Affinage

IL36RN

Interleukin-36 receptor antagonist protein · UniProt Q9UBH0

Round 2 corrected
Length
155 aa
Mass
17.0 kDa
Annotated
2026-04-28
33 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL36RN encodes interleukin-36 receptor antagonist (IL-36Ra), a secreted IL-1 family member that functions as a specific antagonist of the IL-36 signaling axis by binding the IL-36 receptor (IL-1Rrp2/IL-1RL2) and preventing recruitment of the co-receptor IL-1RAcP, thereby blocking NF-κB activation driven by IL-36α, IL-36β, and IL-36γ (PMID:11466363, PMID:21965679, PMID:22315422). Full antagonist activity requires N-terminal processing—removal of the initiator methionine to expose Val-2—and the mature protein adopts an IL-1Ra-like β-trefoil fold, consistent with its origin by duplication of a primordial IL-1 receptor antagonist gene (PMID:21965679, PMID:10744718, PMID:10866108). IL-36Ra is predominantly expressed in keratinocytes and squamous epithelia, is induced by pro-inflammatory stimuli (IL-1α, TNF-α, IFN-γ), and limits IL-36-driven chemokine production and myeloid cell recruitment in the skin (PMID:10744718, PMID:21242515, PMID:24829417). Loss-of-function mutations in IL36RN cause deficiency of IL-36 receptor antagonist (DITRA), manifesting as generalized pustular psoriasis and related pustular inflammatory phenotypes due to unopposed IL-36 signaling (PMID:21839423, PMID:23698098).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1999 Medium

    Identification of IL36RN as a novel IL-1 receptor antagonist family member established that a second receptor antagonist gene existed within the IL-1 locus, raising the question of which receptor system it controlled.

    Evidence cDNA cloning, chromosomal mapping, Northern blot in skin and THP-1 cells

    PMID:10512743

    Open questions at the time
    • Target receptor unknown
    • No demonstration of antagonist activity
    • Processing and activation requirements uncharacterized
  2. 2000 Medium

    Concurrent genomic, structural, and expression studies from multiple groups confirmed IL36RN as a bona fide IL-1 family member with an IL-1Ra-like fold, conserved exon-intron structure indicating gene duplication origin, and highly restricted epithelial expression, resolving its evolutionary relationship but not its function.

    Evidence Genomic sequencing, circular dichroism spectroscopy, protein structure modeling, expression profiling across tissues

    PMID:10625660 PMID:10744718 PMID:10860666 PMID:10866108

    Open questions at the time
    • Functional antagonism not yet demonstrated in any assay
    • Cognate receptor and agonists not identified
    • Biological role in skin immunity not established
  3. 2001 High

    Reporter assays demonstrated that IL-36Ra specifically antagonizes IL-36γ-mediated NF-κB activation through IL-1Rrp2, establishing IL-36Ra/IL-36γ/IL-1Rrp2 as an independent IL-1 family signaling axis analogous to IL-1Ra/IL-1/IL-1R1.

    Evidence NF-κB-luciferase reporter assay with receptor specificity panels, quantitative RT-PCR

    PMID:11466363

    Open questions at the time
    • Mechanism of antagonism (co-receptor blockade vs. competitive displacement) not resolved
    • N-terminal processing requirements unknown
    • Antagonism of IL-36α and IL-36β not tested
  4. 2011 High

    Biochemical reconstitution showed that IL-36Ra requires N-terminal methionine removal to achieve full antagonist potency and that it blocks signaling by preventing IL-1RAcP recruitment to the IL-36R, resolving the molecular mechanism of antagonism and extending it to all three IL-36 agonists.

    Evidence Truncation mutagenesis of recombinant proteins, chimeric receptor experiments, co-immunoprecipitation, cell-based signaling assays

    PMID:21965679

    Open questions at the time
    • Protease responsible for N-terminal processing in vivo not identified
    • Structural basis of receptor binding at atomic resolution not determined
    • Stoichiometry and kinetics of receptor complex blockade not measured
  5. 2011 High

    Two discoveries converged to establish IL36RN in human disease: expression profiling showed massive IL-36Ra upregulation in psoriatic skin, while exome sequencing identified homozygous loss-of-function mutations (p.Ser113Leu, p.Arg48Trp) as the cause of generalized pustular psoriasis, with ex vivo demonstration of unopposed IL-36 signaling in mutation carriers.

    Evidence qRT-PCR and immunohistochemistry in psoriatic lesions; exome sequencing with Sanger validation and ex vivo cytokine stimulation assay in patient PBMCs

    PMID:21242515 PMID:21839423

    Open questions at the time
    • Structural impact of individual missense mutations not resolved
    • Whether partial loss-of-function alleles contribute to common psoriasis unknown
    • Cell-type-specific contribution (keratinocyte vs. myeloid) to disease pathogenesis not delineated
  6. 2012 High

    A systematic receptor-binding screen across all IL-1 receptor family members confirmed exclusive IL-36Ra binding to IL-1Rrp2 and demonstrated functional suppression of IL-22, IL-17, and IL-8 production from primary human immune cells, establishing physiological anti-inflammatory effects beyond keratinocytes.

    Evidence Immobilized extracellular domain binding screen, PBMC and dendritic cell cytokine assays

    PMID:22315422

    Open questions at the time
    • Relative contribution of IL-36Ra vs. IL-38 at the same receptor not resolved
    • In vivo immune cell targets in human tissue not mapped
    • Binding affinity and receptor occupancy not quantified
  7. 2013 Medium

    Expanded genetic studies established that IL36RN mutations account for the majority of GPP-without-psoriasis-vulgaris cases and that the disease spectrum extends to palmoplantar pustulosis and acrodermatitis continua of Hallopeau, defining DITRA as a distinct autoinflammatory entity.

    Evidence IL36RN mutation screening by sequencing in Japanese and European cohorts, genotype-phenotype correlation

    PMID:23303454 PMID:23698098

    Open questions at the time
    • No in vitro functional assessment of most identified mutant proteins
    • Genetic modifiers and incomplete penetrance factors uncharacterized
    • Whether heterozygous carriers have subclinical phenotype not established
  8. 2014 Medium

    Functional studies in keratinocytes and mouse models defined the downstream effector pathway: in the absence of IL-36Ra, IL-36 agonists drive expression of neutrophil-attracting chemokines (CXCL1, CXCL8, CCL20) and activate myeloid dendritic cells, explaining the neutrophilic pustular pathology of DITRA.

    Evidence Keratinocyte cytokine treatment, intradermal IL-36α injection in mice, flow cytometry, ELISA

    PMID:24829417

    Open questions at the time
    • Contribution of adaptive immunity and specific T cell subsets downstream of IL-36 not defined
    • Whether IL-36Ra directly modulates neutrophil function unknown
    • Tissue-specific regulatory mechanisms controlling IL-36Ra expression not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the protease(s) that process IL-36Ra N-terminally in vivo, the atomic-resolution structure of the IL-36Ra–IL-36R complex, and the mechanistic basis by which specific IL36RN missense mutations differentially affect protein stability versus receptor binding.
  • In vivo processing protease not identified
  • No crystal or cryo-EM structure of IL-36Ra bound to IL-36R
  • Structure-function relationship of disease-causing missense mutations not systematically characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
IL1RAPIL1RL2

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 IL36RN (then called IL1HY1) was identified as a novel member of the IL-1 receptor antagonist gene family, encoding a protein with 52% amino acid homology to IL-1Ra, mapped to chromosome 2q near the IL-1 locus, and shown to be predominantly expressed in skin with inducibility in THP-1 cells by PMA and LPS treatment. cDNA cloning, chromosomal mapping, Northern blot expression analysis, EST database searching Biochemical and biophysical research communications Medium 10512743
2000 IL36RN (IL-1RP3/IL-1F5) was identified as one of three novel IL-1 family members within the IL-1 gene cluster on chromosome 2q, sharing a signature IL-1 family motif, more closely related to IL-1Ra, lacking a conventional hydrophobic signal sequence, and showing highly restricted expression in epithelial cell populations. EST database searching, genomic sequencing, sequence homology analysis, expression analysis Genomics Medium 10860666
2000 The IL36RN (IL1HY1) gene was found to contain four coding exons, with the 5' UTR formed by alternatively used exons, and intron positions within the protein-coding region are conserved with IL-1Ra, providing evidence that IL36RN and IL-1Ra arose from duplication of a primordial IL-1 receptor antagonist gene. Genomic sequencing (~7,600 nucleotides), exon-intron structure determination, comparative genomics Immunogenetics Medium 10866108
2000 IL36RN (FIL1delta/IL-1F5) was cloned and characterized as an IL-1 family member with structural homology to IL-1Ra by protein structure modeling, placed in a gene cluster on chromosome 2q with conserved exon-intron arrangement shared with other IL-1 family members. cDNA cloning, protein structure modeling, chromosomal mapping, sequence analysis The Journal of biological chemistry Medium 10625660
2000 IL36RN (IL-1H1) was shown by circular dichroism spectra and thermal stability analysis to fold similarly to IL-1Ra, is constitutively expressed only in placenta and squamous epithelium of the esophagus, and can be induced in keratinocytes by interferon-gamma and TNF-alpha and in vivo via contact hypersensitivity or herpes simplex virus infection. Circular dichroism spectroscopy, thermal stability analysis, expression cloning, in vivo induction models The Journal of biological chemistry Medium 10744718
2001 IL36RN (IL-1delta) was demonstrated to function as a specific and potent antagonist of IL-1epsilon (IL-36γ)-mediated NF-κB activation through the orphan receptor IL-1Rrp2 (IL-36R), establishing that IL-1delta/IL36RN, IL-1epsilon, and IL-1Rrp2 constitute an independent signaling system analogous to IL-1αβ/IL-1Ra/IL-1R1. NF-κB-luciferase reporter assay, receptor specificity assays, quantitative real-time PCR Journal of immunology High 11466363
2002 Precise chromosomal mapping of the IL-1 gene cluster established that IL36RN (IL1F5) is located on chromosome 2q between IL1F8 and IL1F10, with gene order from centromere to telomere being IL1A-IL1B-IL1F7-IL1F9-IL1F6-IL1F8-IL1F5-IL1F10-IL1RN, and that key features of exon boundaries are conserved across family members. Genomic sequencing, physical mapping, SNP and microsatellite marker mapping Genomics Medium 11991722
2011 IL36RN (IL-1F5) antagonist activity requires N-terminal processing: removal of the N-terminal methionine to yield Val-2 as the start residue is required for full antagonist activity. Val-2-initiated IL-36Ra fully inhibits IL-36α, IL-36β, and IL-36γ. The mechanism of IL-36Ra antagonism is analogous to IL-1Ra: IL-36Ra binds to IL-1Rrp2 (IL-36R) and prevents IL-1RAcP recruitment, thereby blocking formation of a functional signaling complex. In vitro antagonist activity assays with N-terminally truncated recombinant proteins, chimeric receptor experiments, co-immunoprecipitation, cell-based signaling assays The Journal of biological chemistry High 21965679
2011 IL36RN (IL-1F5/IL-36Ra) expression is increased 2–3 orders of magnitude in psoriasis plaque skin versus uninvolved skin. IL-36Ra (IL-1F5) is induced in normal keratinocytes by IL-1α and TNF-α, and its expression decreases with etanercept treatment concomitant with clinical improvement, placing it as part of the IL-1F5/F6/F8/F9 signaling system active in inflammatory skin disease. Quantitative RT-PCR, immunohistochemistry, mouse models of psoriasis, microarray analysis of reconstituted human epidermis Journal of immunology Medium 21242515
2011 Loss-of-function mutations in IL36RN (p.Ser113Leu and p.Arg48Trp, altering evolutionarily conserved residues) cause generalized pustular psoriasis (GPP). Homozygosity for the p.Ser113Leu variant is associated with an elevated proinflammatory cytokine response following ex vivo stimulation with IL-36α, demonstrating that IL36RN loss of function leads to unopposed IL-36 signaling and systemic inflammation. Exome sequencing, Sanger validation, population genetics, ex vivo cytokine stimulation assay American journal of human genetics High 21839423
2012 IL-36Ra (IL36RN protein) binds specifically to the IL-36 receptor (IL-1Rrp2) as demonstrated by screening immobilized extracellular domains of all IL-1 receptor family members, and has biological effects on immune cells (inhibiting IL-22 and IL-17 production from T lymphocytes and IL-8 from monocytes stimulated with IL-36γ) similar to those of IL-38 acting via the same receptor. Receptor-binding screen with immobilized extracellular domains of IL-1 receptor family members, PBMC cytokine production assays, dendritic cell activation assays Proceedings of the National Academy of Sciences of the United States of America High 22315422
2013 Homozygous or compound heterozygous IL36RN mutations account for the majority (9 of 11 cases) of GPP without psoriasis vulgaris in a Japanese cohort, establishing that GPP-alone is a distinct disease subtype caused by deficiency of IL-36 receptor antagonist, while GPP with psoriasis vulgaris has a different genetic etiology. IL36RN mutation screening by sequencing, genotype-phenotype correlation analysis The Journal of investigative dermatology Medium 23698098
2013 Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes beyond GPP, including palmoplantar pustulosis and acrodermatitis continua of Hallopeau, extending the loss-of-function disease spectrum of IL36RN. Candidate gene sequencing, genotype-phenotype correlation The Journal of investigative dermatology Medium 23303454
2013 Rare variations in IL36RN are found in patients with acute generalized exanthematous pustulosis (AGEP), a severe adverse drug reaction, suggesting that reduced IL-36 receptor antagonist function is a predisposing factor for this drug-induced pustular phenotype. Candidate gene sequencing in AGEP cases versus controls The Journal of investigative dermatology Low 23358093
2014 IL-36Ra (IL36RN protein), produced by keratinocytes, acts to limit IL-36-driven skin inflammation: in the absence of adequate IL-36Ra, IL-36 cytokines drive expression of chemokines (CXCL1, CXCL8, CCL3, CCL5, CCL20) in keratinocytes and activate myeloid dendritic cells and monocytes via IL-36R, promoting myeloid cell infiltration and acanthosis. Human keratinocyte cytokine treatment, intradermal injection of IL-36α in mice, flow cytometry, ELISA, allogeneic T cell proliferation assay Journal of immunology Medium 24829417
2014 IL36RN mutations (including p.Ser113Leu) define a severe autoinflammatory phenotype of GPP with systemic features, and some patients with IL36RN deficiency respond poorly to conventional psoriasis treatments but may benefit from IL-1 pathway blockade, further validating IL36RN loss-of-function as mechanistically driving IL-36 pathway overactivation. IL36RN sequencing, clinical phenotyping, treatment response analysis The Journal of allergy and clinical immunology Low 25458002

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2011 Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. American journal of human genetics 416 21839423
2012 IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist. Proceedings of the National Academy of Sciences of the United States of America 304 22315422
2011 Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36α, IL-36β, and IL-36γ) or antagonist (IL-36Ra) activity. The Journal of biological chemistry 285 21965679
2003 The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome research 285 12975309
1994 A physical map of the region encompassing the human interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist genes. Genomics 281 8188271
2000 Four new members expand the interleukin-1 superfamily. The Journal of biological chemistry 276 10625660
2000 Identification and initial characterization of four novel members of the interleukin-1 family. The Journal of biological chemistry 275 10744718
2011 IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression. Journal of immunology (Baltimore, Md. : 1950) 254 21242515
2014 IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin. Journal of immunology (Baltimore, Md. : 1950) 253 24829417
2013 The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. The Journal of investigative dermatology 249 23698098
2004 Functional proteomics mapping of a human signaling pathway. Genome research 247 15231748
2001 Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2. Journal of immunology (Baltimore, Md. : 1950) 213 11466363
2001 IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp. Cytokine 169 11145836
2001 Cloning and characterization of IL-1HY2, a novel interleukin-1 family member. The Journal of biological chemistry 169 11278614
2002 A sequence-based map of the nine genes of the human interleukin-1 cluster. Genomics 168 11991722
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2007 Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study. Arteriosclerosis, thrombosis, and vascular biology 142 17975119
2000 Identification and gene organization of three novel members of the IL-1 family on human chromosome 2. Genomics 140 10860666
2013 Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. The Journal of investigative dermatology 137 23303454
2001 A new nomenclature for IL-1-family genes. Trends in immunology 121 11574262
2014 IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis. The Journal of allergy and clinical immunology 115 25458002
2013 Rare variations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis. The Journal of investigative dermatology 112 23358093
1999 IL1HY1: A novel interleukin-1 receptor antagonist gene. Biochemical and biophysical research communications 76 10512743
2000 Organization of the human interleukin-1 receptor antagonist gene IL1HY1. Immunogenetics 16 10866108