Affinage

IL1RAP

Interleukin-1 receptor accessory protein · UniProt Q9NPH3

Length
570 aa
Mass
65.4 kDa
Annotated
2026-04-28
79 papers in source corpus 29 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    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

    PMID:9065432

    Open questions at the time
    • Structural basis of IL-1RAcP engagement with IL-1RI not yet determined
    • Whether IL-1RAcP serves other IL-1 family members unknown
  2. 2000 High

    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

    PMID:11024543

    Open questions at the time
    • Tissue-specific and isoform-specific roles of IL-1RAcP in the brain not dissected
    • Redundancy with other accessory proteins not tested
  3. 2004 High

    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

    PMID:14734551

    Open questions at the time
    • 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
  4. 2007 High

    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

    PMID:17507369

    Open questions at the time
    • 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
  5. 2009 High

    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

    PMID:19836339

    Open questions at the time
    • Atomic-resolution structure of complete ternary complex not yet available
    • How TIR domain juxtaposition drives MyD88 recruitment not structurally resolved
  6. 2012 High

    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

    PMID:22904187

    Open questions at the time
    • Physiological stimuli that regulate MARCH8 activity toward IL1RAP not identified
    • Contribution of other candidate E3 ligases (ITCH, NEDD4) not rigorously established
  7. 2015 High

    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

    PMID:25908590

    Open questions at the time
    • 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
  8. 2018 High

    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

    PMID:29773641

    Open questions at the time
    • 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
  9. 2019 High

    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

    PMID:31427775

    Open questions at the time
    • Long-term immunosuppressive consequences of pan-IL-1R3 blockade not assessed
    • Whether IL-1R3 blockade affects neuronal IL1RAP functions not examined
  10. 2020 High

    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

    PMID:31954058

    Open questions at the time
    • Whether additional patients carry IL1RAP mutations not reported
    • Full spectrum of immunological consequences of human IL1RAP deficiency not characterized
  11. 2021 High

    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

    PMID:34021002

    Open questions at the time
    • Whether IL1RAP modulates system Xc⁻ transport activity directly or via scaffolding not determined
    • Generalizability beyond Ewing sarcoma cells not established
  12. 2021 Medium

    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

    PMID:33614593

    Open questions at the time
    • Crystal structure of peptide–IL-1RAcP interface not solved
    • In vivo pharmacokinetics and specificity of Arg286-targeting peptides not fully characterized
  13. 2022 Medium

    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

    PMID:35181481

    Open questions at the time
    • 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
  14. 2025 High

    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

    PMID:40360498

    Open questions at the time
    • Postsynaptic signaling cascade linking IL1RAP to synapse maintenance not identified
    • Whether other PTPδ ligands compensate in IL1RAP-null synapses not tested
  15. 2025 Medium

    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

    PMID:41031953

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0060090 molecular adaptor activity 3 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005576 extracellular region 1
Pathway
R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 5 R-HSA-112316 Neuronal System 3
Partners
FLT3IL1R1IL1RL1IL1RL2IRAK4KITMYD88PTPRD
Complex memberships
IL-1β/IL-1R1/IL-1RAcP ternary complexIL-33/ST2/IL-1RAcP ternary complexIL-36/IL-1Rrp2/IL-1RAcP ternary complexPTPδ/IL-1RAcP trans-synaptic complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 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. Complementation by cDNA transfection in non-responsive cell line; functional assays for IRAK, SAPK, NF-κB, and gene expression The Journal of biological chemistry High 9065432
2004 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. Antibody blocking, dominant-negative IL-1RAcP transfection, NF-κB reporter assay, MAPK assays, ELISA The Journal of biological chemistry High 14734551
2007 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. Immunoprecipitation of endogenous receptor complex followed by tandem mass spectrometry; time-course phosphorylation analysis Molecular & cellular proteomics : MCP High 17507369
2009 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. NMR structure determination of IL-33, SAXS analysis of binary and ternary complexes, biochemical characterization Structure (London, England : 1993) High 19836339
2012 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. Overexpression and knockdown of MARCH8; co-immunoprecipitation; ubiquitin linkage analysis; site-directed mutagenesis of Lys512; NF-κB and MAPK activation assays Proceedings of the National Academy of Sciences of the United States of America High 22904187
2015 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. X-ray crystallography of PTPδ–IL-1RAcP complex; structure-function mutagenesis; neuronal differentiation assays Nature communications High 25908590
2000 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. IL-1RAcP knockout mouse model; intracerebroventricular IL-1β injection; corticosterone ELISA, splenocyte proliferation assay, IL-6 measurement Journal of neuroimmunology High 11024543
2001 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. Homology modeling, computational docking, experimental validation with IL-1β peptides and mutants FEBS letters Medium 11418113
2013 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. Antisense oligonucleotide exon-skipping, RT-PCR, Western blot for secreted protein, IL-1 signaling inhibition assays in vitro and in vivo Molecular therapy. Nucleic acids Medium 23340324
2018 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. Co-immunoprecipitation of IL1RAP with FLT3 and c-KIT; RNAi knockdown; CRISPR deletion; antibody treatment; in vitro and xenograft in vivo models The Journal of experimental medicine High 29773641
2018 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. Alternative splicing analysis, SRSF10 overexpression/knockdown, NF-κB reporter assay, macrophage phagocytosis assays, rescue experiments Oncogene Medium 29429992
2019 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. Blocking mAb to human and mouse IL-1R3; in vitro cytokine signaling assays; three in vivo disease models with histology and functional readouts Nature immunology High 31427775
2021 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. Proteomic screens, co-immunoprecipitation of IL1RAP with system Xc- transporter, cystine uptake assays, CTH expression analysis, anoikis assays, in vivo metastasis models Cancer discovery High 34021002
2021 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. IL1β stimulation, IL1RAP knockdown, Anakinra treatment, co-culture with mesenchymal stem cells, NF-κB and p38 MAPK pathway analysis, colony formation assays Haematologica Medium 33121233
2021 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. IL1RAP knockdown by lentiviral shRNA, colony formation assays, p38/NF-κB signaling analysis, IL-1β stimulation Haematologica Medium 33121233
2013 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. Flow cytometry, monoclonal antibody generation with isotype switching, ADCC killing assays on primary AML samples including stem cell populations Blood Medium 23479569
2016 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. NF-κB activation assays, proliferation assays, IL1RAP-blocking antibody treatment, in vivo xenograft model Blood High 27621309
2020 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. 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 International immunology High 31954058
2021 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. Molecular modeling, pull-down assay for complex formation, peptide inhibitor IC50 determination, IL-1β signaling cell assays, in vivo OA mouse model Frontiers in chemistry Medium 33614593
2022 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. 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 Neurochemical research Medium 36502418
2022 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. 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 Neuroscience letters Medium 35181481
2024 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. Xenograft model with co-transplantation of PDAC cells and CAFs, RNA sequencing, migration assays, cytokine/chemokine profiling, neutrophil phenotyping Journal for immunotherapy of cancer Medium 39694705
2019 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. Immunoprecipitation for ubiquitination, Western blot for ITCH and IL1RAP, RT-PCR, NF-κB signaling assay, CCK-8 viability, flow cytometry Brazilian journal of medical and biological research Low 31411316
2025 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. Ptprd-meB knock-in mice, proteomic analysis of postsynaptic density, electrophysiology, IL1RAP knockout mice, behavioral testing Nature communications High 40360498
2025 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. Mouse CH model (Tet2-mutant), lentiviral IL1RAP knockdown, in vivo clonal competition assay Cancer discovery Medium 41031953
2025 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. Global and neuron-specific conditional Il1rap knockout mice, LPS systemic inflammation model, phospho-tau immunoblotting with AT8 and AT180 antibodies ASN neuro Medium 41353558
2020 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. Crystal structure of antibody-IL-1β complex, SPR binding competition assays, in vivo IL-6 induction assay, xenograft tumor models Journal of molecular biology High 33359099
2024 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. Surface proteome enrichment, single-cell RNA-seq, antibody internalization assay on primary AML samples Biomarker research Low 40229904
2026 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. Oncofusion expression studies, proteomic/transcriptomic validation, xenograft ADC treatment models, syngeneic tumor models, non-human primate toxicity Cancer discovery Medium 41973074
2024 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. Phosphoproteomics, Western blot, immunofluorescence, ELISA for phospho-S566-IL-1RAP in multiple tissues; intestinal permeability assay International journal of medical sciences Low 39006851

Source papers

Stage 0 corpus · 79 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs. The Journal of biological chemistry 346 14734551
1997 The interleukin-1 receptor accessory protein (IL-1RAcP) is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP kinases). The Journal of biological chemistry 257 9065432
2009 Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors--insight into heterotrimeric IL-1 signaling complexes. Structure (London, England : 1993) 168 19836339
2013 Selective killing of candidate AML stem cells by antibody targeting of IL1RAP. Blood 110 23479569
2015 GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP. Brain : a journal of neurology 109 26268530
2012 The E3 ubiquitin ligase MARCH8 negatively regulates IL-1β-induced NF-κB activation by targeting the IL1RAP coreceptor for ubiquitination and degradation. Proceedings of the National Academy of Sciences of the United States of America 102 22904187
2018 SRSF10-mediated IL1RAP alternative splicing regulates cervical cancer oncogenesis via mIL1RAP-NF-κB-CD47 axis. Oncogene 98 29429992
2015 Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America 98 26261316
2021 Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma. Cancer discovery 83 34021002
2016 IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models. Blood 81 27621309
2018 IL1RAP potentiates multiple oncogenic signaling pathways in AML. The Journal of experimental medicine 74 29773641
2018 CML Hematopoietic Stem Cells Expressing IL1RAP Can Be Targeted by Chimeric Antigen Receptor-Engineered T Cells. Cancer research 73 30514753
2019 IL-1R3 blockade broadly attenuates the functions of six members of the IL-1 family, revealing their contribution to models of disease. Nature immunology 71 31427775
2007 Mass spectrometric analysis of the endogenous type I interleukin-1 (IL-1) receptor signaling complex formed after IL-1 binding identifies IL-1RAcP, MyD88, and IRAK-4 as the stable components. Molecular & cellular proteomics : MCP 63 17507369
2001 Model of interaction of the IL-1 receptor accessory protein IL-1RAcP with the IL-1beta/IL-1R(I) complex. FEBS letters 62 11418113
2015 Mechanisms of splicing-dependent trans-synaptic adhesion by PTPδ-IL1RAPL1/IL-1RAcP for synaptic differentiation. Nature communications 51 25908590
2018 Potential regulatory network in the PSG10P/miR-19a-3p/IL1RAP pathway is possibly involved in preeclampsia pathogenesis. Journal of cellular and molecular medicine 40 30370628
2022 Chimeric antigen receptor T-cells targeting IL-1RAP: a promising new cellular immunotherapy to treat acute myeloid leukemia. Journal for immunotherapy of cancer 32 35803613
2023 RapaCaspase-9-based suicide gene applied to the safety of IL-1RAP CAR-T cells. Gene therapy 31 37173386
2022 IL1RAP expression and the enrichment of IL-33 activation signatures in severe neutrophilic asthma. Allergy 30 35986608
2021 The IL1-IL1RAP axis plays an important role in the inflammatory leukemic niche that favors acute myeloid leukemia proliferation over normal hematopoiesis. Haematologica 29 33121233
2021 Overcoming target epitope masking resistance that can occur on low-antigen-expresser AML blasts after IL-1RAP chimeric antigen receptor T cell therapy using the inducible caspase 9 suicide gene safety switch. Cancer gene therapy 29 33414517
2014 IL1RAP as a surface marker for leukemia stem cells is related to clinical phase of chronic myeloid leukemia patients. International journal of clinical and experimental medicine 29 25663975
2000 Interleukin 1 receptor accessory protein (IL-1RAcP) is necessary for centrally mediated neuroendocrine and immune responses to IL-1beta. Journal of neuroimmunology 29 11024543
2022 Innate immune mediator, Interleukin-1 receptor accessory protein (IL1RAP), is expressed and pro-tumorigenic in pancreatic cancer. Journal of hematology & oncology 24 35606824
2024 Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis. Annals of the rheumatic diseases 23 38594058
2022 IL-1RAP, a Key Therapeutic Target in Cancer. International journal of molecular sciences 22 36499246
2017 microRNA-4331 Promotes Transmissible Gastroenteritis Virus (TGEV)-induced Mitochondrial Damage Via Targeting RB1, Upregulating Interleukin-1 Receptor Accessory Protein (IL1RAP), and Activating p38 MAPK Pathway In Vitro. Molecular & cellular proteomics : MCP 21 29217619
2021 The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma. Technology in cancer research & treatment 19 33602046
2021 First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours. British journal of cancer 19 34903842
2013 Inhibition of IL-1 Signaling by Antisense Oligonucleotide-mediated Exon Skipping of IL-1 Receptor Accessory Protein (IL-1RAcP). Molecular therapy. Nucleic acids 18 23340324
2021 Circ_0037078 promotes trophoblast cell proliferation, migration, invasion and angiogenesis by miR-576-5p/IL1RAP axis. American journal of reproductive immunology (New York, N.Y. : 1989) 17 34724268
2023 CAR-T cells targeting IL-1RAP produced in a closed semiautomatic system are ready for the first phase I clinical investigation in humans. Current research in translational medicine 16 36773434
2024 IL1RAP-specific T cell engager depletes acute myeloid leukemia stem cells. Journal of hematology & oncology 15 39143574
2022 Blockade of IL-1α and IL-1β signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy. Cancer immunology, immunotherapy : CII 15 36036818
2023 Interleukin-1 receptor accessory protein (IL-1RAP): A magic bullet candidate for immunotherapy of human malignancies. Critical reviews in oncology/hematology 14 37981104
2020 Associations of IL1RAP and IL1RL1 gene polymorphisms with obesity and inflammation mediators. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 14 31897507
2020 IL1RAP regulated by PRPRD promotes gliomas progression via inducing neuronal synapse development and neuron differentiation in vitro. Pathology, research and practice 14 32829106
2020 Structure-based Development of Human Interleukin-1β-Specific Antibody That Simultaneously Inhibits Binding to Both IL-1RI and IL-1RAcP. Journal of molecular biology 14 33359099
2024 Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitment. Journal for immunotherapy of cancer 11 39694705
2021 Association of IL33, IL1RL1, IL1RAP Polymorphisms and Asthma in Chinese Han Children. Frontiers in cell and developmental biology 11 34977013
2020 Associations of IL6 rs1800795, BLK rs13277113, TIMP3 rs9621532, IL1RL1 rs1041973 and IL1RAP rs4624606 single gene polymorphisms with laryngeal squamous cell carcinoma. Gene 10 32330537
2019 Association of IL1RAP-related genetic variation with cerebrospinal fluid concentration of Alzheimer-associated tau protein. Scientific reports 10 30792413
2024 IL1RAP Blockade With a Monoclonal Antibody Reduces Cardiac Inflammation and Preserves Heart Function in Viral and Autoimmune Myocarditis. Circulation. Heart failure 7 39513273
2023 CircCRIM1 mediates proliferation, migration, and invasion of trophoblast cell through regulating miR-942-5p/IL1RAP axis. American journal of reproductive immunology (New York, N.Y. : 1989) 7 37382169
2023 Characterisation of IL-1 family members in Sweet syndrome highlights the overexpression of IL-1β and IL-1R3 as possible therapeutic targets. Experimental dermatology 6 37724787
2021 Identification and Targeting of Thomsen-Friedenreich and IL1RAP Antigens on Chronic Myeloid Leukemia Stem Cells Using Bi-Specific Antibodies. OncoTargets and therapy 6 33519209
2021 IL1RAP Pulls a Double Shift in the Cysteine Factory. Cancer discovery 6 34725089
2013 The inhibitory function of Fc-ST2 depends on cell type; IL-1RAcP and ST2 are necessary but insufficient for IL-33 activity. Immunologic research 6 23435764
2024 Efficacy and Safety of the Anti-IL1RAP Antibody Nadunolimab (CAN04) in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Advanced/Metastatic Pancreatic Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 5 39385434
2021 Characterization and Validation of Arg286 Residue of IL-1RAcP as a Potential Drug Target for Osteoarthritis. Frontiers in chemistry 5 33614593
2020 The Role of SNPs in IL1RL1 and IL1RAP Genes in Age-related Macular Degeneration Development and Treatment Efficacy. In vivo (Athens, Greece) 5 32871771
2019 Ginsenoside Rd inhibits IL-1β-induced inflammation and degradation of intervertebral disc chondrocytes by increasing IL1RAP ubiquitination. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 5 31411316
2016 Reconstitution of ST2 (IL-1R4) specific for IL-33 activity; no suppression by IL-1Ra though a common chain IL-1R3 (IL-1RAcP) shared with IL-1. Cytokine 5 27031441
2011 Engagement of IL-1 receptor accessory protein (IL-1RAcP) with the monoclonal antibody AY19 provides co-activating signals and prolongs the CD2-induced proliferation of peripheral blood lymphocytes. Immunology letters 5 21600927
2025 IL1RAP is an immunotherapeutic target for normal karyotype triple-mutated acute myeloid leukemia. Biomarker research 4 40229904
2022 Novel IL1RAP mutation associated with schizophrenia interferes with neuronal growth and related NF-κB signal pathways. Neuroscience letters 4 35181481
2022 IL1RAP Knockdown in LPS-Stimulated Normal Human Astrocytes Suppresses LPS-Induced Reactive Astrogliosis and Promotes Neuronal Cell Proliferation. Neurochemical research 4 36502418
2020 Associations between IL1RAP rs4624606, IL1RL1 rs1041973, IL-6 rs1800795, and HTRA1 rs11200638 gene polymorphisms and development of optic neuritis with or without multiple sclerosis. Ophthalmic genetics 4 32449403
2020 Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome. International immunology 3 31954058
2025 Alternatively spliced mini-exon B in PTPδ regulates excitatory synapses through cell-type-specific trans-synaptic PTPδ-IL1RAP interaction. Nature communications 2 40360498
2025 IL1RAP Expression in Human Atherosclerosis: A Target of Novel Antibodies to Reduce Vascular Inflammation and Adhesion. Journal of the American Heart Association 2 40371594
2024 ZO-1 and IL-1RAP Phosphorylation: Potential Role in Mediated Brain-Gut Axis Dysregulation in Irritable Bowel Syndrome-like Stressed Mice. International journal of medical sciences 2 39006851
2024 Circ_0003314 Combines with the miR-26b-5p/IL1RAP Axis to Inhibit HTR-8/SVneo Cell Proliferation, Migration, Invasion and Tube Formation and Promote Apoptosis. Applied biochemistry and biotechnology 2 39141177
2025 Safety, efficacy, and analysis of biomarkers in patients with advanced non-small cell lung cancer treated with the anti-IL1RAP antibody nadunolimab (CAN04) in combination with platinum doublet. Lung cancer (Amsterdam, Netherlands) 1 40680438
2025 Elevated Clonal Hematopoiesis in 9/11 First Responders Has Distinct Age-related Patterns and Relies on IL1RAP for Clonal Expansion. Cancer discovery 1 41031953
2022 Bacterial production and biophysical characterization of a hard-to-fold scFv against myeloid leukemia cell surface marker, IL-1RAP. Molecular biology reports 1 36435922
2018 [Expressions and clinical significance of GAS1, IL-1RAP and PRF1 in patients with ALK positive anaplastic large cell lymphoma]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 1 29562445
2026 IL1RAP antibody-drug conjugates potently target primary and metastatic disease in multiple oncofusion-driven cancers. Cancer discovery 0 41973074
2026 Peripheral lncRNA-IL1RAP Dysregulation in Schizophrenia: A Multi-Omics Bridge Between Immunity and Diagnosis. Brain and behavior 0 41988836
2025 Association of IL-1RAcP rs16865597 gene polymorphism with susceptibility to essential hypertension: a case-control study in the Chinese Han population. BMC cardiovascular disorders 0 40075282
2025 MicroRNA-142 improves IL1RAP CAR-T cell activity in acute myeloid leukemia. Journal of hematology & oncology 0 41225489
2025 Global Deficiency of Alzheimer's Disease Risk Gene Il1rap Reduces Pathological Tau in a Mouse Model of Systemic Inflammation. ASN neuro 0 41353558
2024 IL1RAP Exacerbates Sepsis-Induced Pulmonary and Spleen Injury Through Regulating CD4+ T Lymphocyte Differentiation. Immunological investigations 0 38329477
2024 Circular RNA circMAN1A2 promotes ovarian cancer progression through the microRNA-135a-3p/IL1RAP/TAK1 pathway. PeerJ 0 38680890
2023 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. Discover oncology 0 36682035
2015 [Preparation and Assessment of IL1RAP Monoclonal Antibody]. Zhongguo shi yan xue ye xue za zhi 0 26314426
2015 [Cloning of VH and VL Gene of Human anti-IL1RAP McAb and Construction of Recombinant Chimeric Receptor]. Zhongguo shi yan xue ye xue za zhi 0 26524021
2013 [Construction of hybridoma cells with IL1RAP as a new marker for leukemia stem cells and detection of its monoclonal antibody]. Zhongguo shi yan xue ye xue za zhi 0 24370017