and which factors could control its expression.\",\n      \"evidence\": \"Genomic cloning and luciferase reporter deletion assays of the mouse gene in transfected CHO cells\",\n      \"pmids\": [\"8972742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional contribution of individual Sp1/NF-κB sites not dissected\", \"Human promoter not directly characterized\", \"No link to cell-type-specific expression differences\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"It was unknown how the two receptor chains behave after ligand binding; this showed an asymmetric fate in which IFNGR-1 internalizes and reaches the nucleus with STAT1α while IFNGR-2 stays at the surface, framing IFNGR2 as a stably surface-resident signaling chain.\",\n      \"evidence\": \"Reciprocal immunoprecipitation and immunofluorescence after IFN-γ stimulation of WISH cells\",\n      \"pmids\": [\"10888113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of differential trafficking not established\", \"Mechanism retaining IFNGR-2 at the surface unknown\", \"Single lab, single cell type\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The question of what controls IFNGR2 surface delivery was answered by showing that N-glycosylation quality control governs trafficking — a misfolding mutant is retained, and chemically altering glycosylation rescues surface expression and IFN-γ responsiveness.\",\n      \"evidence\": \"Transfection, surface MW analysis, IFN-γ response assays, and pharmacological complementation with N-glycosylation-modifying compounds\",\n      \"pmids\": [\"18625743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific glycosylation sites and chaperones not mapped\", \"Generality across other IFNGR2 mutations untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether partial IFNGR2 loss matters was addressed by showing heterozygous frameshift alleles cause non-dominant-negative haploinsufficiency that selectively impairs lymphoid IFN-γ responses, linking gene dosage to cell-type-specific immunity.\",\n      \"evidence\": \"Exome/Sanger sequencing and IFN-γ response assays across B cells, CD4+ T cells, monocytes, and MDMs from heterozygous relatives\",\n      \"pmids\": [\"23161749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of cell-type expression differences not resolved\", \"Clinical penetrance of haploinsufficiency unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The role of IFNGR2-dependent IFN-γ signaling in shaping T helper differentiation was probed, indicating that signaling in antigen-presenting cells suppresses Th17 generation.\",\n      \"evidence\": \"Co-culture of patient monocytes and CD4+ T cells measuring IL-17 production\",\n      \"pmids\": [\"23459074\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single patient-derived cells, single method\", \"Molecular mediator of Th17 suppression not identified\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The signal-transducing identity of IFNGR2 was confirmed by a homozygous frameshift that abolishes protein and downstream IFN-γ signaling, cementing its requirement for IFN-γ-mediated immunity.\",\n      \"evidence\": \"Whole-exome sequencing and downstream signaling assays in patient fibroblasts\",\n      \"pmids\": [\"29106381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of signal transduction not addressed\", \"Single family\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The allelic spectrum of disease-causing variants was extended by a splice variant producing an in-frame three-residue deletion in the extracellular fibronectin type III domain, linking the ligand-binding region to mycobacterial susceptibility.\",\n      \"evidence\": \"Exome sequencing with RT-PCR/cDNA confirmation in patient fibroblasts and blood\",\n      \"pmids\": [\"31497017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect of the deletion on ligand binding not biochemically measured\", \"Single patient\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"How environmental/hormonal signals modulate IFN-γ responsiveness was addressed by showing melatonin acts through MT1–HSF1 to transcriptionally repress IFNGR2, dampening canonical JAK1/2–STAT1–IRF7 signaling and IL-1β.\",\n      \"evidence\": \"RNA-seq, metabolomics, genetic manipulation of MT1/HSF1/GSK3β, and an in vivo infection model in macrophages\",\n      \"pmids\": [\"35184395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HSF1 binding at the IFNGR2 promoter not shown\", \"Physiological relevance of melatonin levels uncertain\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A naturally occurring coding variant was shown to amplify rather than impair signaling, selectively enhancing IFN-γ-driven STAT1 phosphorylation in transitional B cells.\",\n      \"evidence\": \"SNP genotyping and STAT1 phosphorylation assays in cell lines and primary B cells\",\n      \"pmids\": [\"38972102\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single SNP, limited mechanistic depth\", \"Biochemical basis of enhanced phosphorylation unknown\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A post-translational brake on receptor output was defined, with ACOT11-driven fatty acid accumulation promoting palmitoylation of IFNGR2 at C261 to inhibit JAK-STAT signaling and IL-1β maturation.\",\n      \"evidence\": \"GWAS, ACOT11 overexpression, site-directed C261 palmitoylation mutagenesis, signaling assays, and LPS sepsis model\",\n      \"pmids\": [\"40715698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Palmitoyltransferase responsible not identified\", \"How palmitoylation mechanistically disrupts JAK engagement unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How surface-resident IFNGR2 structurally couples ligand engagement to JAK1/2 activation, and how its glycosylation, palmitoylation, and transcriptional controls are integrated in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the active receptor complex in the corpus\", \"Direct JAK1/2 contact sites on IFNGR2 not mapped\", \"Integration of competing regulatory inputs untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 7]}\n    ],\n    \"complexes\": [\"IFN-γ receptor\"],\n    \"partners\": [\"IFNGR1\", \"STAT1\", \"JAK1\", \"JAK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}