{"gene":"IL1RAP","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1997,"finding":"IL-1RAcP is an essential co-receptor component of the IL-1 receptor signaling complex; transfection of IL-1RAcP into non-responsive EL-4 D6/76 cells (which express IL-1RI but lack IL-1RAcP) restored IL-1-induced IRAK activation, SAP kinase activation, NF-κB and IL-1 NF nuclear translocation, and IL-2 mRNA synthesis, proving IL-1RAcP is indispensable for linking plasma membrane events to downstream signaling.","method":"Complementation by cDNA transfection in non-responsive cell line; functional assays for IRAK, SAPK, NF-κB, and gene expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean gain-of-function complementation with multiple orthogonal readouts; foundational paper replicated broadly","pmids":["9065432"],"is_preprint":false},{"year":2004,"finding":"IL-1F6, IL-1F8, and IL-1F9 signal through the orphan receptor IL-1Rrp2 AND require IL-1RAcP as a co-receptor; antibodies against IL-1RAcP and cytoplasmic-deletion IL-1RAcP constructs blocked NF-κB activation by all three cytokines, and the three novel IL-1 family members also activated MAPK (JNK, ERK1/2), IL-8 promoter, and IL-6 secretion in an IL-1RAcP-dependent manner.","method":"Antibody blocking, dominant-negative IL-1RAcP transfection, NF-κB reporter assay, MAPK assays, ELISA","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods across multiple cell lines; highly cited foundational paper","pmids":["14734551"],"is_preprint":false},{"year":2007,"finding":"Mass spectrometric analysis of the endogenous ligand-bound IL-1RI signaling complex identified IL-1RAcP, MyD88, and IRAK-4 as stable components. IL-1RAcP binds within 15 seconds of IL-1 stimulation and remains stably associated, whereas IRAK-1 (p90) is only transiently associated. IRAK-4 is the first component to become phosphorylated on serine/threonine residues.","method":"Immunoprecipitation of endogenous receptor complex followed by tandem mass spectrometry; time-course phosphorylation analysis","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical characterization of endogenous complex by MS/IP with rigorous kinetic analysis","pmids":["17507369"],"is_preprint":false},{"year":2009,"finding":"IL-1RAcP serves as the low-affinity coreceptor in a heterotrimeric signaling complex. SAXS analysis of the IL-33/ST2/IL-1RAcP and IL-1β/IL-1R1/IL-1RAcP complexes revealed a general molecular architecture for IL-1 ternary signaling complexes, with IL-1RAcP engaging the primary ligand-receptor binary complex.","method":"NMR structure determination of IL-33, SAXS analysis of binary and ternary complexes, biochemical characterization","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 — structural determination with SAXS validation, multiple complex architectures resolved","pmids":["19836339"],"is_preprint":false},{"year":2012,"finding":"The E3 ubiquitin ligase MARCH8 negatively regulates IL-1β-induced NF-κB and MAPK activation by interacting with IL1RAP and targeting its Lys512 residue for K48-linked polyubiquitination and proteasomal degradation; MARCH8 overexpression reduces IL1RAP levels and inhibits signaling, while MARCH8 knockdown has the opposite effect.","method":"Overexpression and knockdown of MARCH8; co-immunoprecipitation; ubiquitin linkage analysis; site-directed mutagenesis of Lys512; NF-κB and MAPK activation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — identified specific ubiquitination site by mutagenesis, bidirectional genetic manipulation, multiple signaling readouts","pmids":["22904187"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of PTPδ in complex with IL-1RAcP (and IL1RAPL1) revealed that IL-1RAcP Ig1 domain interacts with PTPδ in a splicing-dependent manner; the second splice insert of PTPδ acts as an adjustable linker positioning Ig2 and Ig3 domains for simultaneous interaction with the Ig1 domain of IL-1RAcP, enabling trans-synaptic adhesion and bidirectional induction of pre- and postsynaptic differentiation.","method":"X-ray crystallography of PTPδ–IL-1RAcP complex; structure-function mutagenesis; neuronal differentiation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation of splice-insert dependent binding mechanism","pmids":["25908590"],"is_preprint":false},{"year":2000,"finding":"IL-1RAcP knockout mice lack IL-1β-induced neuroendocrine responses (corticosterone elevation), immune suppression (splenocyte proliferation depression), and brain/plasma IL-6 induction, demonstrating that IL-1RAcP is necessary for centrally mediated neuroendocrine and immune effects of central IL-1β in vivo.","method":"IL-1RAcP knockout mouse model; intracerebroventricular IL-1β injection; corticosterone ELISA, splenocyte proliferation assay, IL-6 measurement","journal":"Journal of neuroimmunology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple in vivo phenotypic readouts","pmids":["11024543"],"is_preprint":false},{"year":2001,"finding":"Molecular modeling and experimental validation with IL-1β peptides, antibodies, and mutated IL-1β proteins supported a 'BACK model' in which IL-1RAcP establishes contacts with the back of IL-1R(I) wrapped around IL-1β, providing a structural model for the IL-1β/IL-1R(I)/IL-1RAcP ternary complex.","method":"Homology modeling, computational docking, experimental validation with IL-1β peptides and mutants","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 4/3 — computational model with partial experimental support but no direct structural determination","pmids":["11418113"],"is_preprint":false},{"year":2013,"finding":"Antisense oligonucleotide (AON)-mediated skipping of exon 9 (which encodes the transmembrane domain) of IL-1RAcP pre-mRNA generates a novel secreted soluble Δ9IL-1RAcP protein; this soluble form is secreted and substantially inhibits IL-1 signaling in vitro, and a single 10 mg/kg dose induces >90% exon skipping in mouse liver for at least 5 days in vivo.","method":"Antisense oligonucleotide exon-skipping, RT-PCR, Western blot for secreted protein, IL-1 signaling inhibition assays in vitro and in vivo","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo exon skipping with functional inhibition demonstrated","pmids":["23340324"],"is_preprint":false},{"year":2018,"finding":"IL1RAP physically interacts with and mediates signaling through the receptor tyrosine kinases FLT3 and c-KIT in AML cells, extending its function beyond the IL-1 receptor pathway; IL1RAP targeting via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo without perturbing normal hematopoietic function.","method":"Co-immunoprecipitation of IL1RAP with FLT3 and c-KIT; RNAi knockdown; CRISPR deletion; antibody treatment; in vitro and xenograft in vivo models","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP with two RTKs, multiple loss-of-function approaches (RNAi + CRISPR + antibody), in vivo validation","pmids":["29773641"],"is_preprint":false},{"year":2018,"finding":"SRSF10 splicing factor modulates the alternate terminator of IL-1RAP exon 13 to increase production of the membrane form of IL1RAP (mIL1RAP); mIL1RAP upregulates CD47 expression via NF-κB activation, inhibiting macrophage phagocytosis and promoting tumor immune evasion in cervical cancer.","method":"Alternative splicing analysis, SRSF10 overexpression/knockdown, NF-κB reporter assay, macrophage phagocytosis assays, rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — mechanism linking splicing factor to specific isoform to NF-κB to CD47, multiple experimental approaches","pmids":["29429992"],"is_preprint":false},{"year":2019,"finding":"A blocking monoclonal antibody to IL-1R3 (IL-1RAP) specifically inhibits signaling via IL-1, IL-33, and IL-36 pathways in vitro and significantly attenuates disease in three distinct in vivo models (crystal-induced peritonitis, allergic airway inflammation, and psoriasis), confirming IL-1RAP's essential shared co-receptor role across six IL-1 family cytokines.","method":"Blocking mAb to human and mouse IL-1R3; in vitro cytokine signaling assays; three in vivo disease models with histology and functional readouts","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — comprehensive blocking antibody approach across multiple in vitro and in vivo contexts, replicated across disease models","pmids":["31427775"],"is_preprint":false},{"year":2021,"finding":"IL1RAP binds the cell-surface system Xc- transporter (cystine/glutamate antiporter) to enhance exogenous cystine uptake, replenishing cysteine and glutathione to maintain redox homeostasis and anoikis resistance; under cystine depletion, IL1RAP also induces cystathionine gamma lyase (CTH) to activate the transsulfuration pathway for de novo cysteine synthesis. IL1RAP inactivation triggers anoikis and impedes metastatic dissemination of Ewing sarcoma cells.","method":"Proteomic screens, co-immunoprecipitation of IL1RAP with system Xc- transporter, cystine uptake assays, CTH expression analysis, anoikis assays, in vivo metastasis models","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1-2 — direct biochemical interaction identified, multiple functional assays, in vivo validation","pmids":["34021002"],"is_preprint":false},{"year":2021,"finding":"IL1β stimulation of IL1RAP-expressing AML cells via the p38 MAPK and NF-κB signaling pathways induces an inflammatory secretome of chemokines that suppresses normal hematopoiesis; the IL1β receptor antagonist Anakinra can reverse this effect, while IL1β-induced signaling is dispensable for AML cell proliferation itself.","method":"IL1β stimulation, IL1RAP knockdown, Anakinra treatment, co-culture with mesenchymal stem cells, NF-κB and p38 MAPK pathway analysis, colony formation assays","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 — pathway analysis with pharmacological and genetic inhibition, functional hematopoiesis co-culture system","pmids":["33121233"],"is_preprint":false},{"year":2021,"finding":"IL1RAP knockdown in AML cells reduced colony-forming capacity; stimulation with IL-1β activated p38 MAPK and NF-κB signaling pathways to induce chemokines but was dispensable for AML cell proliferation and NF-κB-driven survival, suggesting IL1RAP promotes AML colony formation through non-IL-1 mechanisms at the stem cell level.","method":"IL1RAP knockdown by lentiviral shRNA, colony formation assays, p38/NF-κB signaling analysis, IL-1β stimulation","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockdown with defined cellular phenotype and pathway analysis","pmids":["33121233"],"is_preprint":false},{"year":2013,"finding":"Anti-IL1RAP antibody-mediated selective killing of AML stem cell candidates (CD34+CD38- cells) was demonstrated, with the antibody achieving leukemia-selective killing via antibody-dependent cell-mediated cytotoxicity (ADCC); IL1RAP-intermediate and high AML samples show higher IL1RAP expression in CD34+CD38- cells compared to corresponding normal cells.","method":"Flow cytometry, monoclonal antibody generation with isotype switching, ADCC killing assays on primary AML samples including stem cell populations","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — functional antibody-mediated killing assay with primary patient material at stem cell level","pmids":["23479569"],"is_preprint":false},{"year":2016,"finding":"Primitive (CD34+CD38-) CML cells, in contrast to corresponding normal cells, express a functional IL-1 receptor complex and respond to IL-1 with NF-κB activation and marked proliferation; IL1RAP antibodies that inhibit IL-1 signaling blocked these effects, and in vivo administration in xenograft mice produced therapeutic effects mediated by effector cells.","method":"NF-κB activation assays, proliferation assays, IL1RAP-blocking antibody treatment, in vivo xenograft model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — functional receptor complex demonstrated in primary cells, in vitro and in vivo corroboration","pmids":["27621309"],"is_preprint":false},{"year":2020,"finding":"Biallelic compound heterozygous variants in IL1RAP (p.I175T and p.R221H) were identified in patients with steroid-sensitive nephrotic syndrome; reconstitution experiments showed that IL-1R with variant IL1RAP subunit had impaired binding ability and low reactivity to IL-1β, confirming these are loss-of-function mutations that impair IL-1 signaling. IL-1rap−/− mice showed reduced myeloid-derived suppressor cells in the kidney.","method":"Whole-exome sequencing, cytokine production assays from patient PBMCs, reconstitution of mutant IL1RAP on hematopoietic cell line with IL-1β binding/signaling assays, IL-1rap KO mouse analysis","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 1-2 — human genetic variants validated by reconstitution with functional assays, KO mouse corroboration","pmids":["31954058"],"is_preprint":false},{"year":2021,"finding":"The Arg286 residue of IL-1RAcP is a key mediator of ternary IL-1β/IL-1R1/IL-1RAcP complex formation; inhibitory peptides based on the native IL-1RAcP sequence targeting the Arg286 region had an IC50 of 304 pM in a pull-down complex formation assay and reduced IL-1β signaling by 90% at 2 μM in cells; anti-IL-1RAcP mAbs targeting Arg286 reduced inflammatory cell influx in a mouse OA model.","method":"Molecular modeling, pull-down assay for complex formation, peptide inhibitor IC50 determination, IL-1β signaling cell assays, in vivo OA mouse model","journal":"Frontiers in chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 — key residue identified by modeling validated by peptide inhibition and in vivo functional assay","pmids":["33614593"],"is_preprint":false},{"year":2022,"finding":"IL1RAP knockdown in LPS-stimulated normal human astrocytes suppressed reactive astrogliosis and promoted neuronal cell proliferation; IL1RAP overexpression promoted astrocyte proliferation and LPS-induced NF-κB activation, decreased PTEN protein levels, and increased phosphorylation of Akt and mTOR, indicating IL1RAP activates the PI3K/Akt/mTOR pathway in astrocytes.","method":"IL1RAP knockdown and overexpression in astrocytes, NF-κB activation assays, Western blot for PTEN/Akt/mTOR phosphorylation, conditioned medium transfer to neurons, viability/apoptosis assays","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, bidirectional genetic manipulation with pathway analysis but limited mechanistic depth","pmids":["36502418"],"is_preprint":false},{"year":2022,"finding":"A novel nonsense mutation c.1324C>T (R442*) in IL1RAP identified in a schizophrenia family is a loss-of-function mutation; IL1RAP knockdown by lentiviral shRNA suppressed axon and dendrite growth in cultured mouse cortical neurons, effects rescued by wild-type but not R442* mutant IL1RAP; the mutant also inhibited IL-1β-induced JNK phosphorylation and partially inhibited NF-κB nuclear translocation.","method":"Whole-exome sequencing, lentiviral shRNA knockdown in cortical neurons, rescue experiments with WT vs. mutant construct, morphological analysis, JNK phosphorylation assay, NF-κB translocation assay","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function in neurons with multiple signaling readouts; single lab","pmids":["35181481"],"is_preprint":false},{"year":2024,"finding":"IL1RAP blockade in a xenograft PDAC model required the presence of cancer-associated fibroblasts (CAFs) for antitumor effects; mechanistically, IL-1 stimulation induced CAFs to secrete chemokines that recruited neutrophils and monocytes, an effect blocked by anti-IL1RAP antibody nadunolimab; IL-1-stimulated CAF conditioned media sustained neutrophils with tissue-invasion phenotype, reversed by nadunolimab.","method":"Xenograft model with co-transplantation of PDAC cells and CAFs, RNA sequencing, migration assays, cytokine/chemokine profiling, neutrophil phenotyping","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and ex vivo experiments with RNA-seq mechanistic analysis demonstrating CAF-dependent IL1RAP role in neutrophil recruitment","pmids":["39694705"],"is_preprint":false},{"year":2019,"finding":"IL1RAP ubiquitination by the ITCH E3 ligase increases in the presence of ginsenoside Rd; increased IL1RAP ubiquitination blocks IL-1β stimulation of NF-κB, suppressing inflammatory responses in chondrocytes; bioinformatics identified NEDD4, CBL, CBLB, CBLC, and ITCH as candidate E3 ligases targeting IL1RAP.","method":"Immunoprecipitation for ubiquitination, Western blot for ITCH and IL1RAP, RT-PCR, NF-κB signaling assay, CCK-8 viability, flow cytometry","journal":"Brazilian journal of medical and biological research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, immunoprecipitation with limited mechanistic follow-up; ITCH as E3 for IL1RAP not rigorously proven","pmids":["31411316"],"is_preprint":false},{"year":2025,"finding":"PTPδ mini-exon B (meB) regulates excitatory synapses in dentate gyrus granule cells through a cell-type-specific trans-synaptic interaction with IL1RAP; Ptprd-meB+/- mice show decreased postsynaptic IL1RAP levels and decreased excitatory synaptic transmission in dentate gyrus granule cells; IL1RAP-mutant mice show the same decrease, placing IL1RAP downstream of PTPδ-meB in excitatory synapse regulation.","method":"Ptprd-meB knock-in mice, proteomic analysis of postsynaptic density, electrophysiology, IL1RAP knockout mice, behavioral testing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — genetic epistasis (Ptprd-meB and IL1RAP KO mice show same synaptic phenotype), proteomics, and electrophysiology","pmids":["40360498"],"is_preprint":false},{"year":2025,"finding":"IL1RAP is overexpressed in TET2-mutant clonal hematopoiesis (CH) clones; genetic knockdown of IL1RAP inhibited mutant clone growth in vivo in a mouse model, identifying IL1RAP as a driver of inflammation-dependent CH clonal expansion.","method":"Mouse CH model (Tet2-mutant), lentiviral IL1RAP knockdown, in vivo clonal competition assay","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic knockdown with defined clonal expansion phenotype; single lab","pmids":["41031953"],"is_preprint":false},{"year":2025,"finding":"Global Il1rap deficiency reduces hyperphosphorylated tau (pS202-AT8 and pT231-AT180) in a LPS-induced mouse model of systemic inflammation, while neuron-specific IL-1RAcPb isoform deficiency specifically increased total tau levels, demonstrating isoform-specific roles of IL-1RAcP in regulating tau phosphorylation downstream of IL-1R1 signaling.","method":"Global and neuron-specific conditional Il1rap knockout mice, LPS systemic inflammation model, phospho-tau immunoblotting with AT8 and AT180 antibodies","journal":"ASN neuro","confidence":"Medium","confidence_rationale":"Tier 2 — two genetic mouse models with specific tau phosphorylation readouts; single lab study","pmids":["41353558"],"is_preprint":false},{"year":2020,"finding":"The structure-based antibody IgG26AW simultaneously blocks IL-1β binding to both IL-1RI and prevents IL-1RAcP recruitment; SPR experiments confirmed that IL-1β bound by IgG26AW cannot bind either IL-1RI or IL-1RAcP; crystal structure of 26-Fab/IL-1β complex shows the epitope overlaps with the binding sites for both receptor subunits.","method":"Crystal structure of antibody-IL-1β complex, SPR binding competition assays, in vivo IL-6 induction assay, xenograft tumor models","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus SPR validation of dual blocking mechanism","pmids":["33359099"],"is_preprint":false},{"year":2024,"finding":"IL1RAP is internalized following exposure to specific antibodies, as demonstrated by antibody internalization assays on primary NKt-AML specimens, suggesting IL1RAP undergoes receptor-mediated internalization upon antibody binding, supporting its suitability as an antibody-drug conjugate target.","method":"Surface proteome enrichment, single-cell RNA-seq, antibody internalization assay on primary AML samples","journal":"Biomarker research","confidence":"Low","confidence_rationale":"Tier 3 — internalization assay reported but molecular mechanism of internalization not determined; single study","pmids":["40229904"],"is_preprint":false},{"year":2026,"finding":"EWSR1-ETS oncofusions (Ewing sarcoma) directly induce surface expression of IL1RAP; additionally, NPM-ALK (in ALCL) and ETV6-NTRK3 fusions in multiple tumor types also induce IL1RAP expression, rendering these malignancies vulnerable to IL1RAP-targeting ADCs, demonstrating that diverse oncofusions converge on IL1RAP upregulation.","method":"Oncofusion expression studies, proteomic/transcriptomic validation, xenograft ADC treatment models, syngeneic tumor models, non-human primate toxicity","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 — functional link between oncofusions and IL1RAP surface expression established in multiple models; single lab but multiple independent fusion oncogenes tested","pmids":["41973074"],"is_preprint":false},{"year":2024,"finding":"IL-1RAP Ser566 phosphorylation (p-S566-IL-1RAP) is increased in the brain-gut axis of IBS-like stressed mice, correlating with elevated GFAP and IL-1β levels and increased intestinal epithelial permeability, implicating IL-1RAP phosphorylation at S566 in stress-induced neuroinflammatory signaling along the brain-gut axis.","method":"Phosphoproteomics, Western blot, immunofluorescence, ELISA for phospho-S566-IL-1RAP in multiple tissues; intestinal permeability assay","journal":"International journal of medical sciences","confidence":"Low","confidence_rationale":"Tier 3 — phosphoproteomic discovery with Western blot validation, but functional role of the specific phosphorylation not demonstrated mechanistically","pmids":["39006851"],"is_preprint":false}],"current_model":"IL1RAP (IL-1RAcP/IL-1R3) functions as an essential shared coreceptor that is recruited to primary ligand-bound IL-1 family receptors (IL-1R1, ST2, IL-36R) to form heterotrimeric signaling complexes that stably assemble with MyD88 and IRAK-4 within seconds of cytokine stimulation, activating NF-κB and MAPK pathways; its surface levels are negatively regulated by MARCH8-mediated K48-linked polyubiquitination at Lys512; it also engages in trans-synaptic adhesion with PTPδ in a splice-code-dependent manner to regulate excitatory synapse differentiation; and in cancer cells it potentiates oncogenic signaling through physical interactions with FLT3 and c-KIT, and suppresses anoikis by binding the system Xc- cystine transporter to maintain cysteine and glutathione pools."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing that IL-1RAcP is indispensable for IL-1 signaling resolved the long-standing question of why cells expressing IL-1RI alone failed to respond to IL-1β.","evidence":"Complementation by IL-1RAcP cDNA transfection into non-responsive EL-4 D6/76 cells restored IRAK, SAPK, NF-κB activation and IL-2 mRNA synthesis","pmids":["9065432"],"confidence":"High","gaps":["Structural basis of IL-1RAcP engagement with IL-1RI not yet determined","Whether IL-1RAcP serves other IL-1 family members unknown"]},{"year":2000,"claim":"In vivo confirmation that IL-1RAcP is required for centrally mediated neuroimmune responses established its physiological necessity beyond cell-based systems.","evidence":"IL-1RAcP knockout mice lacked IL-1β-induced corticosterone elevation, splenocyte suppression, and IL-6 induction after intracerebroventricular injection","pmids":["11024543"],"confidence":"High","gaps":["Tissue-specific and isoform-specific roles of IL-1RAcP in the brain not dissected","Redundancy with other accessory proteins not tested"]},{"year":2004,"claim":"Demonstrating that IL-1RAcP is a shared coreceptor for IL-1F6/F8/F9 (IL-36 subfamily) via IL-1Rrp2 expanded its role from a single receptor partner to a hub for multiple IL-1 family signaling axes.","evidence":"Anti-IL-1RAcP antibodies and dominant-negative constructs blocked NF-κB and MAPK activation by all three IL-36 cytokines","pmids":["14734551"],"confidence":"High","gaps":["Whether IL-1RAcP is required for all IL-1 family members (e.g., IL-33/ST2) not yet shown","Stoichiometry of the ternary complex unresolved"]},{"year":2007,"claim":"Proteomic dissection of the endogenous receptor complex revealed the kinetic hierarchy of assembly — IL-1RAcP binds within 15 seconds, MyD88 and IRAK-4 are stable partners, while IRAK-1 is transient — establishing the temporal logic of signal initiation.","evidence":"Endogenous IL-1RI immunoprecipitation followed by tandem mass spectrometry with time-course phosphorylation analysis","pmids":["17507369"],"confidence":"High","gaps":["Structural basis for the preferential stability of IRAK-4 vs. IRAK-1 in the complex unknown","Post-translational modifications on IL-1RAcP within the complex not catalogued"]},{"year":2009,"claim":"SAXS-derived structures of IL-33/ST2/IL-1RAcP and IL-1β/IL-1R1/IL-1RAcP ternary complexes established a conserved architectural principle in which IL-1RAcP engages the ligand–receptor binary complex as a low-affinity coreceptor.","evidence":"SAXS analysis of both binary and ternary complexes combined with NMR structure of IL-33","pmids":["19836339"],"confidence":"High","gaps":["Atomic-resolution structure of complete ternary complex not yet available","How TIR domain juxtaposition drives MyD88 recruitment not structurally resolved"]},{"year":2012,"claim":"Identification of MARCH8 as an E3 ligase that targets IL1RAP Lys512 for K48-linked polyubiquitination revealed a dedicated negative regulatory mechanism controlling receptor surface levels and downstream NF-κB/MAPK signaling.","evidence":"MARCH8 overexpression/knockdown, co-IP, K48 ubiquitin linkage analysis, and Lys512 mutagenesis","pmids":["22904187"],"confidence":"High","gaps":["Physiological stimuli that regulate MARCH8 activity toward IL1RAP not identified","Contribution of other candidate E3 ligases (ITCH, NEDD4) not rigorously established"]},{"year":2015,"claim":"Crystal structures of PTPδ–IL-1RAcP complexes revealed a splice-code-dependent trans-synaptic adhesion mechanism, establishing that IL1RAP has a neuronal function independent of cytokine signaling.","evidence":"X-ray crystallography of PTPδ–IL-1RAcP complex with structure-guided mutagenesis and synaptic differentiation assays","pmids":["25908590"],"confidence":"High","gaps":["Downstream postsynaptic signaling pathway engaged by PTPδ–IL-1RAcP interaction not defined","Whether IL-1 cytokine signaling and synaptic adhesion are coordinated or independent not tested"]},{"year":2018,"claim":"Discovery that IL1RAP physically associates with FLT3 and c-KIT extended its coreceptor function beyond the IL-1 family to receptor tyrosine kinases, explaining its oncogenic role in AML independently of IL-1 stimulation.","evidence":"Reciprocal co-IP of IL1RAP with FLT3 and c-KIT; RNAi, CRISPR deletion, and antibody targeting in vitro and in xenograft models","pmids":["29773641"],"confidence":"High","gaps":["Structural basis of IL1RAP interaction with FLT3/c-KIT unknown","Whether IL1RAP modulates RTK kinase activity directly or acts as a scaffolding coreceptor not resolved"]},{"year":2019,"claim":"A pan-IL-1R3 blocking antibody validated in three disease models (peritonitis, airway inflammation, psoriasis) confirmed that therapeutic blockade of this single shared coreceptor simultaneously suppresses IL-1, IL-33, and IL-36 pathways.","evidence":"Blocking mAb against human and mouse IL-1R3 tested in vitro signaling assays and three in vivo disease models","pmids":["31427775"],"confidence":"High","gaps":["Long-term immunosuppressive consequences of pan-IL-1R3 blockade not assessed","Whether IL-1R3 blockade affects neuronal IL1RAP functions not examined"]},{"year":2020,"claim":"Identification of biallelic loss-of-function IL1RAP variants in patients with steroid-sensitive nephrotic syndrome established that human IL1RAP deficiency impairs IL-1 binding/signaling and affects kidney myeloid cell homeostasis.","evidence":"WES of patient families; reconstitution of mutant IL1RAP showing impaired IL-1β binding; IL-1rap KO mice with reduced kidney myeloid-derived suppressor cells","pmids":["31954058"],"confidence":"High","gaps":["Whether additional patients carry IL1RAP mutations not reported","Full spectrum of immunological consequences of human IL1RAP deficiency not characterized"]},{"year":2021,"claim":"The discovery that IL1RAP binds the system Xc⁻ cystine transporter to maintain glutathione homeostasis and resist anoikis revealed a cytokine-independent metabolic function directly relevant to metastasis.","evidence":"Proteomic screen identifying system Xc⁻ as IL1RAP interactor; co-IP, cystine uptake assays, anoikis assays, and in vivo metastasis models in Ewing sarcoma","pmids":["34021002"],"confidence":"High","gaps":["Whether IL1RAP modulates system Xc⁻ transport activity directly or via scaffolding not determined","Generalizability beyond Ewing sarcoma cells not established"]},{"year":2021,"claim":"Identification of Arg286 as a key interface residue for ternary complex formation provided a druggable epitope, with peptide inhibitors achieving picomolar IC50 values for blocking IL-1β signaling.","evidence":"Molecular modeling validated by pull-down inhibition assays (IC50 304 pM) and in vivo OA mouse model","pmids":["33614593"],"confidence":"Medium","gaps":["Crystal structure of peptide–IL-1RAcP interface not solved","In vivo pharmacokinetics and specificity of Arg286-targeting peptides not fully characterized"]},{"year":2022,"claim":"A nonsense mutation (R442*) in IL1RAP identified in a schizophrenia family impaired neurite outgrowth and IL-1β-induced JNK/NF-κB signaling, linking IL1RAP loss-of-function to neuronal morphogenesis and psychiatric disease.","evidence":"WES in family; lentiviral knockdown and rescue in cortical neurons with morphological and signaling readouts","pmids":["35181481"],"confidence":"Medium","gaps":["Causality between IL1RAP R442* and schizophrenia not established by linkage or large cohort","Whether synaptic adhesion (PTPδ-dependent) or cytokine signaling mediates the neuronal phenotype not dissected"]},{"year":2025,"claim":"Genetic epistasis experiments showed that PTPδ mini-exon B and IL1RAP regulate the same excitatory synapses in dentate gyrus granule cells, placing IL1RAP as the postsynaptic effector downstream of presynaptic PTPδ splice-variant signaling.","evidence":"Ptprd-meB knock-in mice and IL1RAP KO mice show identical decreases in excitatory transmission; postsynaptic density proteomics and electrophysiology","pmids":["40360498"],"confidence":"High","gaps":["Postsynaptic signaling cascade linking IL1RAP to synapse maintenance not identified","Whether other PTPδ ligands compensate in IL1RAP-null synapses not tested"]},{"year":2025,"claim":"IL1RAP drives clonal expansion of TET2-mutant hematopoietic clones, establishing it as a functional mediator of inflammation-dependent clonal hematopoiesis beyond its role in overt leukemia.","evidence":"IL1RAP knockdown in Tet2-mutant mouse CH model with in vivo clonal competition assay","pmids":["41031953"],"confidence":"Medium","gaps":["Whether IL1RAP drives CH through IL-1 signaling, FLT3/c-KIT interaction, or another mechanism not resolved","Human validation of IL1RAP as CH driver not yet reported"]},{"year":null,"claim":"How IL1RAP coordinates its multiple independent functions — cytokine coreceptor, trans-synaptic adhesion molecule, RTK partner, and metabolic transporter regulator — remains unresolved, and no structural model integrates these distinct interaction modes.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified structural model of IL1RAP engaging different partner classes","Isoform-specific (membrane vs. soluble vs. neuronal IL-1RAcPb) contributions to each function not systematically mapped","Whether simultaneous engagement of multiple partners occurs on the same cell not tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,9,12]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[5,23]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,9,11,15]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,4,6,11,16,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,9,10,19]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5,20,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,13,15,24,28]}],"complexes":["IL-1β/IL-1R1/IL-1RAcP ternary complex","IL-33/ST2/IL-1RAcP ternary complex","IL-36/IL-1Rrp2/IL-1RAcP ternary complex","PTPδ/IL-1RAcP trans-synaptic complex"],"partners":["IL1R1","IL1RL1","IL1RL2","MYD88","IRAK4","FLT3","KIT","PTPRD"],"other_free_text":[]},"mechanistic_narrative":"IL1RAP (IL-1R3/IL-1RAcP) is a shared coreceptor essential for signal transduction by multiple IL-1 family cytokines and also functions in trans-synaptic adhesion and oncogenic signaling. It is recruited within seconds to ligand-bound primary receptors (IL-1R1, ST2, IL-1Rrp2/IL-36R) to form heterotrimeric complexes that assemble with MyD88 and IRAK-4, activating NF-κB and MAPK cascades; blocking IL-1RAP with antibodies simultaneously inhibits IL-1, IL-33, and IL-36 signaling in vitro and in vivo [PMID:9065432, PMID:14734551, PMID:17507369, PMID:31427775]. Beyond innate immunity, IL1RAP engages PTPδ in a splice-code-dependent manner to regulate excitatory synapse differentiation in the dentate gyrus [PMID:25908590, PMID:40360498], physically interacts with the receptor tyrosine kinases FLT3 and c-KIT to potentiate oncogenic signaling in AML [PMID:29773641], and binds the system Xc⁻ cystine transporter to maintain redox homeostasis and anoikis resistance in Ewing sarcoma [PMID:34021002]. Surface levels of IL1RAP are negatively regulated by MARCH8-mediated K48-linked polyubiquitination at Lys512, targeting it for proteasomal degradation [PMID:22904187]."},"prefetch_data":{"uniprot":{"accession":"Q9NPH3","full_name":"Interleukin-1 receptor accessory protein","aliases":["Interleukin-1 receptor 3","IL-1R-3","IL-1R3"],"length_aa":570,"mass_kda":65.4,"function":"Coreceptor for IL1RL2 in the IL-36 signaling system (By similarity). Coreceptor with IL1R1 in the IL-1 signaling system. Associates with IL1R1 bound to IL1B to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. Recruits TOLLIP to the signaling complex. Does not bind to interleukin-1 alone; binding of IL1RN to IL1R1, prevents its association with IL1R1 to form a signaling complex. The cellular response is modulated through a non-signaling association with the membrane IL1R2 decoy receptor. Coreceptor for IL1RL1 in the IL-33 signaling system. Can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to PTPRD (By similarity). May play a role in IL1B-mediated costimulation of IFNG production from T-helper 1 (Th1) cells (Probable) Associates with secreted ligand-bound IL1R2 and increases the affinity of secreted IL1R2 for IL1B; this complex formation may be the dominant mechanism for neutralization of IL1B by secreted/soluble receptors (PubMed:12530978). Enhances the ability of secreted IL1R1 to inhibit IL-33 signaling (By similarity) Unable to mediate canonical IL-1 signaling (PubMed:19481478). Required for Src phosphorylation by IL1B. May be involved in IL1B-potentiated NMDA-induced calcium influx in neurons (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9NPH3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL1RAP","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL1RAP","total_profiled":1310},"omim":[{"mim_id":"608678","title":"INTERLEUKIN 33; IL33","url":"https://www.omim.org/entry/608678"},{"mim_id":"608321","title":"TIR DOMAIN-CONTAINING ADAPTOR MOLECULE 2; TICAM2","url":"https://www.omim.org/entry/608321"},{"mim_id":"606277","title":"TOLL-INTERACTING PROTEIN; TOLLIP","url":"https://www.omim.org/entry/606277"},{"mim_id":"605507","title":"INTERLEUKIN 36 RECEPTOR ANTAGONIST; IL36RN","url":"https://www.omim.org/entry/605507"},{"mim_id":"603304","title":"INTERLEUKIN 1 RECEPTOR-ASSOCIATED KINASE 2; IRAK2","url":"https://www.omim.org/entry/603304"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":210.8}],"url":"https://www.proteinatlas.org/search/IL1RAP"},"hgnc":{"alias_symbol":["IL-1RAcP","IL1R3","C3orf13"],"prev_symbol":[]},"alphafold":{"accession":"Q9NPH3","domains":[{"cath_id":"2.60.40.10","chopping":"24-131","consensus_level":"high","plddt":90.4127,"start":24,"end":131},{"cath_id":"2.60.40.10","chopping":"145-234","consensus_level":"high","plddt":94.4017,"start":145,"end":234},{"cath_id":"2.60.40.10","chopping":"242-348","consensus_level":"high","plddt":93.0621,"start":242,"end":348},{"cath_id":"3.40.50.10140","chopping":"404-544","consensus_level":"high","plddt":87.2074,"start":404,"end":544},{"cath_id":"1.20.890","chopping":"353-392","consensus_level":"medium","plddt":83.1942,"start":353,"end":392}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPH3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPH3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPH3-F1-predicted_aligned_error_v6.png","plddt_mean":86.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL1RAP","jax_strain_url":"https://www.jax.org/strain/search?query=IL1RAP"},"sequence":{"accession":"Q9NPH3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPH3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPH3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPH3"}},"corpus_meta":[{"pmid":"14734551","id":"PMC_14734551","title":"Interleukin 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zhi","url":"https://pubmed.ncbi.nlm.nih.gov/24370017","citation_count":0,"is_preprint":false},{"pmid":"36682035","id":"PMC_36682035","title":"The survival rate of laryngeal squamous cell carcinoma: impact of IL1RAP rs4624606, IL1RL1 rs1041973, IL-6 rs1800795, BLK rs13277113, and TIMP3 rs9621532 single nucleotide polymorphisms.","date":"2023","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36682035","citation_count":0,"is_preprint":false},{"pmid":"26524021","id":"PMC_26524021","title":"[Cloning of VH and VL Gene of Human anti-IL1RAP McAb and Construction of Recombinant Chimeric Receptor].","date":"2015","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/26524021","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.08.617276","title":"Ethanol drinking sex-dependently alters cortical IL-1β synaptic signaling and cognitive behavior in 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IL-1RAcP into non-responsive EL-4 D6/76 cells (which express IL-1RI but lack IL-1RAcP) restored IL-1-induced IRAK activation, SAP kinase activation, NF-κB and IL-1 NF nuclear translocation, and IL-2 mRNA synthesis, proving IL-1RAcP is indispensable for linking plasma membrane events to downstream signaling.\",\n      \"method\": \"Complementation by cDNA transfection in non-responsive cell line; functional assays for IRAK, SAPK, NF-κB, and gene expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean gain-of-function complementation with multiple orthogonal readouts; foundational paper replicated broadly\",\n      \"pmids\": [\"9065432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-1F6, IL-1F8, and IL-1F9 signal through the orphan receptor IL-1Rrp2 AND require IL-1RAcP as a co-receptor; antibodies against IL-1RAcP and cytoplasmic-deletion IL-1RAcP constructs blocked NF-κB activation by all three cytokines, and the three novel IL-1 family members also activated MAPK (JNK, ERK1/2), IL-8 promoter, and IL-6 secretion in an IL-1RAcP-dependent manner.\",\n      \"method\": \"Antibody blocking, dominant-negative IL-1RAcP transfection, NF-κB reporter assay, MAPK assays, ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods across multiple cell lines; highly cited foundational paper\",\n      \"pmids\": [\"14734551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mass spectrometric analysis of the endogenous ligand-bound IL-1RI signaling complex identified IL-1RAcP, MyD88, and IRAK-4 as stable components. IL-1RAcP binds within 15 seconds of IL-1 stimulation and remains stably associated, whereas IRAK-1 (p90) is only transiently associated. IRAK-4 is the first component to become phosphorylated on serine/threonine residues.\",\n      \"method\": \"Immunoprecipitation of endogenous receptor complex followed by tandem mass spectrometry; time-course phosphorylation analysis\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical characterization of endogenous complex by MS/IP with rigorous kinetic analysis\",\n      \"pmids\": [\"17507369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-1RAcP serves as the low-affinity coreceptor in a heterotrimeric signaling complex. SAXS analysis of the IL-33/ST2/IL-1RAcP and IL-1β/IL-1R1/IL-1RAcP complexes revealed a general molecular architecture for IL-1 ternary signaling complexes, with IL-1RAcP engaging the primary ligand-receptor binary complex.\",\n      \"method\": \"NMR structure determination of IL-33, SAXS analysis of binary and ternary complexes, biochemical characterization\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination with SAXS validation, multiple complex architectures resolved\",\n      \"pmids\": [\"19836339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The E3 ubiquitin ligase MARCH8 negatively regulates IL-1β-induced NF-κB and MAPK activation by interacting with IL1RAP and targeting its Lys512 residue for K48-linked polyubiquitination and proteasomal degradation; MARCH8 overexpression reduces IL1RAP levels and inhibits signaling, while MARCH8 knockdown has the opposite effect.\",\n      \"method\": \"Overexpression and knockdown of MARCH8; co-immunoprecipitation; ubiquitin linkage analysis; site-directed mutagenesis of Lys512; NF-κB and MAPK activation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — identified specific ubiquitination site by mutagenesis, bidirectional genetic manipulation, multiple signaling readouts\",\n      \"pmids\": [\"22904187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of PTPδ in complex with IL-1RAcP (and IL1RAPL1) revealed that IL-1RAcP Ig1 domain interacts with PTPδ in a splicing-dependent manner; the second splice insert of PTPδ acts as an adjustable linker positioning Ig2 and Ig3 domains for simultaneous interaction with the Ig1 domain of IL-1RAcP, enabling trans-synaptic adhesion and bidirectional induction of pre- and postsynaptic differentiation.\",\n      \"method\": \"X-ray crystallography of PTPδ–IL-1RAcP complex; structure-function mutagenesis; neuronal differentiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation of splice-insert dependent binding mechanism\",\n      \"pmids\": [\"25908590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-1RAcP knockout mice lack IL-1β-induced neuroendocrine responses (corticosterone elevation), immune suppression (splenocyte proliferation depression), and brain/plasma IL-6 induction, demonstrating that IL-1RAcP is necessary for centrally mediated neuroendocrine and immune effects of central IL-1β in vivo.\",\n      \"method\": \"IL-1RAcP knockout mouse model; intracerebroventricular IL-1β injection; corticosterone ELISA, splenocyte proliferation assay, IL-6 measurement\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple in vivo phenotypic readouts\",\n      \"pmids\": [\"11024543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Molecular modeling and experimental validation with IL-1β peptides, antibodies, and mutated IL-1β proteins supported a 'BACK model' in which IL-1RAcP establishes contacts with the back of IL-1R(I) wrapped around IL-1β, providing a structural model for the IL-1β/IL-1R(I)/IL-1RAcP ternary complex.\",\n      \"method\": \"Homology modeling, computational docking, experimental validation with IL-1β peptides and mutants\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 4/3 — computational model with partial experimental support but no direct structural determination\",\n      \"pmids\": [\"11418113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Antisense oligonucleotide (AON)-mediated skipping of exon 9 (which encodes the transmembrane domain) of IL-1RAcP pre-mRNA generates a novel secreted soluble Δ9IL-1RAcP protein; this soluble form is secreted and substantially inhibits IL-1 signaling in vitro, and a single 10 mg/kg dose induces >90% exon skipping in mouse liver for at least 5 days in vivo.\",\n      \"method\": \"Antisense oligonucleotide exon-skipping, RT-PCR, Western blot for secreted protein, IL-1 signaling inhibition assays in vitro and in vivo\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo exon skipping with functional inhibition demonstrated\",\n      \"pmids\": [\"23340324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL1RAP physically interacts with and mediates signaling through the receptor tyrosine kinases FLT3 and c-KIT in AML cells, extending its function beyond the IL-1 receptor pathway; IL1RAP targeting via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo without perturbing normal hematopoietic function.\",\n      \"method\": \"Co-immunoprecipitation of IL1RAP with FLT3 and c-KIT; RNAi knockdown; CRISPR deletion; antibody treatment; in vitro and xenograft in vivo models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP with two RTKs, multiple loss-of-function approaches (RNAi + CRISPR + antibody), in vivo validation\",\n      \"pmids\": [\"29773641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRSF10 splicing factor modulates the alternate terminator of IL-1RAP exon 13 to increase production of the membrane form of IL1RAP (mIL1RAP); mIL1RAP upregulates CD47 expression via NF-κB activation, inhibiting macrophage phagocytosis and promoting tumor immune evasion in cervical cancer.\",\n      \"method\": \"Alternative splicing analysis, SRSF10 overexpression/knockdown, NF-κB reporter assay, macrophage phagocytosis assays, rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanism linking splicing factor to specific isoform to NF-κB to CD47, multiple experimental approaches\",\n      \"pmids\": [\"29429992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A blocking monoclonal antibody to IL-1R3 (IL-1RAP) specifically inhibits signaling via IL-1, IL-33, and IL-36 pathways in vitro and significantly attenuates disease in three distinct in vivo models (crystal-induced peritonitis, allergic airway inflammation, and psoriasis), confirming IL-1RAP's essential shared co-receptor role across six IL-1 family cytokines.\",\n      \"method\": \"Blocking mAb to human and mouse IL-1R3; in vitro cytokine signaling assays; three in vivo disease models with histology and functional readouts\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive blocking antibody approach across multiple in vitro and in vivo contexts, replicated across disease models\",\n      \"pmids\": [\"31427775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL1RAP binds the cell-surface system Xc- transporter (cystine/glutamate antiporter) to enhance exogenous cystine uptake, replenishing cysteine and glutathione to maintain redox homeostasis and anoikis resistance; under cystine depletion, IL1RAP also induces cystathionine gamma lyase (CTH) to activate the transsulfuration pathway for de novo cysteine synthesis. IL1RAP inactivation triggers anoikis and impedes metastatic dissemination of Ewing sarcoma cells.\",\n      \"method\": \"Proteomic screens, co-immunoprecipitation of IL1RAP with system Xc- transporter, cystine uptake assays, CTH expression analysis, anoikis assays, in vivo metastasis models\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical interaction identified, multiple functional assays, in vivo validation\",\n      \"pmids\": [\"34021002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL1β stimulation of IL1RAP-expressing AML cells via the p38 MAPK and NF-κB signaling pathways induces an inflammatory secretome of chemokines that suppresses normal hematopoiesis; the IL1β receptor antagonist Anakinra can reverse this effect, while IL1β-induced signaling is dispensable for AML cell proliferation itself.\",\n      \"method\": \"IL1β stimulation, IL1RAP knockdown, Anakinra treatment, co-culture with mesenchymal stem cells, NF-κB and p38 MAPK pathway analysis, colony formation assays\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway analysis with pharmacological and genetic inhibition, functional hematopoiesis co-culture system\",\n      \"pmids\": [\"33121233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL1RAP knockdown in AML cells reduced colony-forming capacity; stimulation with IL-1β activated p38 MAPK and NF-κB signaling pathways to induce chemokines but was dispensable for AML cell proliferation and NF-κB-driven survival, suggesting IL1RAP promotes AML colony formation through non-IL-1 mechanisms at the stem cell level.\",\n      \"method\": \"IL1RAP knockdown by lentiviral shRNA, colony formation assays, p38/NF-κB signaling analysis, IL-1β stimulation\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown with defined cellular phenotype and pathway analysis\",\n      \"pmids\": [\"33121233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Anti-IL1RAP antibody-mediated selective killing of AML stem cell candidates (CD34+CD38- cells) was demonstrated, with the antibody achieving leukemia-selective killing via antibody-dependent cell-mediated cytotoxicity (ADCC); IL1RAP-intermediate and high AML samples show higher IL1RAP expression in CD34+CD38- cells compared to corresponding normal cells.\",\n      \"method\": \"Flow cytometry, monoclonal antibody generation with isotype switching, ADCC killing assays on primary AML samples including stem cell populations\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional antibody-mediated killing assay with primary patient material at stem cell level\",\n      \"pmids\": [\"23479569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Primitive (CD34+CD38-) CML cells, in contrast to corresponding normal cells, express a functional IL-1 receptor complex and respond to IL-1 with NF-κB activation and marked proliferation; IL1RAP antibodies that inhibit IL-1 signaling blocked these effects, and in vivo administration in xenograft mice produced therapeutic effects mediated by effector cells.\",\n      \"method\": \"NF-κB activation assays, proliferation assays, IL1RAP-blocking antibody treatment, in vivo xenograft model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional receptor complex demonstrated in primary cells, in vitro and in vivo corroboration\",\n      \"pmids\": [\"27621309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Biallelic compound heterozygous variants in IL1RAP (p.I175T and p.R221H) were identified in patients with steroid-sensitive nephrotic syndrome; reconstitution experiments showed that IL-1R with variant IL1RAP subunit had impaired binding ability and low reactivity to IL-1β, confirming these are loss-of-function mutations that impair IL-1 signaling. IL-1rap−/− mice showed reduced myeloid-derived suppressor cells in the kidney.\",\n      \"method\": \"Whole-exome sequencing, cytokine production assays from patient PBMCs, reconstitution of mutant IL1RAP on hematopoietic cell line with IL-1β binding/signaling assays, IL-1rap KO mouse analysis\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — human genetic variants validated by reconstitution with functional assays, KO mouse corroboration\",\n      \"pmids\": [\"31954058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Arg286 residue of IL-1RAcP is a key mediator of ternary IL-1β/IL-1R1/IL-1RAcP complex formation; inhibitory peptides based on the native IL-1RAcP sequence targeting the Arg286 region had an IC50 of 304 pM in a pull-down complex formation assay and reduced IL-1β signaling by 90% at 2 μM in cells; anti-IL-1RAcP mAbs targeting Arg286 reduced inflammatory cell influx in a mouse OA model.\",\n      \"method\": \"Molecular modeling, pull-down assay for complex formation, peptide inhibitor IC50 determination, IL-1β signaling cell assays, in vivo OA mouse model\",\n      \"journal\": \"Frontiers in chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — key residue identified by modeling validated by peptide inhibition and in vivo functional assay\",\n      \"pmids\": [\"33614593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL1RAP knockdown in LPS-stimulated normal human astrocytes suppressed reactive astrogliosis and promoted neuronal cell proliferation; IL1RAP overexpression promoted astrocyte proliferation and LPS-induced NF-κB activation, decreased PTEN protein levels, and increased phosphorylation of Akt and mTOR, indicating IL1RAP activates the PI3K/Akt/mTOR pathway in astrocytes.\",\n      \"method\": \"IL1RAP knockdown and overexpression in astrocytes, NF-κB activation assays, Western blot for PTEN/Akt/mTOR phosphorylation, conditioned medium transfer to neurons, viability/apoptosis assays\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, bidirectional genetic manipulation with pathway analysis but limited mechanistic depth\",\n      \"pmids\": [\"36502418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A novel nonsense mutation c.1324C>T (R442*) in IL1RAP identified in a schizophrenia family is a loss-of-function mutation; IL1RAP knockdown by lentiviral shRNA suppressed axon and dendrite growth in cultured mouse cortical neurons, effects rescued by wild-type but not R442* mutant IL1RAP; the mutant also inhibited IL-1β-induced JNK phosphorylation and partially inhibited NF-κB nuclear translocation.\",\n      \"method\": \"Whole-exome sequencing, lentiviral shRNA knockdown in cortical neurons, rescue experiments with WT vs. mutant construct, morphological analysis, JNK phosphorylation assay, NF-κB translocation assay\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function in neurons with multiple signaling readouts; single lab\",\n      \"pmids\": [\"35181481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL1RAP blockade in a xenograft PDAC model required the presence of cancer-associated fibroblasts (CAFs) for antitumor effects; mechanistically, IL-1 stimulation induced CAFs to secrete chemokines that recruited neutrophils and monocytes, an effect blocked by anti-IL1RAP antibody nadunolimab; IL-1-stimulated CAF conditioned media sustained neutrophils with tissue-invasion phenotype, reversed by nadunolimab.\",\n      \"method\": \"Xenograft model with co-transplantation of PDAC cells and CAFs, RNA sequencing, migration assays, cytokine/chemokine profiling, neutrophil phenotyping\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and ex vivo experiments with RNA-seq mechanistic analysis demonstrating CAF-dependent IL1RAP role in neutrophil recruitment\",\n      \"pmids\": [\"39694705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL1RAP ubiquitination by the ITCH E3 ligase increases in the presence of ginsenoside Rd; increased IL1RAP ubiquitination blocks IL-1β stimulation of NF-κB, suppressing inflammatory responses in chondrocytes; bioinformatics identified NEDD4, CBL, CBLB, CBLC, and ITCH as candidate E3 ligases targeting IL1RAP.\",\n      \"method\": \"Immunoprecipitation for ubiquitination, Western blot for ITCH and IL1RAP, RT-PCR, NF-κB signaling assay, CCK-8 viability, flow cytometry\",\n      \"journal\": \"Brazilian journal of medical and biological research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, immunoprecipitation with limited mechanistic follow-up; ITCH as E3 for IL1RAP not rigorously proven\",\n      \"pmids\": [\"31411316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPδ mini-exon B (meB) regulates excitatory synapses in dentate gyrus granule cells through a cell-type-specific trans-synaptic interaction with IL1RAP; Ptprd-meB+/- mice show decreased postsynaptic IL1RAP levels and decreased excitatory synaptic transmission in dentate gyrus granule cells; IL1RAP-mutant mice show the same decrease, placing IL1RAP downstream of PTPδ-meB in excitatory synapse regulation.\",\n      \"method\": \"Ptprd-meB knock-in mice, proteomic analysis of postsynaptic density, electrophysiology, IL1RAP knockout mice, behavioral testing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic epistasis (Ptprd-meB and IL1RAP KO mice show same synaptic phenotype), proteomics, and electrophysiology\",\n      \"pmids\": [\"40360498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL1RAP is overexpressed in TET2-mutant clonal hematopoiesis (CH) clones; genetic knockdown of IL1RAP inhibited mutant clone growth in vivo in a mouse model, identifying IL1RAP as a driver of inflammation-dependent CH clonal expansion.\",\n      \"method\": \"Mouse CH model (Tet2-mutant), lentiviral IL1RAP knockdown, in vivo clonal competition assay\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic knockdown with defined clonal expansion phenotype; single lab\",\n      \"pmids\": [\"41031953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Global Il1rap deficiency reduces hyperphosphorylated tau (pS202-AT8 and pT231-AT180) in a LPS-induced mouse model of systemic inflammation, while neuron-specific IL-1RAcPb isoform deficiency specifically increased total tau levels, demonstrating isoform-specific roles of IL-1RAcP in regulating tau phosphorylation downstream of IL-1R1 signaling.\",\n      \"method\": \"Global and neuron-specific conditional Il1rap knockout mice, LPS systemic inflammation model, phospho-tau immunoblotting with AT8 and AT180 antibodies\",\n      \"journal\": \"ASN neuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two genetic mouse models with specific tau phosphorylation readouts; single lab study\",\n      \"pmids\": [\"41353558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The structure-based antibody IgG26AW simultaneously blocks IL-1β binding to both IL-1RI and prevents IL-1RAcP recruitment; SPR experiments confirmed that IL-1β bound by IgG26AW cannot bind either IL-1RI or IL-1RAcP; crystal structure of 26-Fab/IL-1β complex shows the epitope overlaps with the binding sites for both receptor subunits.\",\n      \"method\": \"Crystal structure of antibody-IL-1β complex, SPR binding competition assays, in vivo IL-6 induction assay, xenograft tumor models\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus SPR validation of dual blocking mechanism\",\n      \"pmids\": [\"33359099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL1RAP is internalized following exposure to specific antibodies, as demonstrated by antibody internalization assays on primary NKt-AML specimens, suggesting IL1RAP undergoes receptor-mediated internalization upon antibody binding, supporting its suitability as an antibody-drug conjugate target.\",\n      \"method\": \"Surface proteome enrichment, single-cell RNA-seq, antibody internalization assay on primary AML samples\",\n      \"journal\": \"Biomarker research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — internalization assay reported but molecular mechanism of internalization not determined; single study\",\n      \"pmids\": [\"40229904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"EWSR1-ETS oncofusions (Ewing sarcoma) directly induce surface expression of IL1RAP; additionally, NPM-ALK (in ALCL) and ETV6-NTRK3 fusions in multiple tumor types also induce IL1RAP expression, rendering these malignancies vulnerable to IL1RAP-targeting ADCs, demonstrating that diverse oncofusions converge on IL1RAP upregulation.\",\n      \"method\": \"Oncofusion expression studies, proteomic/transcriptomic validation, xenograft ADC treatment models, syngeneic tumor models, non-human primate toxicity\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional link between oncofusions and IL1RAP surface expression established in multiple models; single lab but multiple independent fusion oncogenes tested\",\n      \"pmids\": [\"41973074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-1RAP Ser566 phosphorylation (p-S566-IL-1RAP) is increased in the brain-gut axis of IBS-like stressed mice, correlating with elevated GFAP and IL-1β levels and increased intestinal epithelial permeability, implicating IL-1RAP phosphorylation at S566 in stress-induced neuroinflammatory signaling along the brain-gut axis.\",\n      \"method\": \"Phosphoproteomics, Western blot, immunofluorescence, ELISA for phospho-S566-IL-1RAP in multiple tissues; intestinal permeability assay\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — phosphoproteomic discovery with Western blot validation, but functional role of the specific phosphorylation not demonstrated mechanistically\",\n      \"pmids\": [\"39006851\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL1RAP (IL-1RAcP/IL-1R3) functions as an essential shared coreceptor that is recruited to primary ligand-bound IL-1 family receptors (IL-1R1, ST2, IL-36R) to form heterotrimeric signaling complexes that stably assemble with MyD88 and IRAK-4 within seconds of cytokine stimulation, activating NF-κB and MAPK pathways; its surface levels are negatively regulated by MARCH8-mediated K48-linked polyubiquitination at Lys512; it also engages in trans-synaptic adhesion with PTPδ in a splice-code-dependent manner to regulate excitatory synapse differentiation; and in cancer cells it potentiates oncogenic signaling through physical interactions with FLT3 and c-KIT, and suppresses anoikis by binding the system Xc- cystine transporter to maintain cysteine and glutathione pools.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL1RAP (IL-1R3/IL-1RAcP) is a shared coreceptor essential for signal transduction by multiple IL-1 family cytokines and also functions in trans-synaptic adhesion and oncogenic signaling. It is recruited within seconds to ligand-bound primary receptors (IL-1R1, ST2, IL-1Rrp2/IL-36R) to form heterotrimeric complexes that assemble with MyD88 and IRAK-4, activating NF-κB and MAPK cascades; blocking IL-1RAP with antibodies simultaneously inhibits IL-1, IL-33, and IL-36 signaling in vitro and in vivo [PMID:9065432, PMID:14734551, PMID:17507369, PMID:31427775]. Beyond innate immunity, IL1RAP engages PTPδ in a splice-code-dependent manner to regulate excitatory synapse differentiation in the dentate gyrus [PMID:25908590, PMID:40360498], physically interacts with the receptor tyrosine kinases FLT3 and c-KIT to potentiate oncogenic signaling in AML [PMID:29773641], and binds the system Xc⁻ cystine transporter to maintain redox homeostasis and anoikis resistance in Ewing sarcoma [PMID:34021002]. Surface levels of IL1RAP are negatively regulated by MARCH8-mediated K48-linked polyubiquitination at Lys512, targeting it for proteasomal degradation [PMID:22904187].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that IL-1RAcP is indispensable for IL-1 signaling resolved the long-standing question of why cells expressing IL-1RI alone failed to respond to IL-1β.\",\n      \"evidence\": \"Complementation by IL-1RAcP cDNA transfection into non-responsive EL-4 D6/76 cells restored IRAK, SAPK, NF-κB activation and IL-2 mRNA synthesis\",\n      \"pmids\": [\"9065432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IL-1RAcP engagement with IL-1RI not yet determined\", \"Whether IL-1RAcP serves other IL-1 family members unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"In vivo confirmation that IL-1RAcP is required for centrally mediated neuroimmune responses established its physiological necessity beyond cell-based systems.\",\n      \"evidence\": \"IL-1RAcP knockout mice lacked IL-1β-induced corticosterone elevation, splenocyte suppression, and IL-6 induction after intracerebroventricular injection\",\n      \"pmids\": [\"11024543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific and isoform-specific roles of IL-1RAcP in the brain not dissected\", \"Redundancy with other accessory proteins not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that IL-1RAcP is a shared coreceptor for IL-1F6/F8/F9 (IL-36 subfamily) via IL-1Rrp2 expanded its role from a single receptor partner to a hub for multiple IL-1 family signaling axes.\",\n      \"evidence\": \"Anti-IL-1RAcP antibodies and dominant-negative constructs blocked NF-κB and MAPK activation by all three IL-36 cytokines\",\n      \"pmids\": [\"14734551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-1RAcP is required for all IL-1 family members (e.g., IL-33/ST2) not yet shown\", \"Stoichiometry of the ternary complex unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Proteomic dissection of the endogenous receptor complex revealed the kinetic hierarchy of assembly — IL-1RAcP binds within 15 seconds, MyD88 and IRAK-4 are stable partners, while IRAK-1 is transient — establishing the temporal logic of signal initiation.\",\n      \"evidence\": \"Endogenous IL-1RI immunoprecipitation followed by tandem mass spectrometry with time-course phosphorylation analysis\",\n      \"pmids\": [\"17507369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for the preferential stability of IRAK-4 vs. IRAK-1 in the complex unknown\", \"Post-translational modifications on IL-1RAcP within the complex not catalogued\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"SAXS-derived structures of IL-33/ST2/IL-1RAcP and IL-1β/IL-1R1/IL-1RAcP ternary complexes established a conserved architectural principle in which IL-1RAcP engages the ligand–receptor binary complex as a low-affinity coreceptor.\",\n      \"evidence\": \"SAXS analysis of both binary and ternary complexes combined with NMR structure of IL-33\",\n      \"pmids\": [\"19836339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of complete ternary complex not yet available\", \"How TIR domain juxtaposition drives MyD88 recruitment not structurally resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of MARCH8 as an E3 ligase that targets IL1RAP Lys512 for K48-linked polyubiquitination revealed a dedicated negative regulatory mechanism controlling receptor surface levels and downstream NF-κB/MAPK signaling.\",\n      \"evidence\": \"MARCH8 overexpression/knockdown, co-IP, K48 ubiquitin linkage analysis, and Lys512 mutagenesis\",\n      \"pmids\": [\"22904187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological stimuli that regulate MARCH8 activity toward IL1RAP not identified\", \"Contribution of other candidate E3 ligases (ITCH, NEDD4) not rigorously established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structures of PTPδ–IL-1RAcP complexes revealed a splice-code-dependent trans-synaptic adhesion mechanism, establishing that IL1RAP has a neuronal function independent of cytokine signaling.\",\n      \"evidence\": \"X-ray crystallography of PTPδ–IL-1RAcP complex with structure-guided mutagenesis and synaptic differentiation assays\",\n      \"pmids\": [\"25908590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream postsynaptic signaling pathway engaged by PTPδ–IL-1RAcP interaction not defined\", \"Whether IL-1 cytokine signaling and synaptic adhesion are coordinated or independent not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that IL1RAP physically associates with FLT3 and c-KIT extended its coreceptor function beyond the IL-1 family to receptor tyrosine kinases, explaining its oncogenic role in AML independently of IL-1 stimulation.\",\n      \"evidence\": \"Reciprocal co-IP of IL1RAP with FLT3 and c-KIT; RNAi, CRISPR deletion, and antibody targeting in vitro and in xenograft models\",\n      \"pmids\": [\"29773641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IL1RAP interaction with FLT3/c-KIT unknown\", \"Whether IL1RAP modulates RTK kinase activity directly or acts as a scaffolding coreceptor not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A pan-IL-1R3 blocking antibody validated in three disease models (peritonitis, airway inflammation, psoriasis) confirmed that therapeutic blockade of this single shared coreceptor simultaneously suppresses IL-1, IL-33, and IL-36 pathways.\",\n      \"evidence\": \"Blocking mAb against human and mouse IL-1R3 tested in vitro signaling assays and three in vivo disease models\",\n      \"pmids\": [\"31427775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term immunosuppressive consequences of pan-IL-1R3 blockade not assessed\", \"Whether IL-1R3 blockade affects neuronal IL1RAP functions not examined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of biallelic loss-of-function IL1RAP variants in patients with steroid-sensitive nephrotic syndrome established that human IL1RAP deficiency impairs IL-1 binding/signaling and affects kidney myeloid cell homeostasis.\",\n      \"evidence\": \"WES of patient families; reconstitution of mutant IL1RAP showing impaired IL-1β binding; IL-1rap KO mice with reduced kidney myeloid-derived suppressor cells\",\n      \"pmids\": [\"31954058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional patients carry IL1RAP mutations not reported\", \"Full spectrum of immunological consequences of human IL1RAP deficiency not characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The discovery that IL1RAP binds the system Xc⁻ cystine transporter to maintain glutathione homeostasis and resist anoikis revealed a cytokine-independent metabolic function directly relevant to metastasis.\",\n      \"evidence\": \"Proteomic screen identifying system Xc⁻ as IL1RAP interactor; co-IP, cystine uptake assays, anoikis assays, and in vivo metastasis models in Ewing sarcoma\",\n      \"pmids\": [\"34021002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL1RAP modulates system Xc⁻ transport activity directly or via scaffolding not determined\", \"Generalizability beyond Ewing sarcoma cells not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of Arg286 as a key interface residue for ternary complex formation provided a druggable epitope, with peptide inhibitors achieving picomolar IC50 values for blocking IL-1β signaling.\",\n      \"evidence\": \"Molecular modeling validated by pull-down inhibition assays (IC50 304 pM) and in vivo OA mouse model\",\n      \"pmids\": [\"33614593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Crystal structure of peptide–IL-1RAcP interface not solved\", \"In vivo pharmacokinetics and specificity of Arg286-targeting peptides not fully characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A nonsense mutation (R442*) in IL1RAP identified in a schizophrenia family impaired neurite outgrowth and IL-1β-induced JNK/NF-κB signaling, linking IL1RAP loss-of-function to neuronal morphogenesis and psychiatric disease.\",\n      \"evidence\": \"WES in family; lentiviral knockdown and rescue in cortical neurons with morphological and signaling readouts\",\n      \"pmids\": [\"35181481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between IL1RAP R442* and schizophrenia not established by linkage or large cohort\", \"Whether synaptic adhesion (PTPδ-dependent) or cytokine signaling mediates the neuronal phenotype not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic epistasis experiments showed that PTPδ mini-exon B and IL1RAP regulate the same excitatory synapses in dentate gyrus granule cells, placing IL1RAP as the postsynaptic effector downstream of presynaptic PTPδ splice-variant signaling.\",\n      \"evidence\": \"Ptprd-meB knock-in mice and IL1RAP KO mice show identical decreases in excitatory transmission; postsynaptic density proteomics and electrophysiology\",\n      \"pmids\": [\"40360498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Postsynaptic signaling cascade linking IL1RAP to synapse maintenance not identified\", \"Whether other PTPδ ligands compensate in IL1RAP-null synapses not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"IL1RAP drives clonal expansion of TET2-mutant hematopoietic clones, establishing it as a functional mediator of inflammation-dependent clonal hematopoiesis beyond its role in overt leukemia.\",\n      \"evidence\": \"IL1RAP knockdown in Tet2-mutant mouse CH model with in vivo clonal competition assay\",\n      \"pmids\": [\"41031953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IL1RAP drives CH through IL-1 signaling, FLT3/c-KIT interaction, or another mechanism not resolved\", \"Human validation of IL1RAP as CH driver not yet reported\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IL1RAP coordinates its multiple independent functions — cytokine coreceptor, trans-synaptic adhesion molecule, RTK partner, and metabolic transporter regulator — remains unresolved, and no structural model integrates these distinct interaction modes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural model of IL1RAP engaging different partner classes\", \"Isoform-specific (membrane vs. soluble vs. neuronal IL-1RAcPb) contributions to each function not systematically mapped\", \"Whether simultaneous engagement of multiple partners occurs on the same cell not tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 9, 12]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [5, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 9, 11, 15]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 4, 6, 11, 16, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 9, 10, 19]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5, 20, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 13, 15, 24, 28]}\n    ],\n    \"complexes\": [\n      \"IL-1β/IL-1R1/IL-1RAcP ternary complex\",\n      \"IL-33/ST2/IL-1RAcP ternary complex\",\n      \"IL-36/IL-1Rrp2/IL-1RAcP ternary complex\",\n      \"PTPδ/IL-1RAcP trans-synaptic complex\"\n    ],\n    \"partners\": [\n      \"IL1R1\",\n      \"IL1RL1\",\n      \"IL1RL2\",\n      \"MYD88\",\n      \"IRAK4\",\n      \"FLT3\",\n      \"KIT\",\n      \"PTPRD\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}