{"gene":"IL18RAP","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1998,"finding":"IL18RAP (AcPL) is an obligate co-receptor subunit required for IL-18 signaling: IL18RAP alone cannot bind IL-18, but both IL18RAP and IL-1R-rp1 (IL18R1) are required together to activate NF-κB and c-Jun N-terminal kinase (JNK) in response to IL-18. A dominant-negative version of IL18RAP specifically blocked IL-18 signaling.","method":"Transient transfection reporter assays (NF-κB activation), JNK activation assays, dominant-negative overexpression, and in vitro immunoprecipitation binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal functional assays (reporter, kinase, dominant-negative, binding) in a single foundational study; highly cited (272 citations)","pmids":["9792649"],"is_preprint":false},{"year":2014,"finding":"IL-18RAP amplifies PRR-induced cytokine secretion in macrophages by responding to NOD2-initiated caspase-1-dependent autocrine IL-18, which in turn dramatically enhances MAPK, NF-κB, PI3K, and calcium signaling. Reconstituting MAPK activation rescued decreased cytokine production in IL-18RAP-deficient macrophages. The disease-risk allele (rs917997 AA) leads to decreased cell-surface IL-18RAP protein expression, as well as reduced IL-18R1 and IL-1R1 expression, impairing downstream signaling.","method":"siRNA knockdown of IL-18RAP in human monocyte-derived macrophages, signaling pathway analysis (MAPK, NF-κB, PI3K, calcium), cytokine secretion assays, flow cytometry for surface protein expression, reconstitution experiments","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, pathway rescue, surface expression measurement) with clear mechanistic phenotype in primary human cells","pmids":["24842757"],"is_preprint":false},{"year":2007,"finding":"IL-18RAP mRNA undergoes alternative splicing in human testis and other tissues, producing truncated splice variants; the truncated isoforms are predicted to regulate IL-18 activity, as IL-18RAP is essential for IL-18 signal transduction and increases ligand-binding affinity of the IL-18Rα chain.","method":"RT-PCR of human testicular tissue, cDNA sequencing of splice variants, computer modeling of predicted protein isoforms","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 3 — identifies novel splice variants with predicted functional consequence but no direct functional assay of truncated isoform activity","pmids":["17897836"],"is_preprint":false},{"year":2013,"finding":"The rs917997 SNP modifies IL-18RAP surface protein expression on NK cells and IL18RAP gene expression in activated T cells; susceptibility allele G carriers showed hyperresponsiveness to IL-18 with higher IFNγ production by PBMCs upon IL-12 and IL-18 treatment compared to protective allele carriers.","method":"Flow cytometry for NK cell surface IL-18RAP expression, gene expression analysis in activated T cells, IFNγ ELISA from PBMCs stimulated with IL-12/IL-18","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 3 — direct measurement of surface protein and functional cytokine output linked to genotype, but single-lab study with moderate methodology","pmids":["23891168"],"is_preprint":false},{"year":2024,"finding":"IL18RAP is required for formation of the IL-18 receptor complex (with IL18R1): the natural compound eupafolin directly binds IL18RAP, impeding IL18R complex formation, blocking IL-18-mediated NF-κB activation, reducing IL-6 synthesis/secretion in cancer-associated fibroblasts, and consequently inactivating STAT3 in gastric cancer cells.","method":"Molecular docking, biolayer interferometry (direct binding assay), immunoprecipitation (complex formation), lentiviral knockdown, NF-κB/STAT3 signaling assays, in vitro and in vivo tumor models","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding validated by biolayer interferometry plus functional signaling and complex formation assays, but single study","pmids":["39265444"],"is_preprint":false},{"year":2017,"finding":"The rs7559479 A allele in the 3′ region of IL18RAP increases binding of microRNA-136 (MIR136) to IL18RAP mRNA, providing a post-transcriptional regulatory mechanism that modulates IL-18 system activity.","method":"Luciferase reporter assays with plasmids containing different rs7559479 alleles transfected into cells","journal":"BMJ open","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional reporter assay demonstrating allele-dependent miRNA binding, single study","pmids":["29146643"],"is_preprint":false}],"current_model":"IL18RAP functions as an obligate accessory subunit of the IL-18 receptor complex: it cannot bind IL-18 directly but forms a signaling-competent heterodimer with IL18R1, activating NF-κB, JNK, MAPK, PI3K, and calcium pathways; it also amplifies PRR-induced innate immune responses by responding to autocrine IL-18, and its expression is post-transcriptionally regulated by miR-136 binding and subject to alternative splicing, with disease-associated variants reducing surface expression and impairing downstream cytokine production."},"narrative":{"teleology":[{"year":1998,"claim":"Established that IL18RAP is not a direct IL-18 binder but an essential co-receptor that heterodimerizes with IL18R1 to activate NF-κB and JNK, resolving the composition of the functional IL-18 receptor complex.","evidence":"Transient transfection NF-κB reporter assays, JNK activation assays, dominant-negative overexpression, and in vitro binding assays","pmids":["9792649"],"confidence":"High","gaps":["Structural basis of IL18RAP–IL18R1 heterodimerization not determined","Downstream signaling beyond NF-κB and JNK not mapped","In vivo requirement not tested"]},{"year":2007,"claim":"Revealed that IL18RAP mRNA undergoes alternative splicing yielding truncated isoforms, raising the possibility of endogenous regulation of IL-18 signaling at the receptor level.","evidence":"RT-PCR and cDNA sequencing of human testicular and other tissues with computational modeling of isoforms","pmids":["17897836"],"confidence":"Medium","gaps":["No functional assay of truncated isoforms was performed","Protein-level expression of truncated variants not confirmed","Tissue-specific ratios of splice forms and their physiological impact unknown"]},{"year":2013,"claim":"Linked the rs917997 genotype to differential IL18RAP surface expression on NK cells and T cells and to altered IL-18/IL-12-driven IFN-γ production, connecting a GWAS-identified variant to a discrete receptor-level mechanism.","evidence":"Flow cytometry on NK cells, gene expression in activated T cells, IFN-γ ELISA from PBMCs","pmids":["23891168"],"confidence":"Medium","gaps":["Single-lab study; independent replication in larger cohorts not shown","Molecular mechanism by which the SNP alters surface expression not defined","Cell-type specificity of the effect beyond NK and T cells not explored"]},{"year":2014,"claim":"Demonstrated that IL18RAP amplifies innate immune PRR responses by transducing autocrine IL-18 generated via NOD2/caspase-1, broadening IL18RAP's role from simple co-receptor to an amplifier of MAPK, NF-κB, PI3K, and calcium signaling in macrophages.","evidence":"siRNA knockdown in primary human monocyte-derived macrophages, signaling pathway analysis, MAPK reconstitution rescue, flow cytometry for surface protein","pmids":["24842757"],"confidence":"High","gaps":["Relative contributions of each downstream pathway (PI3K, calcium, MAPK) to cytokine output not dissected","Whether IL18RAP amplifies signals from PRRs other than NOD2 not tested","In vivo validation of autocrine loop not performed"]},{"year":2017,"claim":"Identified a post-transcriptional regulatory mechanism whereby the rs7559479 A allele enhances miR-136 binding to IL18RAP mRNA, explaining allele-specific modulation of IL-18 system activity.","evidence":"Luciferase reporter assays with allele-specific constructs","pmids":["29146643"],"confidence":"Medium","gaps":["Effect on endogenous IL18RAP protein levels not measured","Physiological relevance of miR-136 regulation in immune cells not demonstrated","Whether other miRNAs co-regulate IL18RAP not explored"]},{"year":2024,"claim":"Confirmed IL18RAP's requirement for receptor complex formation by showing that eupafolin directly binds IL18RAP, blocks IL18R complex assembly, inhibits NF-κB activation, and reduces IL-6/STAT3 signaling in cancer-associated fibroblasts and gastric cancer cells.","evidence":"Biolayer interferometry, molecular docking, immunoprecipitation, lentiviral knockdown, in vitro and in vivo tumor models","pmids":["39265444"],"confidence":"Medium","gaps":["Eupafolin binding site on IL18RAP and selectivity over related IL-1 family receptors not structurally resolved","Single study; independent confirmation of the eupafolin–IL18RAP interaction needed","Whether IL18RAP targeting in the tumor microenvironment is therapeutically viable remains untested in clinical settings"]},{"year":null,"claim":"No high-resolution structure of the IL18RAP–IL18R1–IL-18 ternary complex exists, and the precise molecular basis for how IL18RAP enhances IL-18 binding affinity and initiates TIR-domain signaling remains undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No cryo-EM or crystal structure of the heterotrimeric complex","TIR-domain signaling initiation mechanism upon heterodimerization not dissected","In vivo conditional knockout phenotype not reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4]}],"complexes":["IL-18 receptor complex (IL18R1–IL18RAP)"],"partners":["IL18R1"],"other_free_text":[]},"mechanistic_narrative":"IL18RAP is an obligate accessory subunit of the IL-18 receptor complex that does not bind IL-18 directly but heterodimerizes with IL18R1 to form a signaling-competent receptor, activating NF-κB, JNK, MAPK, PI3K, and calcium pathways downstream of IL-18 [PMID:9792649, PMID:24842757]. In macrophages, IL18RAP amplifies pattern-recognition receptor (PRR)-induced cytokine secretion by transducing autocrine IL-18 signals generated through NOD2/caspase-1, and its loss impairs MAPK activation and downstream cytokine production [PMID:24842757]. IL18RAP expression is modulated post-transcriptionally by miR-136 binding at a 3′-region SNP and by alternative splicing that generates truncated isoforms [PMID:29146643, PMID:17897836]. Disease-associated variants (rs917997) reduce IL18RAP surface expression on NK cells and T cells, altering IL-18 responsiveness and IFN-γ output [PMID:23891168, PMID:24842757]."},"prefetch_data":{"uniprot":{"accession":"O95256","full_name":"Interleukin-18 receptor accessory protein","aliases":["Accessory protein-like","AcPL","CD218 antigen-like family member B","CDw218b","IL-1R accessory protein-like","IL-1RAcPL","Interleukin-1 receptor 7","IL-1R-7","IL-1R7","Interleukin-18 receptor accessory protein-like","Interleukin-18 receptor beta","IL-18R-beta","IL-18Rbeta"],"length_aa":599,"mass_kda":68.3,"function":"Within the IL18 receptor complex, does not mediate IL18-binding, but involved in IL18-dependent signal transduction, leading to NF-kappa-B and JNK activation (PubMed:14528293, PubMed:25500532, PubMed:9792649). May play a role in IL18-mediated IFNG synthesis from T-helper 1 (Th1) cells (Probable)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O95256/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL18RAP","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/IL18RAP","total_profiled":1310},"omim":[{"mim_id":"612007","title":"CELIAC DISEASE, SUSCEPTIBILITY TO, 9; CELIAC9","url":"https://www.omim.org/entry/612007"},{"mim_id":"612006","title":"CELIAC DISEASE, SUSCEPTIBILITY TO, 8; CELIAC8","url":"https://www.omim.org/entry/612006"},{"mim_id":"609888","title":"LEPROSY, SUSCEPTIBILITY TO, 1; LPRS1","url":"https://www.omim.org/entry/609888"},{"mim_id":"606001","title":"INTERLEUKIN 32; IL32","url":"https://www.omim.org/entry/606001"},{"mim_id":"604509","title":"INTERLEUKIN 18 RECEPTOR ACCESSORY PROTEIN; IL18RAP","url":"https://www.omim.org/entry/604509"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":101.8}],"url":"https://www.proteinatlas.org/search/IL18RAP"},"hgnc":{"alias_symbol":["AcPL","CD218b"],"prev_symbol":[]},"alphafold":{"accession":"O95256","domains":[{"cath_id":"2.60.40.10","chopping":"163-244","consensus_level":"medium","plddt":88.4646,"start":163,"end":244},{"cath_id":"2.60.40.10","chopping":"253-355","consensus_level":"high","plddt":93.0152,"start":253,"end":355},{"cath_id":"3.40.50.10140","chopping":"406-417_431-559","consensus_level":"high","plddt":87.9316,"start":406,"end":559},{"cath_id":"1.20.5","chopping":"359-397","consensus_level":"medium","plddt":85.0738,"start":359,"end":397}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95256","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95256-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95256-F1-predicted_aligned_error_v6.png","plddt_mean":77.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL18RAP","jax_strain_url":"https://www.jax.org/strain/search?query=IL18RAP"},"sequence":{"accession":"O95256","fasta_url":"https://rest.uniprot.org/uniprotkb/O95256.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95256/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95256"}},"corpus_meta":[{"pmid":"9792649","id":"PMC_9792649","title":"Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9792649","citation_count":272,"is_preprint":false},{"pmid":"18439550","id":"PMC_18439550","title":"Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18439550","citation_count":214,"is_preprint":false},{"pmid":"24842757","id":"PMC_24842757","title":"The IL18RAP region disease polymorphism decreases IL-18RAP/IL-18R1/IL-1R1 expression and signaling through innate receptor-initiated pathways.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24842757","citation_count":53,"is_preprint":false},{"pmid":"27775096","id":"PMC_27775096","title":"Genetic analysis of innate immunity in Behcet's disease identifies an association with IL-37 and IL-18RAP.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27775096","citation_count":34,"is_preprint":false},{"pmid":"19103669","id":"PMC_19103669","title":"Association study of the IL18RAP locus in three European populations with coeliac disease.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19103669","citation_count":27,"is_preprint":false},{"pmid":"22550553","id":"PMC_22550553","title":"An Association Study of Interleukin 18 Receptor Genes (IL18R1 and IL18RAP) in Lumbar Disc Degeneration.","date":"2012","source":"The open orthopaedics journal","url":"https://pubmed.ncbi.nlm.nih.gov/22550553","citation_count":22,"is_preprint":false},{"pmid":"23891168","id":"PMC_23891168","title":"The autoimmune disease-associated SNP rs917997 of IL18RAP controls IFNγ production by PBMC.","date":"2013","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/23891168","citation_count":22,"is_preprint":false},{"pmid":"17897836","id":"PMC_17897836","title":"Identification of IL-18RAP mRNA truncated splice variants in human testis and the other human tissues.","date":"2007","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/17897836","citation_count":19,"is_preprint":false},{"pmid":"26566691","id":"PMC_26566691","title":"Polymorphisms of ST2-IL18R1-IL18RAP gene cluster: a new risk for autoimmune thyroid diseases.","date":"2015","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26566691","citation_count":14,"is_preprint":false},{"pmid":"19473509","id":"PMC_19473509","title":"Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project.","date":"2009","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19473509","citation_count":13,"is_preprint":false},{"pmid":"29146643","id":"PMC_29146643","title":"Are IL18RAP gene polymorphisms associated with body mass regulation? A cross-sectional study.","date":"2017","source":"BMJ open","url":"https://pubmed.ncbi.nlm.nih.gov/29146643","citation_count":10,"is_preprint":false},{"pmid":"39265444","id":"PMC_39265444","title":"Eupafolin hinders cross-talk between gastric cancer cells and cancer-associated fibroblasts by abrogating the IL18/IL18RAP signaling axis.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39265444","citation_count":5,"is_preprint":false},{"pmid":"26289103","id":"PMC_26289103","title":"Systematic review and meta-analysis of the association between IL18RAP rs917997 and CCR3 rs6441961 polymorphisms with celiac disease risks.","date":"2015","source":"Expert review of gastroenterology & hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/26289103","citation_count":4,"is_preprint":false},{"pmid":"31126849","id":"PMC_31126849","title":"Role of APOE and IL18RAP gene polymorphisms in cervical spondylotic myelopathy in Indian population.","date":"2019","source":"Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia","url":"https://pubmed.ncbi.nlm.nih.gov/31126849","citation_count":3,"is_preprint":false},{"pmid":"31147177","id":"PMC_31147177","title":"IL18RAP polymorphisms and its plasma levels in patients with Lumbar disc degeneration.","date":"2019","source":"Clinical neurology and neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/31147177","citation_count":2,"is_preprint":false},{"pmid":"40124360","id":"PMC_40124360","title":"Immune and vascular modulation by HERVs: the role of CXCR1 and IL18RAP in dengue severity progression.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40124360","citation_count":1,"is_preprint":false},{"pmid":"29285382","id":"PMC_29285382","title":"IL18 rs360719 A>G, IL18R1 rs13015714 G>T, IL18RAP rs917997 C>T and IL28B rs8099917 T>G polymorphisms and risk of gastric cardiac adenocarcinoma.","date":"2017","source":"Molecular and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29285382","citation_count":1,"is_preprint":false},{"pmid":"24909718","id":"PMC_24909718","title":"Analysis of the association of polymorphic loci rs917997 in IL18RAP gene and rs187238 in IL18 gene with the risk for non-Hodgkin's malignant lymphomas in Novosibirsk population.","date":"2014","source":"Bulletin of experimental biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24909718","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.19.25336165","title":"Biobank-scale Bayesian TWAS reveals splicing-mediated mechanisms of complex disease","date":"2025-09-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.19.25336165","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.09.658549","title":"Identification of reactive CpGs and RNA expression in early COVID-19 through <i>cis</i> -eQTM analysis reflecting disease severity and recovery","date":"2025-06-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.09.658549","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11647,"output_tokens":1633,"usd":0.029718},"stage2":{"model":"claude-opus-4-6","input_tokens":4904,"output_tokens":1930,"usd":0.109155},"total_usd":0.138873,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"IL18RAP (AcPL) is an obligate co-receptor subunit required for IL-18 signaling: IL18RAP alone cannot bind IL-18, but both IL18RAP and IL-1R-rp1 (IL18R1) are required together to activate NF-κB and c-Jun N-terminal kinase (JNK) in response to IL-18. A dominant-negative version of IL18RAP specifically blocked IL-18 signaling.\",\n      \"method\": \"Transient transfection reporter assays (NF-κB activation), JNK activation assays, dominant-negative overexpression, and in vitro immunoprecipitation binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal functional assays (reporter, kinase, dominant-negative, binding) in a single foundational study; highly cited (272 citations)\",\n      \"pmids\": [\"9792649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-18RAP amplifies PRR-induced cytokine secretion in macrophages by responding to NOD2-initiated caspase-1-dependent autocrine IL-18, which in turn dramatically enhances MAPK, NF-κB, PI3K, and calcium signaling. Reconstituting MAPK activation rescued decreased cytokine production in IL-18RAP-deficient macrophages. The disease-risk allele (rs917997 AA) leads to decreased cell-surface IL-18RAP protein expression, as well as reduced IL-18R1 and IL-1R1 expression, impairing downstream signaling.\",\n      \"method\": \"siRNA knockdown of IL-18RAP in human monocyte-derived macrophages, signaling pathway analysis (MAPK, NF-κB, PI3K, calcium), cytokine secretion assays, flow cytometry for surface protein expression, reconstitution experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, pathway rescue, surface expression measurement) with clear mechanistic phenotype in primary human cells\",\n      \"pmids\": [\"24842757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-18RAP mRNA undergoes alternative splicing in human testis and other tissues, producing truncated splice variants; the truncated isoforms are predicted to regulate IL-18 activity, as IL-18RAP is essential for IL-18 signal transduction and increases ligand-binding affinity of the IL-18Rα chain.\",\n      \"method\": \"RT-PCR of human testicular tissue, cDNA sequencing of splice variants, computer modeling of predicted protein isoforms\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — identifies novel splice variants with predicted functional consequence but no direct functional assay of truncated isoform activity\",\n      \"pmids\": [\"17897836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The rs917997 SNP modifies IL-18RAP surface protein expression on NK cells and IL18RAP gene expression in activated T cells; susceptibility allele G carriers showed hyperresponsiveness to IL-18 with higher IFNγ production by PBMCs upon IL-12 and IL-18 treatment compared to protective allele carriers.\",\n      \"method\": \"Flow cytometry for NK cell surface IL-18RAP expression, gene expression analysis in activated T cells, IFNγ ELISA from PBMCs stimulated with IL-12/IL-18\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct measurement of surface protein and functional cytokine output linked to genotype, but single-lab study with moderate methodology\",\n      \"pmids\": [\"23891168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL18RAP is required for formation of the IL-18 receptor complex (with IL18R1): the natural compound eupafolin directly binds IL18RAP, impeding IL18R complex formation, blocking IL-18-mediated NF-κB activation, reducing IL-6 synthesis/secretion in cancer-associated fibroblasts, and consequently inactivating STAT3 in gastric cancer cells.\",\n      \"method\": \"Molecular docking, biolayer interferometry (direct binding assay), immunoprecipitation (complex formation), lentiviral knockdown, NF-κB/STAT3 signaling assays, in vitro and in vivo tumor models\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding validated by biolayer interferometry plus functional signaling and complex formation assays, but single study\",\n      \"pmids\": [\"39265444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The rs7559479 A allele in the 3′ region of IL18RAP increases binding of microRNA-136 (MIR136) to IL18RAP mRNA, providing a post-transcriptional regulatory mechanism that modulates IL-18 system activity.\",\n      \"method\": \"Luciferase reporter assays with plasmids containing different rs7559479 alleles transfected into cells\",\n      \"journal\": \"BMJ open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional reporter assay demonstrating allele-dependent miRNA binding, single study\",\n      \"pmids\": [\"29146643\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL18RAP functions as an obligate accessory subunit of the IL-18 receptor complex: it cannot bind IL-18 directly but forms a signaling-competent heterodimer with IL18R1, activating NF-κB, JNK, MAPK, PI3K, and calcium pathways; it also amplifies PRR-induced innate immune responses by responding to autocrine IL-18, and its expression is post-transcriptionally regulated by miR-136 binding and subject to alternative splicing, with disease-associated variants reducing surface expression and impairing downstream cytokine production.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL18RAP is an obligate accessory subunit of the IL-18 receptor complex that does not bind IL-18 directly but heterodimerizes with IL18R1 to form a signaling-competent receptor, activating NF-κB, JNK, MAPK, PI3K, and calcium pathways downstream of IL-18 [PMID:9792649, PMID:24842757]. In macrophages, IL18RAP amplifies pattern-recognition receptor (PRR)-induced cytokine secretion by transducing autocrine IL-18 signals generated through NOD2/caspase-1, and its loss impairs MAPK activation and downstream cytokine production [PMID:24842757]. IL18RAP expression is modulated post-transcriptionally by miR-136 binding at a 3′-region SNP and by alternative splicing that generates truncated isoforms [PMID:29146643, PMID:17897836]. Disease-associated variants (rs917997) reduce IL18RAP surface expression on NK cells and T cells, altering IL-18 responsiveness and IFN-γ output [PMID:23891168, PMID:24842757].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that IL18RAP is not a direct IL-18 binder but an essential co-receptor that heterodimerizes with IL18R1 to activate NF-κB and JNK, resolving the composition of the functional IL-18 receptor complex.\",\n      \"evidence\": \"Transient transfection NF-κB reporter assays, JNK activation assays, dominant-negative overexpression, and in vitro binding assays\",\n      \"pmids\": [\"9792649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of IL18RAP–IL18R1 heterodimerization not determined\",\n        \"Downstream signaling beyond NF-κB and JNK not mapped\",\n        \"In vivo requirement not tested\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed that IL18RAP mRNA undergoes alternative splicing yielding truncated isoforms, raising the possibility of endogenous regulation of IL-18 signaling at the receptor level.\",\n      \"evidence\": \"RT-PCR and cDNA sequencing of human testicular and other tissues with computational modeling of isoforms\",\n      \"pmids\": [\"17897836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional assay of truncated isoforms was performed\",\n        \"Protein-level expression of truncated variants not confirmed\",\n        \"Tissue-specific ratios of splice forms and their physiological impact unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked the rs917997 genotype to differential IL18RAP surface expression on NK cells and T cells and to altered IL-18/IL-12-driven IFN-γ production, connecting a GWAS-identified variant to a discrete receptor-level mechanism.\",\n      \"evidence\": \"Flow cytometry on NK cells, gene expression in activated T cells, IFN-γ ELISA from PBMCs\",\n      \"pmids\": [\"23891168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication in larger cohorts not shown\",\n        \"Molecular mechanism by which the SNP alters surface expression not defined\",\n        \"Cell-type specificity of the effect beyond NK and T cells not explored\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that IL18RAP amplifies innate immune PRR responses by transducing autocrine IL-18 generated via NOD2/caspase-1, broadening IL18RAP's role from simple co-receptor to an amplifier of MAPK, NF-κB, PI3K, and calcium signaling in macrophages.\",\n      \"evidence\": \"siRNA knockdown in primary human monocyte-derived macrophages, signaling pathway analysis, MAPK reconstitution rescue, flow cytometry for surface protein\",\n      \"pmids\": [\"24842757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contributions of each downstream pathway (PI3K, calcium, MAPK) to cytokine output not dissected\",\n        \"Whether IL18RAP amplifies signals from PRRs other than NOD2 not tested\",\n        \"In vivo validation of autocrine loop not performed\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a post-transcriptional regulatory mechanism whereby the rs7559479 A allele enhances miR-136 binding to IL18RAP mRNA, explaining allele-specific modulation of IL-18 system activity.\",\n      \"evidence\": \"Luciferase reporter assays with allele-specific constructs\",\n      \"pmids\": [\"29146643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Effect on endogenous IL18RAP protein levels not measured\",\n        \"Physiological relevance of miR-136 regulation in immune cells not demonstrated\",\n        \"Whether other miRNAs co-regulate IL18RAP not explored\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed IL18RAP's requirement for receptor complex formation by showing that eupafolin directly binds IL18RAP, blocks IL18R complex assembly, inhibits NF-κB activation, and reduces IL-6/STAT3 signaling in cancer-associated fibroblasts and gastric cancer cells.\",\n      \"evidence\": \"Biolayer interferometry, molecular docking, immunoprecipitation, lentiviral knockdown, in vitro and in vivo tumor models\",\n      \"pmids\": [\"39265444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Eupafolin binding site on IL18RAP and selectivity over related IL-1 family receptors not structurally resolved\",\n        \"Single study; independent confirmation of the eupafolin–IL18RAP interaction needed\",\n        \"Whether IL18RAP targeting in the tumor microenvironment is therapeutically viable remains untested in clinical settings\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structure of the IL18RAP–IL18R1–IL-18 ternary complex exists, and the precise molecular basis for how IL18RAP enhances IL-18 binding affinity and initiates TIR-domain signaling remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No cryo-EM or crystal structure of the heterotrimeric complex\",\n        \"TIR-domain signaling initiation mechanism upon heterodimerization not dissected\",\n        \"In vivo conditional knockout phenotype not reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"complexes\": [\n      \"IL-18 receptor complex (IL18R1–IL18RAP)\"\n    ],\n    \"partners\": [\n      \"IL18R1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}