Affinage

IL20RB

Interleukin-20 receptor subunit beta · UniProt Q6UXL0

Length
311 aa
Mass
35.1 kDa
Annotated
2026-04-28
26 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-20RB (IL-20R2) is a shared cytokine receptor subunit that heterodimerizes with either IL-20R1 or IL-22R1 to transduce signals from the IL-20 subfamily cytokines IL-19, IL-20, and IL-24, activating JAK1/STAT3 (and JAK2/PI3K-Akt) cascades in keratinocytes, macrophages, and tumor cells (PMID:11706020, PMID:36006737, PMID:38583686). Crystal structures of the IL-20/IL-20R1/IL-20R2 and IL-24/IL-22R1/IL-20R2 ternary complexes reveal affinity-tuned binding interfaces that allow IL-20RB to discriminate among its three cognate ligands, with tyrosine 70 of IL-20R2 serving as a critical contact residue for IL-24 binding (PMID:22802649, PMID:30111632, PMID:37484532). IL-20RB is non-redundantly required downstream of IL-23 for epidermal hyperplasia and psoriasis-like pathology, and it drives profibrotic macrophage polarization in pulmonary fibrosis as well as cancer stemness, chemoresistance, and bone metastasis in lung and pancreatic cancers (PMID:17074928, PMID:31167692, PMID:38583686, PMID:36006737, PMID:38098005). IL-20RB expression is transcriptionally repressed by TAp63α, which is itself targeted for ubiquitin-dependent degradation by the E3 ligase TRIM21, linking upstream proteasomal control to IL-20RB-dependent STAT3 activation and metastatic progression (PMID:40460193).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2001 High

    Establishing that IL-20RB is a shared receptor subunit resolved how IL-24 signals through two distinct heterodimeric complexes (IL-20R1/IL-20R2 and IL-22R1/IL-20R2) to activate STAT transcription factors.

    Evidence Ligand binding assays on transfected COS cells and STAT activation assays in keratinocytes and BHK cells

    PMID:11706020

    Open questions at the time
    • Relative contributions of each heterodimer to IL-24 signaling in physiological tissues unknown
    • Signaling specificity downstream of each complex not resolved
  2. 2006 High

    Demonstrating that IL-20R2 knockout abolished IL-23-induced epidermal hyperplasia — while single IL-19 or IL-24 knockouts did not — established IL-20RB as a non-redundant signaling node integrating multiple IL-20 subfamily ligands in skin inflammation.

    Evidence Intradermal IL-23 injection in IL-20R2−/−, IL-19−/−, and IL-24−/− mice with histological readout

    PMID:17074928

    Open questions at the time
    • Which individual IL-20 subfamily ligand(s) are essential downstream of IL-23 remained unresolved
    • Cellular source of ligands in the epidermal niche not defined
  3. 2012 High

    The crystal structure of the IL-20/IL-20R1/IL-20R2 ternary complex provided the first atomic-level explanation for how IL-20RB serves as a shared subunit for three cytokines through affinity-tuned binding interfaces.

    Evidence X-ray crystallography of the IL-20/IL-20R1/IL-20R2 complex

    PMID:22802649

    Open questions at the time
    • Structure of the IL-19-containing complex not determined
    • How affinity differences translate to signaling kinetics in vivo not tested
  4. 2016 Medium

    Discovery of an alternatively spliced IL-20RB isoform that escapes exon I deletion explained why earlier knockout mice showed incomplete psoriatic phenotypes, revealing a layer of transcript-level regulation.

    Evidence Cloning of alternative transcript, PCR, western blot, imiquimod psoriasis model in exon I knockout mice

    PMID:27009487

    Open questions at the time
    • Functional activity and signaling competence of the alternative isoform not fully characterized
    • Tissue distribution of isoforms not comprehensively mapped
  5. 2018 High

    The 2.15 Å structure of the IL-24/IL-22R1/IL-20R2 complex revealed that IL-20R2 is the higher-affinity subunit in this complex and explained IL-24 instability through unpaired cysteines, completing the structural picture of both IL-20RB-containing receptor assemblies.

    Evidence X-ray crystallography of fusion-stabilized IL-24/IL-22R1/IL-20R2 complex with STAT activation validation

    PMID:30111632

    Open questions at the time
    • No IL-19/receptor complex structure available for comparison
    • How differential affinity governs cell-type-specific responses not addressed
  6. 2019 Medium

    IL-20R2 knockdown attenuated imiquimod-induced psoriasis in mice, independently confirming the non-redundant requirement for IL-20RB signaling in keratinocyte-driven epidermal inflammation first observed in full knockouts.

    Evidence IL-20R2 knockdown mice, imiquimod psoriasis model, histology and western blot

    PMID:31167692

    Open questions at the time
    • Knockdown efficiency and residual IL-20RB activity not precisely quantified
    • Relative contribution of macrophage vs. keratinocyte IL-20RB not dissected
  7. 2020 Medium

    Identification of Toxoplasma gondii ROP18 as an exogenous activator that co-opts IL-20RB to trigger host JAK/STAT3 signaling expanded the receptor's biology beyond endogenous cytokine signaling to pathogen exploitation.

    Evidence FRET, co-immunoprecipitation, STAT3 phosphorylation in IL-20RB-positive vs. IL-20RB-negative cell lines using CRISPR knockout parasites

    PMID:32767999

    Open questions at the time
    • In vivo relevance during Toxoplasma infection not demonstrated
    • Binding site on IL-20RB for ROP18 not structurally defined
  8. 2022 High

    Showing that IL-19/IL-20RB signaling through JAK1/STAT3 in the bone metastatic niche drives lung cancer cell proliferation — suppressible by neutralizing anti-IL-20RB antibody — established a tumor-extrinsic paracrine loop and therapeutic vulnerability.

    Evidence IL-20RB overexpression/knockdown in lung cancer cells, in vivo bone metastasis model, neutralizing antibody, JAK1/STAT3 western blot

    PMID:36006737

    Open questions at the time
    • Patient-derived data on IL-20RB expression in bone metastases limited
    • Contribution of IL-20 and IL-24 ligands to the same niche not separated
  9. 2023 Medium

    Photocaging of tyrosine 70 in IL-20R2 blocked IL-24 binding and signaling, with UV-mediated restoration proving that this single residue is a critical determinant of ligand–receptor complex assembly.

    Evidence Genetic code expansion with ortho-nitrobenzyl-tyrosine incorporation, biophysical binding and STAT phosphorylation assays

    PMID:37484532

    Open questions at the time
    • Whether Y70 is equally important for IL-19 or IL-20 binding not tested
    • Approach not validated in primary cells
  10. 2023 Medium

    IL-20RB/STAT3 signaling was shown to promote cancer stemness and chemoresistance in pancreatic cancer, broadening the receptor's oncogenic roles beyond metastasis to treatment resistance.

    Evidence IL-20RB overexpression/knockdown in pancreatic cancer cells, spheroid formation, side-population analysis, in vivo tumor formation, STAT3 inhibitor rescue

    PMID:38098005

    Open questions at the time
    • Identity of microenvironmental cells supplying IL-19 in pancreatic tumors not defined
    • Whether other IL-20 subfamily members contribute equally not resolved
  11. 2024 Medium

    Demonstrating that IL-20RB drives profibrotic M2-like macrophage polarization via JAK2/STAT3 and PI3K/Akt signaling extended its pathological roles to pulmonary fibrosis and identified JAK2 as an additional kinase partner beyond JAK1.

    Evidence Bleomycin-induced pulmonary fibrosis model, THP1 macrophage polarization, IL-20RB knockdown and neutralizing antibody, JAK2/STAT3 and PI3K/Akt western blot

    PMID:38583686

    Open questions at the time
    • Whether JAK2 directly associates with IL-20RB or with IL-20R1 not biochemically resolved
    • Ligand identity driving macrophage IL-20RB signaling in fibrotic lung not pinpointed
  12. 2025 Medium

    Discovery that TRIM21-mediated ubiquitin degradation of TAp63α derepresses IL-20RB transcription defined the first upstream regulatory axis controlling IL-20RB expression and linked it to PDAC metastasis.

    Evidence TRIM21/TAp63α overexpression/knockdown, promoter methylation analysis, ubiquitination assays, in vivo metastasis seeding in PDAC models

    PMID:40460193

    Open questions at the time
    • Direct TAp63α binding to IL-20RB promoter not shown by ChIP
    • Whether this regulatory axis operates in non-tumor tissues not examined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the two IL-20RB-containing receptor complexes (type I and type II) differentially activate downstream transcriptional programs in specific cell types, and the structural basis of IL-19 recognition by IL-20RB, remain unresolved.
  • No crystal structure of an IL-19-containing receptor complex
  • Cell-type-specific signaling outputs of the two receptor complexes not systematically compared
  • Role of alternative IL-20RB isoform in disease contexts unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 4
Pathway
GO:0060089 molecular transducer activity 1
Partners
IL19IL20IL20R1IL22R1IL24JAK1STAT3TAP63
Complex memberships
IL-20R1/IL-20R2 type I receptor complexIL-22R1/IL-20R2 type II receptor complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 IL-20RB (IL-20R2) forms two distinct heterodimeric receptor complexes—IL-22R1/IL-20R2 and IL-20R1/IL-20R2—that both serve as functional receptors for IL-24, with binding leading to activation of STAT transcription factors in keratinocytes and BHK cells. Ligand binding assays on transfected COS cells, STAT activation assays in keratinocytes and BHK cells expressing ectopic receptors The Journal of biological chemistry High 11706020
2006 IL-20R2 (IL-20RB) is required downstream of IL-23 for epidermal hyperplasia in mouse skin; IL-23-induced epidermal hyperplasia was abolished in IL-20R2-/- mice but not in IL-19-/- or IL-24-/- single knockouts, placing IL-20R2 as a non-redundant effector in the IL-23 → IL-20 subfamily cytokine → epidermal hyperplasia pathway. Intradermal IL-23 injection in IL-20R2-/-, IL-19-/-, and IL-24-/- mice with histological readout of epidermal hyperplasia The Journal of experimental medicine High 17074928
2012 Crystal structure of the IL-20/IL-20R1/IL-20R2 ternary complex reveals the molecular basis for shared IL-20R2 usage by three cytokines (IL-19, IL-20, IL-24): receptor-cytokine interfaces are affinity-tuned to allow discrimination of cognate from noncognate ligands across type I (IL-20R1/IL-20R2) and type II (IL-22R1/IL-20R2) complexes. X-ray crystallography of the IL-20/IL-20R1/IL-20R2 ternary complex Proceedings of the National Academy of Sciences of the United States of America High 22802649
2018 Crystal structure of the IL-24/IL-22R1/IL-20R2 ternary complex at 2.15 Å resolution shows that two cysteines in IL-24 do not form a predicted disulfide bond, explaining IL-24 instability, and reveals that the IL-24–IL-20R2 interface is slightly more stable than the IL-24–IL-22R1 interface, suggesting IL-20R2 is the higher-affinity receptor in this complex. X-ray crystallography of fusion-stabilized IL-24/IL-22R1/IL-20R2 complex; cell-based STAT activation assay to confirm IL-24 activity Journal of immunology High 30111632
2016 Alternative splicing of the IL-20R2 (IL-20RB) gene produces two isoforms; deletion of exon I leaves the alternatively spliced isoform intact, explaining why exon I knockout mice showed an incomplete loss of IL-20R2-dependent psoriatic phenotypes. Molecular cloning of alternatively spliced transcript, PCR sequencing, western blot, imiquimod-induced psoriasis mouse model Genes and immunity Medium 27009487
2020 Toxoplasma gondii rhoptry protein TgROP18 physically interacts with the extracellular domain of IL-20RB and activates the host JAK/STAT3 pathway through this interaction; STAT3 phosphorylation by recombinant ROP18 was only observed in cells with endogenous IL-20RB expression, and the effect was dose-dependent. FRET, co-immunoprecipitation, CRISPR-Cas9 double-knockout parasite strain (RH-Δrop16Δrop18), western blot of STAT3 phosphorylation in IL-20RB-positive vs. negative cell lines Parasites & vectors Medium 32767999
2022 IL-20RB mediates IL-19-driven JAK1/STAT3 signaling in lung cancer cells in the bone metastatic niche; tumor cells induce osteoclasts to secrete IL-19, which activates IL-20RB on tumor cells to promote proliferation, and a neutralizing anti-IL-20RB antibody suppressed bone metastasis in vivo. IL-20RB overexpression/knockdown in lung cancer cell lines, in vivo bone metastasis models, neutralizing antibody treatment, western blot for JAK1/STAT3 phosphorylation The Journal of clinical investigation High 36006737
2023 IL-20RB promotes stemness and chemotherapy resistance in pancreatic cancer by activating STAT3 phosphorylation downstream of IL-19 (its primary microenvironmental ligand); STAT3 phosphorylation inhibitors counteracted these effects. IL-20RB overexpression and knockdown in pancreatic cancer cell lines, clonal/spheroid formation, side-population analysis, in vivo tumor formation, STAT3 inhibitor rescue Journal of translational medicine Medium 38098005
2023 Introduction of a photocaged non-canonical amino acid (ortho-nitrobenzyl-tyrosine) at tyrosine70 of IL-20R2 impairs IL-24/IL-20R2 heterocomplex assembly; UV irradiation restores native tyrosine and reconstitutes JAK/STAT signaling, demonstrating that tyrosine70 is critical for IL-24 binding to IL-20R2. Genetic code expansion/photocaged amino acid incorporation, biophysical binding assays, cell signaling (STAT phosphorylation) assays Frontiers in molecular biosciences Medium 37484532
2024 IL-20RB promotes profibrotic macrophage (M2-like) polarization and pulmonary fibrosis by activating JAK2/STAT3 and PI3K/Akt signaling pathways; IL-20RB knockdown or neutralizing antibody treatment attenuated bleomycin-induced fibrosis. Bleomycin-induced pulmonary fibrosis model, IL4/IL-13-induced THP1 M2 polarization model, IL-20RB knockdown, neutralizing antibody treatment, western blot for JAK2/STAT3 and PI3K/Akt Pharmacological research Medium 38583686
2025 TAp63α transcriptionally represses IL-20RB expression (potentially via promoter methylation); TRIM21 E3 ligase promotes ubiquitin-dependent degradation of TAp63α, thereby derepressing IL-20RB and enabling IL-20 receptor complex formation and downstream JAK1-STAT3 activation that drives PDAC cell proliferation, EMT, migration, and metastatic seeding. TRIM21 and TAp63α overexpression/knockdown in PDAC cell lines, promoter methylation analysis, ubiquitination assays, STAT3 phosphorylation western blot, in vivo metastasis seeding assay Science signaling Medium 40460193
2019 Knockdown of IL-20R2 in mice significantly reduces imiquimod-induced psoriasis-like skin pathology, confirming an essential role of IL-20RB signaling in keratinocyte-driven epidermal inflammation. IL-20R2 knockdown mice, imiquimod-induced psoriasis model, HE staining, western blot, PCR Xi bao yu fen zi mian yi xue za zhi Medium 31167692
2022 In grass carp (teleost ortholog), IL-20R2 binds directly to IL-20 (shown by co-immunoprecipitation), while IL-20R1 is responsible for STAT3 phosphorylation signaling; key residues at the IL-20/receptor interface are conserved between fish and human, suggesting conserved receptor assembly mechanism. Co-immunoprecipitation, STAT3 phosphorylation western blot, structural modeling Fish & shellfish immunology Medium 36414129

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. The Journal of experimental medicine 556 17074928
2001 Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2. The Journal of biological chemistry 224 11706020
1985 Sequence of Dictyostelium DIRS-1: an apparent retrotransposon with inverted terminal repeats and an internal circle junction sequence. Cell 93 2416457
2012 Structural basis for receptor sharing and activation by interleukin-20 receptor-2 (IL-20R2) binding cytokines. Proceedings of the National Academy of Sciences of the United States of America 77 22802649
2022 IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer. The Journal of clinical investigation 76 36006737
2005 DIRS-1 and the other tyrosine recombinase retrotransposons. Cytogenetic and genome research 55 16093711
2012 ALOG domains: provenance of plant homeotic and developmental regulators from the DNA-binding domain of a novel class of DIRS1-type retroposons. Biology direct 43 23146749
1984 Dictyostelium transposable element DIRS-1 has 350-base-pair inverted terminal repeats that contain a heat shock promoter. Proceedings of the National Academy of Sciences of the United States of America 36 6326136
2006 The murine liver is a potential target organ for IL-19, IL-20 and IL-24: Type I Interferons and LPS regulate the expression of IL-20R2. Journal of hepatology 24 17069926
2008 Association analysis of IL20RA and IL20RB genes in psoriasis. Genes and immunity 22 18480827
2018 Crystal Structure of the Labile Complex of IL-24 with the Extracellular Domains of IL-22R1 and IL-20R2. Journal of immunology (Baltimore, Md. : 1950) 20 30111632
2024 IL20Rb aggravates pulmonary fibrosis through enhancing bone marrow derived profibrotic macrophage activation. Pharmacological research 15 38583686
1984 Transcription of Dictyostelium discoideum transposable element DIRS-1. Molecular and cellular biology 15 6096693
2020 TgROP18 targets IL20RB for host-defense-related-STAT3 activation during Toxoplasma gondii infection. Parasites & vectors 12 32767999
2019 Insertion Hot Spots of DIRS1 Retrotransposon and Chromosomal Diversifications among the Antarctic Teleosts Nototheniidae. International journal of molecular sciences 12 30736325
2013 The Dictyostelium discoideum RNA-dependent RNA polymerase RrpC silences the centromeric retrotransposon DIRS-1 post-transcriptionally and is required for the spreading of RNA silencing signals. Nucleic acids research 12 24369430
2023 IL20RB signaling enhances stemness and chemotherapy resistance in pancreatic cancer. Journal of translational medicine 10 38098005
2014 Argonaute proteins affect siRNA levels and accumulation of a novel extrachromosomal DNA from the Dictyostelium retrotransposon DIRS-1. The Journal of biological chemistry 9 25352599
2023 Regulation of IL-24/IL-20R2 complex formation using photocaged tyrosines and UV light. Frontiers in molecular biosciences 7 37484532
2025 The E3 ligase TRIM21 promotes progression of pancreatic ductal adenocarcinoma by down-regulating TAp63α and derepressing IL20RB. Science signaling 6 40460193
2022 Grass carp IL-20 binds to IL-20R2 but induces STAT3 phosphorylation via IL-20R1. Fish & shellfish immunology 6 36414129
2022 The IL-20RB receptor and the IL-20 signaling pathway in regulating host defense in oral mucosal candidiasis. Frontiers in cellular and infection microbiology 5 36225230
2013 Detection of IL-20R1 and IL-20R2 mRNA in C57BL/6 mice astroglial cells and brain cortex following LPS stimulation. Iranian journal of immunology : IJI 4 23811545
2016 Alternative splicing directs two IL-20R2 isoforms and is responsible for the incomplete gene knockout via the exon I ablation. Genes and immunity 2 27009487
2019 [Knockdown of interleukin 20 receptor 2 (IL-20R2) inhibits the development of psoriasis induced by imiquimod in mice]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 1 31167692
2011 Purification, crystallization and preliminary X-ray diffraction analysis of the IL-20-IL-20R1-IL-20R2 complex. Acta crystallographica. Section F, Structural biology and crystallization communications 0 22232181