Affinage

IL20RA

Interleukin-20 receptor subunit alpha · UniProt Q9UHF4

Length
553 aa
Mass
62.5 kDa
Annotated
2026-06-10
20 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL20RA (IL-20R1/ZCYTOR7) is a cytokine receptor subunit that assembles heterodimeric signaling complexes to transduce IL-19, IL-20, and IL-24 family signals into JAK1–STAT3 transcriptional programs governing epithelial homeostasis, inflammation, and tumor biology (PMID:11706020, PMID:33456560). It pairs with IL-20R2 to form ligand-binding heterodimers: IL-24 signals through both IL-20R1/IL-20R2 and IL-22R1/IL-20R2 complexes, with IL-20R1 binding ligand and activating STAT transcription factors in keratinocytes and other cells (PMID:11706020), and the IL-20/IL-20R1/IL-20R2 assembly forms a 1:1:1 ternary complex (PMID:22232181). Ligand engagement of receptor-1 subunits is governed by a flexible region around residue T198 in IL-24, which controls binding affinity to IL-20R1 and IL-22R1 and signaling competence (PMID:31152679). Within the heterodimer, IL-20R1 contributes the signal-transducing function, placing it upstream of JAK1–STAT3—but not JAK1–STAT1—signaling (PMID:34283251). Through this axis IL-20RA drives diverse physiology: it is required for IL-20-mediated hepatic stellate cell activation and CCl4-induced liver fibrosis (PMID:24763901), activates a JAK1–STAT3–SOX2 program that enhances cancer stemness and induces PD-L1 while remodeling the immune microenvironment in breast cancer (PMID:33456560), and mediates rIL-19-driven CD163 scavenger-receptor upregulation and hematoma resolution via an IL-20R1/ERK/Nrf2 pathway (PMID:33532035). IL-20RA expression is itself regulated post-transcriptionally by miR-452 (PMID:34283251) and through a distal NF-κB-bound regulatory element near TNFAIP3 that loops to the IL-20RA locus (PMID:29483615), and it contributes to leukocyte transmigration across intestinal lymphatic endothelium in Crohn's disease (PMID:31426584).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2001 High

    Established which receptor complexes transduce IL-24/IL-20 signals, defining IL-20R1 as a shared signaling subunit that activates STATs upon ligand binding.

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

    PMID:11706020

    Open questions at the time
    • Did not resolve the relative contributions of IL-20R1 versus IL-20R2 to ligand capture vs signal transduction
    • No structural basis for heterodimer assembly
  2. 2011 Medium

    Defined the stoichiometry of the signaling complex by purifying and crystallizing a 1:1:1 IL-20/IL-20R1/IL-20R2 ternary assembly.

    Evidence Protein purification, crystallization, and preliminary X-ray diffraction to 3 Å

    PMID:22232181

    Open questions at the time
    • No full refined structure reported in this work
    • Interface residues mediating receptor assembly not yet mapped
  3. 2014 High

    Demonstrated a required in vivo role for IL-20R1 in disease by showing it drives IL-20-mediated hepatic stellate cell activation and liver fibrosis.

    Evidence IL-20R1-deficient mice, anti-IL-20R1 antibody blockade, and in vitro HSC assays in a CCl4 liver injury model

    PMID:24763901

    Open questions at the time
    • Downstream transcription factors in HSCs not specified
    • Cell-type-specific receptor requirement (HSC vs hepatocyte) not dissected genetically
  4. 2018 Medium

    Identified a distal cis-regulatory mechanism controlling IL-20RA expression, linking an autoimmune risk variant to receptor levels.

    Evidence CRISPR/Cas9 deletion in HEK293T, EMSA, and 3C chromatin conformation capture of an element ~140 kb upstream of TNFAIP3

    PMID:29483615

    Open questions at the time
    • Physiological cell types where this looping operates not defined
    • Functional consequence of altered IL-20RA dose on signaling output not measured
  5. 2019 High

    Mapped the ligand determinant governing receptor-1 engagement, showing residue T198 in IL-24 dictates IL-20R1/IL-22R1 binding affinity and signaling.

    Evidence PROSS-based protein engineering, biophysical binding to receptor ectodomains, signaling assays, and crystal structure (PDB 6GG1)

    PMID:31152679

    Open questions at the time
    • Corresponding receptor-side binding residues on IL-20R1 not resolved
    • Does not address IL-19/IL-20 binding determinants
  6. 2019 Medium

    Implicated IL-20RA intracellular signaling in pathological leukocyte trafficking across lymphatic endothelium in Crohn's disease.

    Evidence Transcriptomics of human intestinal lymphatic endothelial cells, transwell transmigration assay, and mTOR pathway manipulation

    PMID:31426584

    Open questions at the time
    • Downstream signaling effectors in endothelial cells not defined
    • Ligand driving the response not identified
  7. 2021 Medium

    Connected IL-20RA to cancer stemness and immune evasion through a JAK1–STAT3–SOX2 axis and PD-L1 induction.

    Evidence Gain- and loss-of-function in breast cancer cell lines and mouse models with flow cytometry and in vivo tumor assays

    PMID:33456560

    Open questions at the time
    • Ligand driving tumor-cell IL-20RA signaling not defined
    • Single-lab in vivo validation
  8. 2021 Medium

    Placed IL-20RA upstream of JAK1–STAT3 (but not STAT1) and identified miR-452 as a direct post-transcriptional regulator in colorectal cancer.

    Evidence Luciferase 3'UTR reporter, siRNA knockdown, Western blot, and RT-PCR

    PMID:34283251

    Open questions at the time
    • Mechanistic basis for STAT3 vs STAT1 selectivity not resolved
    • In vivo relevance of miR-452/IL-20RA axis not tested
  9. 2021 Medium

    Revealed an ERK/Nrf2 branch of IL-20R1 signaling driving CD163 scavenger-receptor upregulation and hematoma resolution.

    Evidence Rat germinal matrix hemorrhage model with rIL-19 treatment, IL-20R1 CRISPR knockdown, and immunohistochemistry

    PMID:33532035

    Open questions at the time
    • Whether ERK/Nrf2 acts independently of JAK–STAT not clarified
    • Single-lab in vivo model
  10. 2022 Medium

    Refined the division of labor within the heterodimer in a fish ortholog, with IL-20R2 capturing ligand and IL-20R1 transducing STAT3 phosphorylation.

    Evidence Co-immunoprecipitation, STAT3 phosphorylation assay, and structural modeling in grass carp

    PMID:36414129

    Open questions at the time
    • Non-mammalian model; mammalian receptor labor division not directly retested
    • Co-IP not reciprocally validated for human receptors
  11. 2024 Medium

    Extended the receptor-1 transducer role to IL-26 signaling and mucosal barrier protection in a fish ortholog.

    Evidence Co-immunoprecipitation, RNAi knockdown of IL20R1, JAK1–STAT3 readout, and in vivo bacterial challenge in crucian carp hybrid

    PMID:39154973

    Open questions at the time
    • IL-26/IL-20R1 interaction not demonstrated for the human receptor
    • Single-lab non-mammalian system
  12. 2024 Low

    Linked IL-20RA to mitochondrial antioxidant capacity in pig Sertoli cells.

    Evidence siRNA knockdown with ROS, mitochondrial superoxide, catalase, and transcriptomic readouts

    PMID:39765872

    Open questions at the time
    • Single-method knockdown without rescue or pathway dissection
    • Non-human cells; mechanism linking receptor to mitochondria undefined
  13. 2025 Low

    Associated IL-20RA with apoptosis/ferroptosis suppression and STAT3/SNAIL-driven EMT in Wilms tumor cells.

    Evidence siRNA knockdown with apoptosis, ferroptosis, and EMT marker analysis

    PMID:40185911

    Open questions at the time
    • Pathway placement inferred without full mechanistic validation
    • Abstract-level description; not independently confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the assembled signaling heterodimer and the molecular basis for IL-20R1's STAT3-over-STAT1 selectivity remain unresolved.
  • No refined full structure of the ternary signaling complex reported
  • Determinants of STAT3 vs STAT1 bias not mechanistically defined
  • Receptor-side ligand-binding residues on IL-20R1 not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2
Complex memberships
IL-20R1/IL-20R2 receptor complexIL-22R1/IL-20R2 receptor complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 IL-24 (MDA-7/MOB-5) binds to and signals through two heterodimeric receptor complexes: IL-22R1/IL-20R2 and IL-20R1/IL-20R2 (the latter being the same receptor used by IL-20). COS cells transfected with either receptor heterodimer bind IL-24 with similar saturation kinetics, and IL-24 binding to either receptor complex on keratinocytes or ectopically expressing BHK cells activates STAT transcription factors. Ligand binding assay (COS cell transfection, saturation kinetics), STAT activation assay in keratinocytes and BHK cells The Journal of biological chemistry High 11706020
2011 The IL-20–IL-20R1–IL-20R2 ternary complex was successfully purified and crystallized, forming a 1:1:1 complex that diffracted to 3 Å resolution, establishing the stoichiometry and feasibility of structural determination of the IL-20/IL-20R1/IL-20R2 signaling complex. Protein purification, crystallization, preliminary X-ray diffraction analysis Acta crystallographica. Section F, Structural biology and crystallization communications Medium 22232181
2014 IL-20 signals through IL-20R1-containing receptor complexes to activate hepatic stellate cells, upregulate TGF-β1, TNF-α, and type I collagen expression, promote HSC proliferation and migration, and induce hepatocyte cell-cycle arrest. IL-20R1-deficient mice were protected from both short-term and long-term CCl4-induced liver injury, establishing IL-20R1 as required for IL-20-mediated hepatic fibrosis. Anti-IL-20R1 monoclonal antibody (51D) treatment in vivo; IL-20R1-deficient mouse model; in vitro HSC activation assays; CCl4 liver injury model Hepatology (Baltimore, Md.) High 24763901
2019 IL-24 binding to receptor 1 subunits (IL-20R1 and IL-22R1) is governed by a flexible region around residue T198 in IL-24; a single back-engineered wild-type residue (T198) restored 80% of binding affinity to IL-20R1 and IL-22R1 and restored signaling capacity, while affinity to IL-20R2 was preserved in stabilized IL-24 variants. Protein engineering (PROSS algorithm-based mutagenesis), biophysical binding assays to extracellular receptor domains, signaling capacity assay, crystal structure of IL-24 variant (PDB 6GG1) The FEBS journal High 31152679
2019 In intestinal lymphatic endothelial cells from Crohn's disease patients, mTOR signaling drives upregulation of IL-20RA, and IL-20RA-mediated intracellular signaling is required for LPMC transmigration through the lymphatic endothelial barrier; blocking this pathway reduced leukocyte trafficking. Transcriptomic profiling of isolated human intestinal lymphatic endothelial cells, transwell co-culture transmigration assay, mTOR pathway manipulation Cells Medium 31426584
2021 IL-20RA activates the JAK1–STAT3–SOX2 signaling axis in breast cancer cells, enhancing stemness (increased SP proportion, ALDH activity, sphere formation, Sox2/Oct4 expression) and promoting PD-L1 expression while reducing CD8+ T cell and NK cell recruitment and increasing MDSC proportions in the tumor microenvironment. Gain- and loss-of-function (overexpression and knockdown) in breast cancer cell lines and mouse models; ELISA; flow cytometry; in vivo tumor initiation and metastasis assays Theranostics Medium 33456560
2021 MIR452 directly targets IL-20RA (confirmed by luciferase reporter assay); overexpression of MIR452 decreases IL-20RA protein and downstream JAK1 and STAT3 (but not STAT1), and IL-20RA knockdown similarly decreases JAK1 and STAT3, placing IL-20RA upstream of JAK1–STAT3 (but not JAK1–STAT1) signaling in colorectal cancer cells. Luciferase reporter assay (miR-452 targeting IL-20RA 3'UTR), siRNA knockdown, Western blot, RT-PCR Inflammation research Medium 34283251
2021 IL-20R1 mediates hematoma resolution after germinal matrix hemorrhage via the IL-20R1/ERK/Nrf2 pathway: rIL-19 treatment upregulated ERK, Nrf2, and CD163 expression, while IL-20R1 CRISPR knockdown abolished these effects, demonstrating that IL-20R1 is required for rIL-19-mediated scavenger receptor CD163 upregulation. In vivo rat GMH model; intranasal rIL-19 administration; IL-20R1 CRISPR knockdown (intracerebroventricular); Western blot; immunohistochemistry; hemoglobin assay; neurobehavioral testing Oxidative medicine and cellular longevity Medium 33532035
2018 CRISPR/Cas9 deletion of a genomic region containing variant rs6927172 (located ~140 kb upstream of TNFAIP3) altered expression of IL-20RA; EMSA and chromatin conformation capture demonstrated that the DNA element carrying rs6927172 physically interacts with the IL-20RA locus and that the risk allele enhances NFκB binding and chromatin looping to regulate IL-20RA expression. CRISPR/Cas9 knockout in HEK293T cells, EMSA, Western blot, chromatin conformation capture (3C), TALE-based transcriptional analysis Genes and immunity Medium 29483615
2022 In grass carp, IL-20R1 (CiIL-20R1/CRFB8) but not IL-20R2 is responsible for STAT3 phosphorylation downstream of IL-20 signaling; co-immunoprecipitation showed that IL-20 binds CiIL-20R2 but not CiIL-20R1, suggesting a division of labor where R2 captures ligand and R1 transduces the intracellular STAT3 signal. Structural modeling showed conservation of key residues with human IL-20R1. Co-immunoprecipitation, STAT3 phosphorylation assay, structural modeling Fish & shellfish immunology Medium 36414129
2024 In fish (crucian carp hybrid), WR-IL-26 forms a complex with both WR-IL10R2 and WR-IL20R1 (co-immunoprecipitation); silencing WR-IL20R1 via RNA interference significantly attenuated IL-26-mediated JAK1–STAT3 pathway activation and reduced gut mucosal barrier protection against Aeromonas hydrophila infection. Co-immunoprecipitation, RNA interference knockdown, JAK1–STAT3 signaling assay, in vivo bacterial challenge Developmental and comparative immunology Medium 39154973
2025 IL-20RA knockdown in nephroblastoma (Wilms tumor) cells increased apoptosis and ferroptosis, and IL-20RA promotes epithelial-mesenchymal transition through the STAT3/SNAIL pathway. siRNA knockdown, apoptosis/ferroptosis assays, EMT marker analysis, Western blot Scientific reports Low 40185911
2024 In pig Sertoli cells, IL-20RA knockdown (siRNA) affected mitochondrial superoxide production and catalase secretion, identifying IL-20RA as a regulator of mitochondrial antioxidant capacity in these cells. siRNA knockdown, ROS measurement, mitochondrial superoxide assay, catalase activity assay, transcriptomic analysis Antioxidants (Basel, Switzerland) Low 39765872

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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 225 11706020
2021 IL20RA signaling enhances stemness and promotes the formation of an immunosuppressive microenvironment in breast cancer. Theranostics 77 33456560
2016 Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23. Genome biology 72 27799070
2014 IL-20 and IL-20R1 antibodies protect against liver fibrosis. Hepatology (Baltimore, Md.) 65 24763901
2021 Super-Enhancer Induced IL-20RA Promotes Proliferation/Metastasis and Immune Evasion in Colorectal Cancer. Frontiers in oncology 34 34336707
2018 CRISPR/cas9 mediated knockout of an intergenic variant rs6927172 identified IL-20RA as a new risk gene for multiple autoimmune diseases. Genes and immunity 23 29483615
2021 MicroRNA 452 regulates IL20RA-mediated JAK1/STAT3 pathway in inflammatory colitis and colorectal cancer. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 22 34283251
2008 Association analysis of IL20RA and IL20RB genes in psoriasis. Genes and immunity 22 18480827
2019 Flexible regions govern promiscuous binding of IL-24 to receptors IL-20R1 and IL-22R1. The FEBS journal 19 31152679
2019 mTOR-Dependent Stimulation of IL20RA Orchestrates Immune Cell Trafficking through Lymphatic Endothelium in Patients with Crohn's Disease. Cells 13 31426584
2024 Fish IL-26 collaborates with IL-10R2 and IL-20R1 to enhance gut mucosal barrier during the antibacterial innate immunity. Developmental and comparative immunology 9 39154973
2022 Grass carp IL-20 binds to IL-20R2 but induces STAT3 phosphorylation via IL-20R1. Fish & shellfish immunology 6 36414129
2021 IL-20R Activation via rIL-19 Enhances Hematoma Resolution through the IL-20R1/ERK/Nrf2 Pathway in an Experimental GMH Rat Pup Model. Oxidative medicine and cellular longevity 6 33532035
2025 Programmed cell death-related gene IL20RA facilitates tumor progression and remodels tumor microenvironment in thyroid cancer. Scientific reports 5 39875436
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
2024 IL-20RA is Associated with the Risk of Diabetic Microangiopathy: A Bidirectional Mendelian Randomization Analysis and Clinical Validation. Diabetes, metabolic syndrome and obesity : targets and therapy 2 39712242
2025 The signature based on interleukin family and receptors identified IL19 and IL20RA in promoting nephroblastoma progression through STAT3 pathway. Scientific reports 1 40185911
2025 Downregulation of IL-20RA in Cerebrospinal Fluid Associated with the Risk of Moyamoya Disease: A Molecular Signatures Analysis with an Inflammation Proteomics Landscape. Journal of inflammation research 0 40989758
2024 IL20RA Is the Key Factor Contributing to the Stronger Antioxidant Capacity of Rongchang Pig Sertoli Cells. Antioxidants (Basel, Switzerland) 0 39765872
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

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