{"gene":"IL1RAP","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1997,"finding":"IL-1RAcP (IL1RAP) is an indispensable co-receptor component of the IL-1 receptor signaling complex: transfection of IL-1RAcP into IL-1 non-responder cells (EL-4 D6/76, which express IL-1RI but lack IL-1RAcP) was sufficient to restore IL-1-induced activation of IRAK, stress-activated protein kinases, NF-κB and IL-1 NF nuclear translocation, and IL-2 mRNA induction.","method":"cDNA transfection into IL-1 non-responder cell line, IRAK kinase assay, SAPK/JNK activation assay, nuclear translocation assay, mRNA induction","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — functional reconstitution in defined non-responder cell line with multiple orthogonal readouts; foundational mechanism paper replicated broadly","pmids":["9065432"],"is_preprint":false},{"year":2004,"finding":"IL-1F6, IL-1F8, and IL-1F9 (novel IL-1 family cytokines) signal through the orphan receptor IL-1Rrp2 AND require IL-1RAcP as a co-receptor: antibodies against IL-1RAcP and transfection of cytoplasmically-deleted (dominant-negative) IL-1RAcP blocked NF-κB activation by all three cytokines; full signaling activated NF-κB, JNK, ERK1/2, IL-8 promoter, and IL-6 secretion.","method":"Blocking antibodies against IL-1RAcP, dominant-negative cytoplasmic deletion transfection, NF-κB reporter assay, MAPK activation assay, cytokine secretion","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (antibody blockade + dominant-negative construct + multiple cell lines), multiple readouts","pmids":["14734551"],"is_preprint":false},{"year":2000,"finding":"IL-1RAcP is required in vivo for centrally mediated neuroendocrine and immune responses to IL-1β: IL-1RAcP knockout mice fail to show IL-1β-induced plasma corticosterone elevation, splenocyte proliferation depression, or increases in plasma/brain IL-6 following intracerebroventricular IL-1β injection.","method":"IL-1RAcP knockout mice, intracerebroventricular injection, corticosterone ELISA, splenocyte proliferation assay, IL-6 measurement","journal":"Journal of neuroimmunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with multiple defined physiological readouts, single lab","pmids":["11024543"],"is_preprint":false},{"year":2007,"finding":"The endogenous IL-1RI signaling complex formed after IL-1 binding stably contains IL-1RAcP, MyD88, and IRAK-4 (p60); IRAK-4 is the earliest phosphorylated component. IRAK-1 (p90) is only transiently associated. IL-1RAcP, MyD88, and IRAK-4 associate with the liganded receptor within 15 seconds and remain stably associated.","method":"Immunoprecipitation of endogenous IL-1RI complex followed by tandem mass spectrometry, in vitro phosphorylation assay, SDS-PAGE mobility shift","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry identification of endogenous complex with kinetic analysis; single lab but rigorous biochemical characterization","pmids":["17507369"],"is_preprint":false},{"year":2001,"finding":"Computational/experimental modeling of the IL-1RAcP interaction with the IL-1β/IL-1R(I) complex supports a 'BACK' model in which IL-1RAcP contacts the back of IL-1RI wrapped around IL-1β; this was validated by IL-1β peptide/antibody experiments and mutated IL-1β proteins.","method":"Homology modeling, computational docking, validation with IL-1β peptides, antibody blocking experiments, and mutated IL-1β proteins","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 4 / Weak — primarily computational modeling with limited experimental validation using indirect readouts","pmids":["11418113"],"is_preprint":false},{"year":2009,"finding":"IL-33 forms a heterotrimeric signaling complex with its primary receptor ST2 and the coreceptor IL-1RAcP; solution structure of IL-33 was solved by NMR and SAXS was used to characterize the IL-33/ST2/IL-1RAcP and IL-1β/IL-1R1/IL-1RAcP ternary complexes, proposing a general model of IL-1 family ternary signaling complex architecture.","method":"NMR structure determination, small-angle X-ray scattering (SAXS), biochemical binding assays","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure + SAXS validation of ternary complex architecture; single lab but multiple orthogonal structural methods","pmids":["19836339"],"is_preprint":false},{"year":2012,"finding":"The E3 ubiquitin ligase MARCH8 negatively regulates IL-1β-induced NF-κB signaling by physically interacting with IL1RAP and targeting its Lys512 for K48-linked polyubiquitination, leading to IL1RAP degradation. MARCH8 overexpression inhibits IL-1β-induced NF-κB and MAPK activation; MARCH8 knockdown has the opposite effect.","method":"Co-immunoprecipitation, ubiquitination assay with K48-linkage-specific analysis, site-directed mutagenesis (Lys512), overexpression and knockdown, NF-κB reporter assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal Co-IP, site-specific mutagenesis identifying Lys512, K48-linkage characterization, functional rescue; single lab with multiple orthogonal methods","pmids":["22904187"],"is_preprint":false},{"year":2013,"finding":"Antisense oligonucleotide (AON)-mediated skipping of exon 9 of IL-1RAcP (which encodes the transmembrane domain) produces a novel soluble, secreted form of IL-1RAcP (Δ9IL-1RAcP) that substantially inhibits IL-1 signaling in vitro; a single 10 mg/kg AON injection induced 90% exon skipping in mouse liver for at least 5 days.","method":"AON-mediated exon skipping in vitro and in vivo, RT-PCR, Western blot for secreted protein, IL-1 signaling inhibition assay","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo exon-skipping with demonstrated production of soluble protein and functional inhibition; single lab","pmids":["23340324"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of PTPδ in complex with IL-1RAcP and IL1RAPL1 reveal that the first Ig domain of IL-1RAcP binds to the second and third Ig domains of PTPδ in a splice-insert-dependent manner; the second splice insert of PTPδ acts as an adjustable linker positioning Ig2/Ig3 for simultaneous interaction with IL-1RAcP or IL1RAPL1 Ig1. This trans-synaptic interaction mediates synapse differentiation.","method":"X-ray crystallography of PTPδ/IL-1RAcP and PTPδ/IL1RAPL1 complexes, structure-function analysis of splice inserts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures of protein complexes with functional domain mapping; single lab but rigorous structural biology","pmids":["25908590"],"is_preprint":false},{"year":2018,"finding":"IL1RAP physically interacts with FLT3 and c-KIT receptor tyrosine kinases in AML cells, mediating signaling and pro-proliferative effects through these receptors in addition to its known role in IL-1 receptor signaling. Targeting IL1RAP via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo without perturbing healthy hematopoietic function.","method":"Co-immunoprecipitation demonstrating IL1RAP-FLT3 and IL1RAP-c-KIT interaction, RNA interference, genetic deletion, antibody treatment, in vitro and in vivo AML models","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for novel interaction partners, loss-of-function with defined phenotype; single lab with multiple approaches","pmids":["29773641"],"is_preprint":false},{"year":2018,"finding":"IL1RAP alternative splicing is regulated by the splicing factor SRSF10 (upregulated by HPV E6/E7 via E2F1): SRSF10 promotes use of an alternate terminator in IL1RAP exon 13 to increase production of the membrane form of IL1RAP (mIL1RAP). mIL1RAP activates NF-κB, which upregulates CD47 ('don't eat me' signal) to inhibit macrophage phagocytosis.","method":"RNA splicing assay, RT-PCR for isoform switching, NF-κB reporter, CD47 expression analysis, macrophage phagocytosis assay, SRSF10 knockdown/overexpression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway defined with splicing assay, NF-κB reporter, and functional phagocytosis readout; single lab","pmids":["29429992"],"is_preprint":false},{"year":2019,"finding":"A single blocking monoclonal antibody against IL-1R3/IL1RAP simultaneously inhibits signaling by IL-1α, IL-1β, IL-33, IL-36α, IL-36β, and IL-36γ in vitro and in vivo, confirming IL1RAP as the shared co-receptor for all three signaling pathways (IL-1R1, ST2/IL-1RL1, and IL-36R).","method":"Blocking monoclonal antibody in vitro signaling assays, in vivo mouse models (crystal-induced peritonitis, allergic airway inflammation, psoriasis)","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — single blocking antibody tested across three distinct in vivo disease models and multiple cytokine pathways; multiple labs/approaches","pmids":["31427775"],"is_preprint":false},{"year":2021,"finding":"IL1RAP binds the cell-surface system Xc- cystine/glutamate antiporter (SLC3A2) to enhance exogenous cystine uptake and replenish glutathione. Under cystine depletion, IL1RAP induces cystathionine gamma lyase (CTH) to activate the transsulfuration pathway for de novo cysteine synthesis, thereby maintaining redox homeostasis and suppressing anoikis in Ewing sarcoma cells.","method":"Proteomic screens, IL1RAP inactivation (loss-of-function), co-immunoprecipitation with SLC3A2, cystine uptake assay, glutathione measurement, CTH expression analysis, anoikis assay, metastasis models","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — proteomic screen plus functional validation, Co-IP demonstrating SLC3A2 interaction, metabolic assays, in vivo metastasis model; single lab with multiple orthogonal methods","pmids":["34021002"],"is_preprint":false},{"year":2019,"finding":"IL1RAP (IL1R3) is required for IL-1-induced NF-κB activation and proliferation in primitive CML cells (CD34+CD38-): antibodies blocking IL-1RAP signaling inhibit these effects. In vivo administration of IL1RAP antibodies in CML xenograft mice produced therapeutic effects mediated by effector cells (ADCC).","method":"NF-κB activation assay, proliferation assay, IL1RAP-blocking antibodies, CML xenograft mouse model, flow cytometry","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional IL-1/NF-κB signaling established in primary CML cells with antibody blocking and in vivo model; single lab","pmids":["27621309"],"is_preprint":false},{"year":2022,"finding":"A nonsense mutation (c.1324C>T; R442*) in IL1RAP identified in schizophrenia patients is a loss-of-function mutation: lentiviral shRNA knockdown of IL1RAP suppressed axon and dendrite growth in mouse cortical neurons; this was rescued by wild-type but not R442* IL1RAP. Overexpression of R442* inhibited neuronal growth and IL-1β-induced JNK phosphorylation, and partially blocked NF-κB nuclear translocation in HePG2 cells.","method":"Whole-exome sequencing, lentiviral shRNA knockdown, wild-type rescue, mutant overexpression, JNK phosphorylation assay, NF-κB nuclear translocation assay, cortical neuron culture","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue with WT vs. mutant, multiple signaling readouts; single lab","pmids":["35181481"],"is_preprint":false},{"year":2020,"finding":"Biallelic IL1RAP variants (p.I175T and p.R221H) in patients with steroid-sensitive nephrotic syndrome cause impaired IL-1R complex function: peripheral blood mononuclear cells from patients showed markedly lower cytokine production upon IL-1β stimulation; reconstitution of IL-1R with variant IL1RAP subunits showed impaired IL-1β binding and low reactivity.","method":"Whole-exome sequencing, cytokine production assay from patient PBMCs, reconstitution of IL-1R complex in hematopoietic cell line with variant IL1RAP, binding assay","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution assay in cell line plus primary patient cell data; single lab","pmids":["31954058"],"is_preprint":false},{"year":2021,"finding":"Arg286 of IL-1RAcP is a key mediator of ternary IL-1β/IL-1R1/IL-1RAcP complex formation: molecular modeling identified Arg286 as a high-energy interaction mediator; inhibitory peptides based on 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 cell models; anti-IL-1RAcP mAbs targeting Arg286 reduced inflammatory cell influx in a mouse OA model.","method":"Molecular modeling, pull-down complex formation assay, cell-based IL-1β signaling assay with peptide inhibitors, anti-IL-1RAcP monoclonal antibody in mouse OA model","journal":"Frontiers in chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — computational modeling validated by pull-down inhibition assay and cell signaling assay; single lab","pmids":["33614593"],"is_preprint":false},{"year":2021,"finding":"IL1RAP knockdown in AML cells reduced colony-forming capacity; IL-1β stimulation of IL1RAP-expressing AML cells via p38 MAPK and NF-κB induced a pro-inflammatory secretome of chemokines that suppressed normal hematopoietic stem/progenitor cell function; blockade with the IL-1 receptor antagonist Anakinra reversed this effect.","method":"IL1RAP knockdown, colony formation assay, IL-1β stimulation, NF-κB/p38 pathway analysis, cytokine/chemokine secretome profiling, co-culture with mesenchymal stem cells, Anakinra rescue experiment","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, pathway identification via p38/NF-κB, pharmacological rescue; single lab","pmids":["33121233"],"is_preprint":false},{"year":2019,"finding":"Ginsenoside Rd suppresses IL-1β-induced inflammation in intervertebral disc chondrocytes by increasing IL1RAP ubiquitination mediated by the E3 ligase ITCH; Rd increased intracellular ITCH levels and the amount of ITCH attached to IL1RAP, blocking NF-κB stimulation.","method":"Immunoprecipitation, Western blot, PCR, bioinformatics analysis of E3 ligase candidates, CCK-8 viability assay, flow cytometry","journal":"Brazilian journal of medical and biological research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying ITCH-IL1RAP interaction with functional assay; single lab, single method for the key interaction claim","pmids":["31411316"],"is_preprint":false},{"year":2025,"finding":"PTPδ-meB (mini-exon B of PTPδ/PTPRD) regulates excitatory synapses specifically in dentate gyrus granule cells in an IL1RAP-dependent manner: Ptprd-meB+/- mice showed decreased excitatory synaptic density and transmission in DG-GCs and reduced postsynaptic density levels of IL1RAP; IL1RAP-mutant mice showed the same decrease in excitatory synaptic transmission.","method":"Knock-in mutant mice (Ptprd-meB-/-), electrophysiology, proteomics of postsynaptic density, IL1RAP-mutant mouse phenotyping, behavioral analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with complementary mutant mouse lines, proteomics, and electrophysiology; single lab with multiple orthogonal methods","pmids":["40360498"],"is_preprint":false},{"year":2025,"finding":"Global and neuron-specific IL-1RAcP isoform deficiency reduces hyperphosphorylated tau (pS202/AT8 and pT231/AT180) levels in LPS-induced systemic inflammation mouse model; neuron-specific IL-1RAcPb deficiency specifically increased total tau levels, indicating isoform-specific roles in tau regulation.","method":"Il1rap global and neuron-specific knockout mice, LPS-induced systemic inflammation model, immunohistochemistry/Western blot for phospho-tau epitopes","journal":"ASN neuro","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic KO with defined tau phosphorylation readouts, but single lab and single paper","pmids":["41353558"],"is_preprint":false},{"year":2024,"finding":"IL1RAP blockade in PDAC inhibits IL-1-induced chemokine secretion from cancer-associated fibroblasts (CAFs), reducing recruitment of neutrophils and monocytes; media conditioned by IL-1-stimulated CAFs maintained a neutrophil tissue-invasion phenotype that was reversed by nadunolimab; antitumor effects of nadunolimab required CAF co-transplantation.","method":"CAF/PDAC xenograft co-transplantation model, RNA sequencing, migration assay, neutrophil phenotype analysis, IL1RAP-blocking antibody (nadunolimab)","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with defined mechanistic requirement for CAFs, RNA-seq pathway analysis, functional migration assay; single lab","pmids":["39694705"],"is_preprint":false},{"year":2022,"finding":"IL1RAP blockade reduces IL-1β-induced chemoresistance; chemotherapy induces IL-1α release from tumor cells and upregulates ICE (caspase-1) in tumor stroma, which processes IL-1β; IL-1α acts on stromal cells to further induce IL-1β secretion—effects disrupted by anti-IL1RAP antibody nadunolimab but not by anti-IL-1β antibody alone.","method":"NSCLC PDX model and syngeneic MC38 model, cytokine measurement, in vitro tumor cell line experiments, antibody blockade","journal":"Cancer immunology, immunotherapy : CII","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection of IL-1α/IL-1β crosstalk using anti-IL1RAP vs. anti-IL-1β with in vivo PDX validation; single lab","pmids":["36036818"],"is_preprint":false},{"year":2025,"finding":"IL1RAP is overexpressed in Tet2-mutant clonal hematopoiesis clones; genetic knockdown of IL1RAP inhibited mutant clone growth in vivo in particulate matter-exposed mice, identifying IL1RAP as a driver of inflammation-dependent CH expansion.","method":"IL1RAP knockdown in vivo, murine CH model with Tet2 mutation, flow cytometry for clonal expansion","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo knockdown with defined clonal expansion phenotype; single paper, single lab","pmids":["41031953"],"is_preprint":false},{"year":2025,"finding":"Structural basis for IL-36R activation by IL-36γ involves low-affinity IL-36R binding followed by high-affinity IL-1RAcP recruitment; the IL-1RAcP shared receptor is recruited to the IL-36R complex with high affinity following cytokine engagement; spesolimab acts as an allosteric antagonist of IL-36R.","method":"Cryo-EM/X-ray crystallography of IL-36R/IL-36γ and IL-36R/IL-37 complexes, binding affinity measurements, functional signaling assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural determination of ternary complex, preprint not yet peer-reviewed; single lab","pmids":[],"is_preprint":true},{"year":2024,"finding":"Ethanol drinking sex-dependently shifts mPFC IL-1RAcP isoform gene expression (brain-specific vs. peripheral isoform), which correlates with sex-dependent changes in IL-1β regulation of mPFC GABA synapses; this isoform shift is proposed to contribute to female mPFC resiliency and male susceptibility in AUD.","method":"Two-bottle choice ethanol drinking paradigm in C57BL/6J mice, mPFC IL-1RAcP isoform mRNA quantification, electrophysiology of GABA synapses","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mRNA expression analysis + electrophysiology, preprint, correlational; mechanistic link between isoform shift and synaptic phenotype not directly tested","pmids":[],"is_preprint":true}],"current_model":"IL1RAP (IL-1RAcP/IL1R3) is an essential shared co-receptor that forms stable heterotrimeric signaling complexes with multiple primary IL-1 family receptors (IL-1R1, ST2/IL-1RL1, IL-36R, and IL-1Rrp2), recruiting IRAK-4 and MyD88 to activate NF-κB and MAPK pathways; it is subject to negative regulation via MARCH8-mediated K48-linked polyubiquitination of Lys512 leading to degradation; in the nervous system, IL-1RAcP serves as a trans-synaptic adhesion partner for PTPδ (in a splice-insert-dependent manner) to regulate excitatory synapse formation; in cancer contexts, IL1RAP additionally physically interacts with FLT3, c-KIT, and the system Xc- transporter (SLC3A2) to mediate oncogenic signaling and anoikis resistance; and isoform-specific splicing of IL1RAcP modulates pathway activity in neurons and other cell types."},"narrative":{"mechanistic_narrative":"IL1RAP (IL-1RAcP) is an essential shared co-receptor that assembles ligand-induced heterotrimeric signaling complexes for the IL-1 cytokine family, converting cytokine engagement of primary receptors into intracellular activation of NF-κB and MAPK pathways [PMID:9065432, PMID:31427775]. Reconstitution in non-responder cells established IL-1RAcP as the indispensable second chain that restores IL-1-driven IRAK activation, SAPK/JNK signaling, and NF-κB nuclear translocation [PMID:9065432], and a single blocking antibody against IL1RAP simultaneously neutralizes signaling by IL-1α, IL-1β, IL-33, and the IL-36 cytokines, confirming its role as the common co-receptor across the IL-1R1, ST2/IL-1RL1, and IL-36R primary receptors [PMID:31427775, PMID:14734551]. Within the liganded complex, IL-1RAcP nucleates a stable signaling module containing MyD88 and IRAK-4, with IRAK-4 the earliest phosphorylated component [PMID:17507369]; structural work on the IL-1β/IL-1R1/IL-1RAcP and IL-33/ST2/IL-1RAcP ternary complexes defines the architecture by which the co-receptor wraps onto the primary-receptor/cytokine assembly [PMID:19836339]. Receptor abundance is restrained by MARCH8, an E3 ligase that interacts with IL1RAP and directs K48-linked polyubiquitination of Lys512 to drive its degradation and dampen NF-κB and MAPK output [PMID:22904187]. Beyond canonical cytokine sensing, IL-1RAcP acts as a trans-synaptic adhesion molecule whose first Ig domain engages PTPδ (PTPRD) in a splice-insert-dependent manner to organize excitatory synapse differentiation, a function required for normal synaptic transmission in dentate gyrus granule cells [PMID:25908590, PMID:40360498]. In cancer, IL1RAP physically associates with the receptor tyrosine kinases FLT3 and c-KIT in AML to sustain proliferative signaling [PMID:29773641] and with the system Xc- antiporter subunit SLC3A2 in Ewing sarcoma, where it enhances cystine uptake, induces the transsulfuration enzyme CTH, and suppresses anoikis [PMID:34021002]. Loss-of-function and biallelic IL1RAP variants in patients link the gene to schizophrenia, via impaired neurite growth and signaling [PMID:35181481], and to steroid-sensitive nephrotic syndrome, via defective IL-1β binding and reduced cytokine production [PMID:31954058]. Isoform-specific splicing of IL1RAP further tunes pathway output and contributes to tau phosphorylation and immune evasion phenotypes [PMID:41353558, PMID:29429992].","teleology":[{"year":1997,"claim":"Established that IL-1RAcP is not a passive accessory chain but an indispensable signaling component, resolving why IL-1RI alone cannot transduce IL-1.","evidence":"cDNA transfection into an IL-1 non-responder line with IRAK, SAPK/JNK, NF-κB, and mRNA-induction readouts","pmids":["9065432"],"confidence":"High","gaps":["Did not define the stoichiometry or contact surfaces of the receptor complex","Did not address other IL-1 family ligands"]},{"year":2000,"claim":"Demonstrated an in vivo physiological requirement for IL-1RAcP in centrally driven neuroendocrine and immune responses to IL-1β.","evidence":"IL-1RAcP knockout mice with intracerebroventricular IL-1β and corticosterone, splenocyte, and IL-6 readouts","pmids":["11024543"],"confidence":"High","gaps":["Did not distinguish which downstream pathway accounts for each phenotype","Did not address tissue-specific or isoform-specific contributions"]},{"year":2001,"claim":"Proposed a structural model for how IL-1RAcP docks onto the IL-1β/IL-1RI assembly, beginning to explain ternary complex geometry.","evidence":"Homology modeling and docking validated with IL-1β peptides, blocking antibodies, and mutant IL-1β","pmids":["11418113"],"confidence":"Low","gaps":["Primarily computational with indirect experimental validation","No high-resolution structure of the full ternary complex"]},{"year":2004,"claim":"Extended IL-1RAcP's co-receptor role beyond IL-1 to the IL-36 cytokines (IL-1F6/F8/F9) signaling through IL-1Rrp2.","evidence":"Blocking antibodies and dominant-negative IL-1RAcP with NF-κB/MAPK and cytokine-secretion readouts","pmids":["14734551"],"confidence":"High","gaps":["Did not resolve the structural basis of IL-36R/IL-1RAcP assembly","Did not test in vivo relevance"]},{"year":2007,"claim":"Defined the composition and kinetics of the endogenous IL-1RI signaling complex, identifying the stable IL-1RAcP/MyD88/IRAK-4 module and IRAK-4 as the earliest phosphorylated component.","evidence":"Immunoprecipitation of endogenous complex with tandem mass spectrometry and in vitro phosphorylation","pmids":["17507369"],"confidence":"High","gaps":["Did not establish direct contacts between IL-1RAcP and MyD88/IRAK-4","Kinetics defined in one cell context"]},{"year":2009,"claim":"Provided a unifying structural model of IL-1 family ternary signaling by characterizing both the IL-33/ST2/IL-1RAcP and IL-1β/IL-1R1/IL-1RAcP complexes.","evidence":"NMR structure of IL-33 and SAXS of the ternary complexes with biochemical binding assays","pmids":["19836339"],"confidence":"High","gaps":["Low-resolution envelope rather than atomic complex structure","Did not map signaling-critical residues"]},{"year":2012,"claim":"Identified a negative-regulatory mechanism controlling IL-1RAcP abundance through MARCH8-mediated K48 ubiquitination of Lys512.","evidence":"Reciprocal Co-IP, K48-linkage ubiquitination assay, Lys512 mutagenesis, and overexpression/knockdown with NF-κB reporter","pmids":["22904187"],"confidence":"High","gaps":["Did not establish the physiological trigger for MARCH8 engagement","In vivo relevance not tested"]},{"year":2013,"claim":"Showed that exon-9 skipping generates a soluble decoy IL-1RAcP that inhibits IL-1 signaling, providing a splicing-based therapeutic strategy.","evidence":"AON-mediated exon skipping in vitro and in mouse liver with RT-PCR, Western blot, and signaling inhibition","pmids":["23340324"],"confidence":"Medium","gaps":["Did not demonstrate disease efficacy in vivo","Single lab"]},{"year":2015,"claim":"Revealed a non-cytokine function: IL-1RAcP acts as a trans-synaptic adhesion partner of PTPδ, defining the structural basis of splice-insert-dependent synaptic organization.","evidence":"X-ray crystallography of PTPδ/IL-1RAcP and PTPδ/IL1RAPL1 complexes with splice-insert domain mapping","pmids":["25908590"],"confidence":"High","gaps":["Did not establish in vivo synaptic phenotype at the time","Did not link to downstream signaling"]},{"year":2016,"claim":"Implicated IL1RAP in leukemic stem cell biology by showing it is required for IL-1-driven NF-κB activation and proliferation in primitive CML cells and is therapeutically targetable.","evidence":"NF-κB and proliferation assays with IL1RAP-blocking antibodies and CML xenograft ADCC model","pmids":["27621309"],"confidence":"Medium","gaps":["Did not define IL1RAP partners beyond IL-1 signaling in CML","Single lab"]},{"year":2018,"claim":"Expanded IL1RAP's oncogenic role by showing physical interaction with FLT3 and c-KIT in AML, coupling it to receptor tyrosine kinase signaling.","evidence":"Co-IP of IL1RAP-FLT3/c-KIT, RNAi, genetic deletion, and antibody treatment in AML models","pmids":["29773641"],"confidence":"Medium","gaps":["Co-IP did not establish direct versus indirect binding","Mechanism of kinase activation by IL1RAP not resolved"]},{"year":2018,"claim":"Linked IL1RAP splicing to immune evasion, showing SRSF10-driven membrane isoform production activates NF-κB and CD47 to inhibit phagocytosis.","evidence":"Splicing assay, isoform RT-PCR, NF-κB reporter, CD47 analysis, and macrophage phagocytosis assay with SRSF10 manipulation","pmids":["29429992"],"confidence":"Medium","gaps":["Did not define how membrane isoform selectively drives CD47","Single lab"]},{"year":2019,"claim":"Confirmed IL1RAP as the single shared co-receptor for IL-1, IL-33, and IL-36 signaling in vivo through a pan-blocking antibody.","evidence":"Blocking monoclonal antibody across in vitro signaling and three in vivo disease models","pmids":["31427775"],"confidence":"High","gaps":["Did not resolve receptor-specific recruitment mechanisms","Did not address non-cytokine functions"]},{"year":2020,"claim":"Connected IL1RAP to a Mendelian disease by showing biallelic variants impair IL-1R complex function in steroid-sensitive nephrotic syndrome.","evidence":"Whole-exome sequencing, patient PBMC cytokine assays, and reconstitution of IL-1R with variant IL1RAP plus binding assays","pmids":["31954058"],"confidence":"Medium","gaps":["Small patient cohort","Causal mechanism linking signaling defect to renal phenotype not established"]},{"year":2021,"claim":"Identified Arg286 as a key interaction residue for ternary complex formation and a druggable target for IL-1 signaling inhibition.","evidence":"Molecular modeling, pull-down complex-formation assay with peptide inhibitors, and anti-IL-1RAcP mAb in a mouse OA model","pmids":["33614593"],"confidence":"Medium","gaps":["Key residue identification relied on modeling","In vivo efficacy limited to one disease model"]},{"year":2021,"claim":"Revealed a metabolic function of IL1RAP via SLC3A2 binding that supports cysteine supply, redox homeostasis, and anoikis resistance in Ewing sarcoma.","evidence":"Proteomic screen, Co-IP with SLC3A2, cystine uptake/glutathione assays, CTH analysis, anoikis and metastasis models","pmids":["34021002"],"confidence":"High","gaps":["Direct versus complex-mediated SLC3A2 interaction not fully resolved","Generalizability beyond Ewing sarcoma untested"]},{"year":2021,"claim":"Showed IL1RAP enables AML cells to remodel the marrow niche by driving an IL-1β/p38/NF-κB pro-inflammatory secretome that suppresses normal HSPCs.","evidence":"IL1RAP knockdown, colony assays, secretome profiling, MSC co-culture, and Anakinra rescue","pmids":["33121233"],"confidence":"Medium","gaps":["Did not separate IL1RAP secretome effects from RTK signaling","Single lab"]},{"year":2022,"claim":"Linked IL1RAP loss-of-function to schizophrenia through impaired neurite growth and IL-1 signaling.","evidence":"Whole-exome sequencing, shRNA knockdown, WT versus R442* rescue, JNK and NF-κB readouts in cortical neurons","pmids":["35181481"],"confidence":"Medium","gaps":["Single patient variant","Causal contribution to disease at population level not established"]},{"year":2022,"claim":"Established that IL1RAP blockade overcomes IL-1-driven chemoresistance by disrupting tumor-stroma IL-1α/IL-1β crosstalk.","evidence":"NSCLC PDX and MC38 models with cytokine measurement and anti-IL1RAP versus anti-IL-1β comparison","pmids":["36036818"],"confidence":"Medium","gaps":["Did not define which stromal cell types dominate the response","Single lab"]},{"year":2024,"claim":"Showed IL1RAP blockade reprograms the PDAC microenvironment by blocking CAF-derived chemokine secretion and myeloid recruitment.","evidence":"CAF/PDAC co-transplantation model, RNA-seq, migration assays, and nadunolimab treatment","pmids":["39694705"],"confidence":"Medium","gaps":["Antitumor effect required CAF co-transplant, limiting interpretation in native tumors","Single lab"]},{"year":2025,"claim":"Provided genetic epistasis demonstrating that PTPδ-meB regulates excitatory synapses in dentate gyrus granule cells in an IL1RAP-dependent manner.","evidence":"Ptprd-meB and IL1RAP mutant mice with electrophysiology and postsynaptic density proteomics","pmids":["40360498"],"confidence":"High","gaps":["Did not resolve the downstream signaling from the synaptic adhesion complex","Limited to one neuronal population"]},{"year":2025,"claim":"Demonstrated isoform-specific roles of IL-1RAcP in tau regulation during systemic inflammation.","evidence":"Global and neuron-specific Il1rap knockout mice in an LPS model with phospho-tau and total-tau readouts","pmids":["41353558"],"confidence":"Medium","gaps":["Mechanism linking IL-1RAcP isoforms to tau kinases unresolved","Single lab"]},{"year":2025,"claim":"Implicated IL1RAP as a driver of inflammation-dependent clonal hematopoiesis expansion in Tet2-mutant clones.","evidence":"IL1RAP knockdown in vivo in a particulate-matter-exposed murine Tet2 CH model with flow cytometry","pmids":["41031953"],"confidence":"Medium","gaps":["Did not define the signaling pathway driving clonal advantage","Single lab"]},{"year":null,"claim":"How IL1RAP coordinates its distinct functions — cytokine co-receptor, RTK-associated oncogenic scaffold, metabolic SLC3A2 partner, and trans-synaptic adhesion molecule — within a single cell, and which isoforms and post-translational states partition these roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No integrated model reconciling cytokine signaling versus RTK and metabolic functions","Isoform-specific structural and signaling determinants incompletely mapped","Atomic structures of IL1RAP in non-cytokine complexes (FLT3, c-KIT, SLC3A2) lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,11]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[8,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,7,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,11]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,12,14,15]}],"complexes":["IL-1β/IL-1R1/IL-1RAcP ternary complex","IL-33/ST2/IL-1RAcP complex","IL-36γ/IL-36R/IL-1RAcP complex","PTPδ/IL-1RAcP trans-synaptic complex"],"partners":["MYD88","IRAK4","MARCH8","PTPRD","FLT3","KIT","SLC3A2","IL1R1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPH3","full_name":"Interleukin-1 receptor accessory protein","aliases":["Interleukin-1 receptor 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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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with platinum doublet.","date":"2025","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/40680438","citation_count":1,"is_preprint":false},{"pmid":"36435922","id":"PMC_36435922","title":"Bacterial production and biophysical characterization of a hard-to-fold scFv against myeloid leukemia cell surface marker, IL-1RAP.","date":"2022","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/36435922","citation_count":1,"is_preprint":false},{"pmid":"29562445","id":"PMC_29562445","title":"[Expressions and clinical significance of GAS1, IL-1RAP and PRF1 in patients with ALK positive anaplastic large cell lymphoma].","date":"2018","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/29562445","citation_count":1,"is_preprint":false},{"pmid":"38680890","id":"PMC_38680890","title":"Circular RNA circMAN1A2 promotes ovarian cancer progression through the microRNA-135a-3p/IL1RAP/TAK1 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nucleotide polymorphisms.","date":"2023","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36682035","citation_count":0,"is_preprint":false},{"pmid":"41973074","id":"PMC_41973074","title":"IL1RAP antibody-drug conjugates potently target primary and metastatic disease in multiple oncofusion-driven cancers.","date":"2026","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41973074","citation_count":0,"is_preprint":false},{"pmid":"41988836","id":"PMC_41988836","title":"Peripheral lncRNA-IL1RAP Dysregulation in Schizophrenia: A Multi-Omics Bridge Between Immunity and Diagnosis.","date":"2026","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/41988836","citation_count":0,"is_preprint":false},{"pmid":"26314426","id":"PMC_26314426","title":"[Preparation and Assessment of IL1RAP Monoclonal Antibody].","date":"2015","source":"Zhongguo shi yan xue ye xue za 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co-receptor component of the IL-1 receptor signaling complex: transfection of IL-1RAcP into IL-1 non-responder cells (EL-4 D6/76, which express IL-1RI but lack IL-1RAcP) was sufficient to restore IL-1-induced activation of IRAK, stress-activated protein kinases, NF-κB and IL-1 NF nuclear translocation, and IL-2 mRNA induction.\",\n      \"method\": \"cDNA transfection into IL-1 non-responder cell line, IRAK kinase assay, SAPK/JNK activation assay, nuclear translocation assay, mRNA induction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — functional reconstitution in defined non-responder cell line with multiple orthogonal readouts; foundational mechanism paper replicated broadly\",\n      \"pmids\": [\"9065432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-1F6, IL-1F8, and IL-1F9 (novel IL-1 family cytokines) signal through the orphan receptor IL-1Rrp2 AND require IL-1RAcP as a co-receptor: antibodies against IL-1RAcP and transfection of cytoplasmically-deleted (dominant-negative) IL-1RAcP blocked NF-κB activation by all three cytokines; full signaling activated NF-κB, JNK, ERK1/2, IL-8 promoter, and IL-6 secretion.\",\n      \"method\": \"Blocking antibodies against IL-1RAcP, dominant-negative cytoplasmic deletion transfection, NF-κB reporter assay, MAPK activation assay, cytokine secretion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (antibody blockade + dominant-negative construct + multiple cell lines), multiple readouts\",\n      \"pmids\": [\"14734551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-1RAcP is required in vivo for centrally mediated neuroendocrine and immune responses to IL-1β: IL-1RAcP knockout mice fail to show IL-1β-induced plasma corticosterone elevation, splenocyte proliferation depression, or increases in plasma/brain IL-6 following intracerebroventricular IL-1β injection.\",\n      \"method\": \"IL-1RAcP knockout mice, intracerebroventricular injection, corticosterone ELISA, splenocyte proliferation assay, IL-6 measurement\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with multiple defined physiological readouts, single lab\",\n      \"pmids\": [\"11024543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The endogenous IL-1RI signaling complex formed after IL-1 binding stably contains IL-1RAcP, MyD88, and IRAK-4 (p60); IRAK-4 is the earliest phosphorylated component. IRAK-1 (p90) is only transiently associated. IL-1RAcP, MyD88, and IRAK-4 associate with the liganded receptor within 15 seconds and remain stably associated.\",\n      \"method\": \"Immunoprecipitation of endogenous IL-1RI complex followed by tandem mass spectrometry, in vitro phosphorylation assay, SDS-PAGE mobility shift\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry identification of endogenous complex with kinetic analysis; single lab but rigorous biochemical characterization\",\n      \"pmids\": [\"17507369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Computational/experimental modeling of the IL-1RAcP interaction with the IL-1β/IL-1R(I) complex supports a 'BACK' model in which IL-1RAcP contacts the back of IL-1RI wrapped around IL-1β; this was validated by IL-1β peptide/antibody experiments and mutated IL-1β proteins.\",\n      \"method\": \"Homology modeling, computational docking, validation with IL-1β peptides, antibody blocking experiments, and mutated IL-1β proteins\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — primarily computational modeling with limited experimental validation using indirect readouts\",\n      \"pmids\": [\"11418113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-33 forms a heterotrimeric signaling complex with its primary receptor ST2 and the coreceptor IL-1RAcP; solution structure of IL-33 was solved by NMR and SAXS was used to characterize the IL-33/ST2/IL-1RAcP and IL-1β/IL-1R1/IL-1RAcP ternary complexes, proposing a general model of IL-1 family ternary signaling complex architecture.\",\n      \"method\": \"NMR structure determination, small-angle X-ray scattering (SAXS), biochemical binding assays\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure + SAXS validation of ternary complex architecture; single lab but multiple orthogonal structural methods\",\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 signaling by physically interacting with IL1RAP and targeting its Lys512 for K48-linked polyubiquitination, leading to IL1RAP degradation. MARCH8 overexpression inhibits IL-1β-induced NF-κB and MAPK activation; MARCH8 knockdown has the opposite effect.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with K48-linkage-specific analysis, site-directed mutagenesis (Lys512), overexpression and knockdown, NF-κB reporter assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal Co-IP, site-specific mutagenesis identifying Lys512, K48-linkage characterization, functional rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22904187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Antisense oligonucleotide (AON)-mediated skipping of exon 9 of IL-1RAcP (which encodes the transmembrane domain) produces a novel soluble, secreted form of IL-1RAcP (Δ9IL-1RAcP) that substantially inhibits IL-1 signaling in vitro; a single 10 mg/kg AON injection induced 90% exon skipping in mouse liver for at least 5 days.\",\n      \"method\": \"AON-mediated exon skipping in vitro and in vivo, RT-PCR, Western blot for secreted protein, IL-1 signaling inhibition assay\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo exon-skipping with demonstrated production of soluble protein and functional inhibition; single lab\",\n      \"pmids\": [\"23340324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of PTPδ in complex with IL-1RAcP and IL1RAPL1 reveal that the first Ig domain of IL-1RAcP binds to the second and third Ig domains of PTPδ in a splice-insert-dependent manner; the second splice insert of PTPδ acts as an adjustable linker positioning Ig2/Ig3 for simultaneous interaction with IL-1RAcP or IL1RAPL1 Ig1. This trans-synaptic interaction mediates synapse differentiation.\",\n      \"method\": \"X-ray crystallography of PTPδ/IL-1RAcP and PTPδ/IL1RAPL1 complexes, structure-function analysis of splice inserts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of protein complexes with functional domain mapping; single lab but rigorous structural biology\",\n      \"pmids\": [\"25908590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL1RAP physically interacts with FLT3 and c-KIT receptor tyrosine kinases in AML cells, mediating signaling and pro-proliferative effects through these receptors in addition to its known role in IL-1 receptor signaling. Targeting IL1RAP via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo without perturbing healthy hematopoietic function.\",\n      \"method\": \"Co-immunoprecipitation demonstrating IL1RAP-FLT3 and IL1RAP-c-KIT interaction, RNA interference, genetic deletion, antibody treatment, in vitro and in vivo AML models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for novel interaction partners, loss-of-function with defined phenotype; single lab with multiple approaches\",\n      \"pmids\": [\"29773641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL1RAP alternative splicing is regulated by the splicing factor SRSF10 (upregulated by HPV E6/E7 via E2F1): SRSF10 promotes use of an alternate terminator in IL1RAP exon 13 to increase production of the membrane form of IL1RAP (mIL1RAP). mIL1RAP activates NF-κB, which upregulates CD47 ('don't eat me' signal) to inhibit macrophage phagocytosis.\",\n      \"method\": \"RNA splicing assay, RT-PCR for isoform switching, NF-κB reporter, CD47 expression analysis, macrophage phagocytosis assay, SRSF10 knockdown/overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway defined with splicing assay, NF-κB reporter, and functional phagocytosis readout; single lab\",\n      \"pmids\": [\"29429992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A single blocking monoclonal antibody against IL-1R3/IL1RAP simultaneously inhibits signaling by IL-1α, IL-1β, IL-33, IL-36α, IL-36β, and IL-36γ in vitro and in vivo, confirming IL1RAP as the shared co-receptor for all three signaling pathways (IL-1R1, ST2/IL-1RL1, and IL-36R).\",\n      \"method\": \"Blocking monoclonal antibody in vitro signaling assays, in vivo mouse models (crystal-induced peritonitis, allergic airway inflammation, psoriasis)\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single blocking antibody tested across three distinct in vivo disease models and multiple cytokine pathways; multiple labs/approaches\",\n      \"pmids\": [\"31427775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL1RAP binds the cell-surface system Xc- cystine/glutamate antiporter (SLC3A2) to enhance exogenous cystine uptake and replenish glutathione. Under cystine depletion, IL1RAP induces cystathionine gamma lyase (CTH) to activate the transsulfuration pathway for de novo cysteine synthesis, thereby maintaining redox homeostasis and suppressing anoikis in Ewing sarcoma cells.\",\n      \"method\": \"Proteomic screens, IL1RAP inactivation (loss-of-function), co-immunoprecipitation with SLC3A2, cystine uptake assay, glutathione measurement, CTH expression analysis, anoikis assay, metastasis models\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — proteomic screen plus functional validation, Co-IP demonstrating SLC3A2 interaction, metabolic assays, in vivo metastasis model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34021002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL1RAP (IL1R3) is required for IL-1-induced NF-κB activation and proliferation in primitive CML cells (CD34+CD38-): antibodies blocking IL-1RAP signaling inhibit these effects. In vivo administration of IL1RAP antibodies in CML xenograft mice produced therapeutic effects mediated by effector cells (ADCC).\",\n      \"method\": \"NF-κB activation assay, proliferation assay, IL1RAP-blocking antibodies, CML xenograft mouse model, flow cytometry\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional IL-1/NF-κB signaling established in primary CML cells with antibody blocking and in vivo model; single lab\",\n      \"pmids\": [\"27621309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A nonsense mutation (c.1324C>T; R442*) in IL1RAP identified in schizophrenia patients is a loss-of-function mutation: lentiviral shRNA knockdown of IL1RAP suppressed axon and dendrite growth in mouse cortical neurons; this was rescued by wild-type but not R442* IL1RAP. Overexpression of R442* inhibited neuronal growth and IL-1β-induced JNK phosphorylation, and partially blocked NF-κB nuclear translocation in HePG2 cells.\",\n      \"method\": \"Whole-exome sequencing, lentiviral shRNA knockdown, wild-type rescue, mutant overexpression, JNK phosphorylation assay, NF-κB nuclear translocation assay, cortical neuron culture\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue with WT vs. mutant, multiple signaling readouts; single lab\",\n      \"pmids\": [\"35181481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Biallelic IL1RAP variants (p.I175T and p.R221H) in patients with steroid-sensitive nephrotic syndrome cause impaired IL-1R complex function: peripheral blood mononuclear cells from patients showed markedly lower cytokine production upon IL-1β stimulation; reconstitution of IL-1R with variant IL1RAP subunits showed impaired IL-1β binding and low reactivity.\",\n      \"method\": \"Whole-exome sequencing, cytokine production assay from patient PBMCs, reconstitution of IL-1R complex in hematopoietic cell line with variant IL1RAP, binding assay\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution assay in cell line plus primary patient cell data; single lab\",\n      \"pmids\": [\"31954058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Arg286 of IL-1RAcP is a key mediator of ternary IL-1β/IL-1R1/IL-1RAcP complex formation: molecular modeling identified Arg286 as a high-energy interaction mediator; inhibitory peptides based on 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 cell models; anti-IL-1RAcP mAbs targeting Arg286 reduced inflammatory cell influx in a mouse OA model.\",\n      \"method\": \"Molecular modeling, pull-down complex formation assay, cell-based IL-1β signaling assay with peptide inhibitors, anti-IL-1RAcP monoclonal antibody in mouse OA model\",\n      \"journal\": \"Frontiers in chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — computational modeling validated by pull-down inhibition assay and cell signaling assay; single lab\",\n      \"pmids\": [\"33614593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL1RAP knockdown in AML cells reduced colony-forming capacity; IL-1β stimulation of IL1RAP-expressing AML cells via p38 MAPK and NF-κB induced a pro-inflammatory secretome of chemokines that suppressed normal hematopoietic stem/progenitor cell function; blockade with the IL-1 receptor antagonist Anakinra reversed this effect.\",\n      \"method\": \"IL1RAP knockdown, colony formation assay, IL-1β stimulation, NF-κB/p38 pathway analysis, cytokine/chemokine secretome profiling, co-culture with mesenchymal stem cells, Anakinra rescue experiment\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, pathway identification via p38/NF-κB, pharmacological rescue; single lab\",\n      \"pmids\": [\"33121233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ginsenoside Rd suppresses IL-1β-induced inflammation in intervertebral disc chondrocytes by increasing IL1RAP ubiquitination mediated by the E3 ligase ITCH; Rd increased intracellular ITCH levels and the amount of ITCH attached to IL1RAP, blocking NF-κB stimulation.\",\n      \"method\": \"Immunoprecipitation, Western blot, PCR, bioinformatics analysis of E3 ligase candidates, CCK-8 viability assay, flow cytometry\",\n      \"journal\": \"Brazilian journal of medical and biological research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying ITCH-IL1RAP interaction with functional assay; single lab, single method for the key interaction claim\",\n      \"pmids\": [\"31411316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPδ-meB (mini-exon B of PTPδ/PTPRD) regulates excitatory synapses specifically in dentate gyrus granule cells in an IL1RAP-dependent manner: Ptprd-meB+/- mice showed decreased excitatory synaptic density and transmission in DG-GCs and reduced postsynaptic density levels of IL1RAP; IL1RAP-mutant mice showed the same decrease in excitatory synaptic transmission.\",\n      \"method\": \"Knock-in mutant mice (Ptprd-meB-/-), electrophysiology, proteomics of postsynaptic density, IL1RAP-mutant mouse phenotyping, behavioral analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with complementary mutant mouse lines, proteomics, and electrophysiology; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40360498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Global and neuron-specific IL-1RAcP isoform deficiency reduces hyperphosphorylated tau (pS202/AT8 and pT231/AT180) levels in LPS-induced systemic inflammation mouse model; neuron-specific IL-1RAcPb deficiency specifically increased total tau levels, indicating isoform-specific roles in tau regulation.\",\n      \"method\": \"Il1rap global and neuron-specific knockout mice, LPS-induced systemic inflammation model, immunohistochemistry/Western blot for phospho-tau epitopes\",\n      \"journal\": \"ASN neuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic KO with defined tau phosphorylation readouts, but single lab and single paper\",\n      \"pmids\": [\"41353558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL1RAP blockade in PDAC inhibits IL-1-induced chemokine secretion from cancer-associated fibroblasts (CAFs), reducing recruitment of neutrophils and monocytes; media conditioned by IL-1-stimulated CAFs maintained a neutrophil tissue-invasion phenotype that was reversed by nadunolimab; antitumor effects of nadunolimab required CAF co-transplantation.\",\n      \"method\": \"CAF/PDAC xenograft co-transplantation model, RNA sequencing, migration assay, neutrophil phenotype analysis, IL1RAP-blocking antibody (nadunolimab)\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with defined mechanistic requirement for CAFs, RNA-seq pathway analysis, functional migration assay; single lab\",\n      \"pmids\": [\"39694705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL1RAP blockade reduces IL-1β-induced chemoresistance; chemotherapy induces IL-1α release from tumor cells and upregulates ICE (caspase-1) in tumor stroma, which processes IL-1β; IL-1α acts on stromal cells to further induce IL-1β secretion—effects disrupted by anti-IL1RAP antibody nadunolimab but not by anti-IL-1β antibody alone.\",\n      \"method\": \"NSCLC PDX model and syngeneic MC38 model, cytokine measurement, in vitro tumor cell line experiments, antibody blockade\",\n      \"journal\": \"Cancer immunology, immunotherapy : CII\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection of IL-1α/IL-1β crosstalk using anti-IL1RAP vs. anti-IL-1β with in vivo PDX validation; single lab\",\n      \"pmids\": [\"36036818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL1RAP is overexpressed in Tet2-mutant clonal hematopoiesis clones; genetic knockdown of IL1RAP inhibited mutant clone growth in vivo in particulate matter-exposed mice, identifying IL1RAP as a driver of inflammation-dependent CH expansion.\",\n      \"method\": \"IL1RAP knockdown in vivo, murine CH model with Tet2 mutation, flow cytometry for clonal expansion\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo knockdown with defined clonal expansion phenotype; single paper, single lab\",\n      \"pmids\": [\"41031953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Structural basis for IL-36R activation by IL-36γ involves low-affinity IL-36R binding followed by high-affinity IL-1RAcP recruitment; the IL-1RAcP shared receptor is recruited to the IL-36R complex with high affinity following cytokine engagement; spesolimab acts as an allosteric antagonist of IL-36R.\",\n      \"method\": \"Cryo-EM/X-ray crystallography of IL-36R/IL-36γ and IL-36R/IL-37 complexes, binding affinity measurements, functional signaling assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural determination of ternary complex, preprint not yet peer-reviewed; single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ethanol drinking sex-dependently shifts mPFC IL-1RAcP isoform gene expression (brain-specific vs. peripheral isoform), which correlates with sex-dependent changes in IL-1β regulation of mPFC GABA synapses; this isoform shift is proposed to contribute to female mPFC resiliency and male susceptibility in AUD.\",\n      \"method\": \"Two-bottle choice ethanol drinking paradigm in C57BL/6J mice, mPFC IL-1RAcP isoform mRNA quantification, electrophysiology of GABA synapses\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mRNA expression analysis + electrophysiology, preprint, correlational; mechanistic link between isoform shift and synaptic phenotype not directly tested\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IL1RAP (IL-1RAcP/IL1R3) is an essential shared co-receptor that forms stable heterotrimeric signaling complexes with multiple primary IL-1 family receptors (IL-1R1, ST2/IL-1RL1, IL-36R, and IL-1Rrp2), recruiting IRAK-4 and MyD88 to activate NF-κB and MAPK pathways; it is subject to negative regulation via MARCH8-mediated K48-linked polyubiquitination of Lys512 leading to degradation; in the nervous system, IL-1RAcP serves as a trans-synaptic adhesion partner for PTPδ (in a splice-insert-dependent manner) to regulate excitatory synapse formation; in cancer contexts, IL1RAP additionally physically interacts with FLT3, c-KIT, and the system Xc- transporter (SLC3A2) to mediate oncogenic signaling and anoikis resistance; and isoform-specific splicing of IL1RAcP modulates pathway activity in neurons and other cell types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL1RAP (IL-1RAcP) is an essential shared co-receptor that assembles ligand-induced heterotrimeric signaling complexes for the IL-1 cytokine family, converting cytokine engagement of primary receptors into intracellular activation of NF-κB and MAPK pathways [#0, #11]. Reconstitution in non-responder cells established IL-1RAcP as the indispensable second chain that restores IL-1-driven IRAK activation, SAPK/JNK signaling, and NF-κB nuclear translocation [#0], and a single blocking antibody against IL1RAP simultaneously neutralizes signaling by IL-1α, IL-1β, IL-33, and the IL-36 cytokines, confirming its role as the common co-receptor across the IL-1R1, ST2/IL-1RL1, and IL-36R primary receptors [#11, #1]. Within the liganded complex, IL-1RAcP nucleates a stable signaling module containing MyD88 and IRAK-4, with IRAK-4 the earliest phosphorylated component [#3]; structural work on the IL-1β/IL-1R1/IL-1RAcP and IL-33/ST2/IL-1RAcP ternary complexes defines the architecture by which the co-receptor wraps onto the primary-receptor/cytokine assembly [#5]. Receptor abundance is restrained by MARCH8, an E3 ligase that interacts with IL1RAP and directs K48-linked polyubiquitination of Lys512 to drive its degradation and dampen NF-κB and MAPK output [#6]. Beyond canonical cytokine sensing, IL-1RAcP acts as a trans-synaptic adhesion molecule whose first Ig domain engages PTPδ (PTPRD) in a splice-insert-dependent manner to organize excitatory synapse differentiation, a function required for normal synaptic transmission in dentate gyrus granule cells [#8, #19]. In cancer, IL1RAP physically associates with the receptor tyrosine kinases FLT3 and c-KIT in AML to sustain proliferative signaling [#9] and with the system Xc- antiporter subunit SLC3A2 in Ewing sarcoma, where it enhances cystine uptake, induces the transsulfuration enzyme CTH, and suppresses anoikis [#12]. Loss-of-function and biallelic IL1RAP variants in patients link the gene to schizophrenia, via impaired neurite growth and signaling [#14], and to steroid-sensitive nephrotic syndrome, via defective IL-1β binding and reduced cytokine production [#15]. Isoform-specific splicing of IL1RAP further tunes pathway output and contributes to tau phosphorylation and immune evasion phenotypes [#20, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that IL-1RAcP is not a passive accessory chain but an indispensable signaling component, resolving why IL-1RI alone cannot transduce IL-1.\",\n      \"evidence\": \"cDNA transfection into an IL-1 non-responder line with IRAK, SAPK/JNK, NF-κB, and mRNA-induction readouts\",\n      \"pmids\": [\"9065432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the stoichiometry or contact surfaces of the receptor complex\", \"Did not address other IL-1 family ligands\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated an in vivo physiological requirement for IL-1RAcP in centrally driven neuroendocrine and immune responses to IL-1β.\",\n      \"evidence\": \"IL-1RAcP knockout mice with intracerebroventricular IL-1β and corticosterone, splenocyte, and IL-6 readouts\",\n      \"pmids\": [\"11024543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish which downstream pathway accounts for each phenotype\", \"Did not address tissue-specific or isoform-specific contributions\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Proposed a structural model for how IL-1RAcP docks onto the IL-1β/IL-1RI assembly, beginning to explain ternary complex geometry.\",\n      \"evidence\": \"Homology modeling and docking validated with IL-1β peptides, blocking antibodies, and mutant IL-1β\",\n      \"pmids\": [\"11418113\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Primarily computational with indirect experimental validation\", \"No high-resolution structure of the full ternary complex\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended IL-1RAcP's co-receptor role beyond IL-1 to the IL-36 cytokines (IL-1F6/F8/F9) signaling through IL-1Rrp2.\",\n      \"evidence\": \"Blocking antibodies and dominant-negative IL-1RAcP with NF-κB/MAPK and cytokine-secretion readouts\",\n      \"pmids\": [\"14734551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of IL-36R/IL-1RAcP assembly\", \"Did not test in vivo relevance\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the composition and kinetics of the endogenous IL-1RI signaling complex, identifying the stable IL-1RAcP/MyD88/IRAK-4 module and IRAK-4 as the earliest phosphorylated component.\",\n      \"evidence\": \"Immunoprecipitation of endogenous complex with tandem mass spectrometry and in vitro phosphorylation\",\n      \"pmids\": [\"17507369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish direct contacts between IL-1RAcP and MyD88/IRAK-4\", \"Kinetics defined in one cell context\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided a unifying structural model of IL-1 family ternary signaling by characterizing both the IL-33/ST2/IL-1RAcP and IL-1β/IL-1R1/IL-1RAcP complexes.\",\n      \"evidence\": \"NMR structure of IL-33 and SAXS of the ternary complexes with biochemical binding assays\",\n      \"pmids\": [\"19836339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Low-resolution envelope rather than atomic complex structure\", \"Did not map signaling-critical residues\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a negative-regulatory mechanism controlling IL-1RAcP abundance through MARCH8-mediated K48 ubiquitination of Lys512.\",\n      \"evidence\": \"Reciprocal Co-IP, K48-linkage ubiquitination assay, Lys512 mutagenesis, and overexpression/knockdown with NF-κB reporter\",\n      \"pmids\": [\"22904187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the physiological trigger for MARCH8 engagement\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that exon-9 skipping generates a soluble decoy IL-1RAcP that inhibits IL-1 signaling, providing a splicing-based therapeutic strategy.\",\n      \"evidence\": \"AON-mediated exon skipping in vitro and in mouse liver with RT-PCR, Western blot, and signaling inhibition\",\n      \"pmids\": [\"23340324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not demonstrate disease efficacy in vivo\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a non-cytokine function: IL-1RAcP acts as a trans-synaptic adhesion partner of PTPδ, defining the structural basis of splice-insert-dependent synaptic organization.\",\n      \"evidence\": \"X-ray crystallography of PTPδ/IL-1RAcP and PTPδ/IL1RAPL1 complexes with splice-insert domain mapping\",\n      \"pmids\": [\"25908590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish in vivo synaptic phenotype at the time\", \"Did not link to downstream signaling\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Implicated IL1RAP in leukemic stem cell biology by showing it is required for IL-1-driven NF-κB activation and proliferation in primitive CML cells and is therapeutically targetable.\",\n      \"evidence\": \"NF-κB and proliferation assays with IL1RAP-blocking antibodies and CML xenograft ADCC model\",\n      \"pmids\": [\"27621309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define IL1RAP partners beyond IL-1 signaling in CML\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded IL1RAP's oncogenic role by showing physical interaction with FLT3 and c-KIT in AML, coupling it to receptor tyrosine kinase signaling.\",\n      \"evidence\": \"Co-IP of IL1RAP-FLT3/c-KIT, RNAi, genetic deletion, and antibody treatment in AML models\",\n      \"pmids\": [\"29773641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP did not establish direct versus indirect binding\", \"Mechanism of kinase activation by IL1RAP not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked IL1RAP splicing to immune evasion, showing SRSF10-driven membrane isoform production activates NF-κB and CD47 to inhibit phagocytosis.\",\n      \"evidence\": \"Splicing assay, isoform RT-PCR, NF-κB reporter, CD47 analysis, and macrophage phagocytosis assay with SRSF10 manipulation\",\n      \"pmids\": [\"29429992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define how membrane isoform selectively drives CD47\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed IL1RAP as the single shared co-receptor for IL-1, IL-33, and IL-36 signaling in vivo through a pan-blocking antibody.\",\n      \"evidence\": \"Blocking monoclonal antibody across in vitro signaling and three in vivo disease models\",\n      \"pmids\": [\"31427775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve receptor-specific recruitment mechanisms\", \"Did not address non-cytokine functions\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected IL1RAP to a Mendelian disease by showing biallelic variants impair IL-1R complex function in steroid-sensitive nephrotic syndrome.\",\n      \"evidence\": \"Whole-exome sequencing, patient PBMC cytokine assays, and reconstitution of IL-1R with variant IL1RAP plus binding assays\",\n      \"pmids\": [\"31954058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Small patient cohort\", \"Causal mechanism linking signaling defect to renal phenotype not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified Arg286 as a key interaction residue for ternary complex formation and a druggable target for IL-1 signaling inhibition.\",\n      \"evidence\": \"Molecular modeling, pull-down complex-formation assay with peptide inhibitors, and anti-IL-1RAcP mAb in a mouse OA model\",\n      \"pmids\": [\"33614593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Key residue identification relied on modeling\", \"In vivo efficacy limited to one disease model\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a metabolic function of IL1RAP via SLC3A2 binding that supports cysteine supply, redox homeostasis, and anoikis resistance in Ewing sarcoma.\",\n      \"evidence\": \"Proteomic screen, Co-IP with SLC3A2, cystine uptake/glutathione assays, CTH analysis, anoikis and metastasis models\",\n      \"pmids\": [\"34021002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus complex-mediated SLC3A2 interaction not fully resolved\", \"Generalizability beyond Ewing sarcoma untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed IL1RAP enables AML cells to remodel the marrow niche by driving an IL-1β/p38/NF-κB pro-inflammatory secretome that suppresses normal HSPCs.\",\n      \"evidence\": \"IL1RAP knockdown, colony assays, secretome profiling, MSC co-culture, and Anakinra rescue\",\n      \"pmids\": [\"33121233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not separate IL1RAP secretome effects from RTK signaling\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked IL1RAP loss-of-function to schizophrenia through impaired neurite growth and IL-1 signaling.\",\n      \"evidence\": \"Whole-exome sequencing, shRNA knockdown, WT versus R442* rescue, JNK and NF-κB readouts in cortical neurons\",\n      \"pmids\": [\"35181481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient variant\", \"Causal contribution to disease at population level not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established that IL1RAP blockade overcomes IL-1-driven chemoresistance by disrupting tumor-stroma IL-1α/IL-1β crosstalk.\",\n      \"evidence\": \"NSCLC PDX and MC38 models with cytokine measurement and anti-IL1RAP versus anti-IL-1β comparison\",\n      \"pmids\": [\"36036818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define which stromal cell types dominate the response\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed IL1RAP blockade reprograms the PDAC microenvironment by blocking CAF-derived chemokine secretion and myeloid recruitment.\",\n      \"evidence\": \"CAF/PDAC co-transplantation model, RNA-seq, migration assays, and nadunolimab treatment\",\n      \"pmids\": [\"39694705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antitumor effect required CAF co-transplant, limiting interpretation in native tumors\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided genetic epistasis demonstrating that PTPδ-meB regulates excitatory synapses in dentate gyrus granule cells in an IL1RAP-dependent manner.\",\n      \"evidence\": \"Ptprd-meB and IL1RAP mutant mice with electrophysiology and postsynaptic density proteomics\",\n      \"pmids\": [\"40360498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the downstream signaling from the synaptic adhesion complex\", \"Limited to one neuronal population\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated isoform-specific roles of IL-1RAcP in tau regulation during systemic inflammation.\",\n      \"evidence\": \"Global and neuron-specific Il1rap knockout mice in an LPS model with phospho-tau and total-tau readouts\",\n      \"pmids\": [\"41353558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking IL-1RAcP isoforms to tau kinases unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated IL1RAP as a driver of inflammation-dependent clonal hematopoiesis expansion in Tet2-mutant clones.\",\n      \"evidence\": \"IL1RAP knockdown in vivo in a particulate-matter-exposed murine Tet2 CH model with flow cytometry\",\n      \"pmids\": [\"41031953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the signaling pathway driving clonal advantage\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IL1RAP coordinates its distinct functions — cytokine co-receptor, RTK-associated oncogenic scaffold, metabolic SLC3A2 partner, and trans-synaptic adhesion molecule — within a single cell, and which isoforms and post-translational states partition these roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No integrated model reconciling cytokine signaling versus RTK and metabolic functions\", \"Isoform-specific structural and signaling determinants incompletely mapped\", \"Atomic structures of IL1RAP in non-cytokine complexes (FLT3, c-KIT, SLC3A2) lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [8, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 11]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 12, 14, 15]}\n    ],\n    \"complexes\": [\n      \"IL-1β/IL-1R1/IL-1RAcP ternary complex\",\n      \"IL-33/ST2/IL-1RAcP complex\",\n      \"IL-36γ/IL-36R/IL-1RAcP complex\",\n      \"PTPδ/IL-1RAcP trans-synaptic complex\"\n    ],\n    \"partners\": [\n      \"MyD88\",\n      \"IRAK4\",\n      \"MARCH8\",\n      \"PTPRD\",\n      \"FLT3\",\n      \"KIT\",\n      \"SLC3A2\",\n      \"IL1R1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}