id: MODULE:il22_signaling title: Interleukin-22 signaling pathway module description: >- Secreted Interleukin-22 (IL22), produced by Th17/Th22 cells, gamma-delta T cells, and group 3 innate lymphoid cells (ILC3), binds with high affinity to the private epithelial receptor subunit IL22RA1 (IL-22R1) and recruits the shared class II cytokine receptor subunit IL10RB (IL-10R2) into a ternary signaling complex on barrier epithelial cells, keratinocytes, and hepatocytes. Receptor assembly activates IL22RA1-associated JAK1 and IL10RB-associated TYK2, which phosphorylate IL22RA1 cytoplasmic tyrosines (Y251, Y301) to recruit and phosphorylate STAT3, driving antimicrobial peptide expression, acute-phase protein synthesis, and epithelial barrier proliferation and repair. Extracellular IL22 bioactivity is antagonized by the secreted soluble decoy receptor IL22RA2 (IL-22BP). status: DRAFT evidence: - source_id: GO:0140865 title: interleukin-22-mediated signaling pathway statement: >- Grounded in the GO biological process term for interleukin-22-mediated signaling pathway, defined as the series of molecular signals initiated by interleukin-22 binding to its heterodimeric cell-surface receptor complex (IL22RA1/IL10RB). - source_id: PMID:10875937 title: Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. statement: >- Identified human IL22 and demonstrated that it signals through the heterodimeric IL22RA1 (IL-22R) and IL10RB (CRF2-4) receptor complex to activate STAT3 (and STAT1/STAT5). - source_id: PMID:10954742 title: 'Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor.' statement: >- Cloned human IL22 (IL-TIF) and demonstrated STAT3 activation and induction of acute-phase reactants in human hepatoma cells. - source_id: PMID:11481447 title: A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. statement: >- Boundary evidence. Identified IL22RA2 (IL-22BP) as an apparently soluble class II cytokine receptor that binds IL22 specifically and neutralizes IL22-induced proliferation of cells expressing IL22 receptor subunits. IL22RA2 is a negative regulator of this pathway and is kept outside the module boundary (see notes). - source_id: PMID:18675809 title: Crystal structure of the IL-22/IL-22R1 complex and its implications for the IL-22 signaling mechanism. statement: >- Crystal structure of the binary human IL22:IL22RA1 complex revealing the high-affinity site 1 interface and the composite site 2 surface created for subsequent IL10RB recruitment. - source_id: PMID:20462497 title: Structure and mechanism of receptor sharing by the IL-10R2 common chain. statement: >- Defines the structural basis by which the binary IL22:IL22RA1 complex recruits the shared low-affinity IL10RB (IL-10R2) chain to assemble the active ternary signaling complex. - source_id: Reactome:R-HSA-448480 title: IL22 binds IL22RA1:JAK1 receptor complex statement: >- Reactome reaction documenting high-affinity binding of secreted IL22 to the IL22RA1:JAK1 complex at the plasma membrane. - source_id: Reactome:R-HSA-448741 title: IL22RA2 binds IL22 statement: >- Boundary evidence. Reactome reaction documenting extracellular sequestration of IL22 by the soluble decoy receptor IL22RA2 (IL-22BP), which is kept outside the module boundary (see notes). - source_id: Reactome:R-HSA-8854645 title: IL22:IL22RA1:JAK1 binds IL10RB:TYK2 statement: >- Reactome reaction documenting recruitment of IL10RB:TYK2 to the binary IL22:IL22RA1:JAK1 complex. - source_id: Reactome:R-HSA-8987042 title: IL22:IL22RA1:JAK1:IL10RB:TYK2 phosphorylates JAK1,TYK2 statement: >- Reactome reaction documenting reciprocal trans-phosphorylation of JAK1 and TYK2 in the assembled IL22 receptor complex. - source_id: Reactome:R-HSA-8987070 title: IL22:p-Y251,p-Y301-IL22RA1:p-JAK1:IL10RB:p-TYK2:STAT3 phosphorylates STAT3 statement: >- Reactome reaction documenting JAK1/TYK2-mediated phosphorylation of STAT3 docked at phosphorylated IL22RA1 Y251/Y301. - source_id: file:genes/human/IL22/IL22-ai-review.yaml title: Human IL22 gene review statement: >- Curates human IL22 (UniProtKB:Q9GZX6) with GO:0005125 (cytokine activity) and GO:0140865 (interleukin-22-mediated signaling pathway), upgrading GO:0045518 (interleukin-22 receptor binding) and GO:0007165 (signal transduction). - source_id: file:interpro/panther/PTHR48488/PTHR48488-review.yaml title: PANTHER PTHR48488 (INTERLEUKIN-22) family review statement: >- Assesses PAINT node PTN009232695 (node taxon Euteleostomi) and recommends GO:0005125 (cytokine activity, already asserted there) and GO:0140865 (interleukin-22-mediated signaling pathway, not asserted there) as family-wide terms for PTHR48488. - source_id: PANTHER:PTN009232695 title: PAINT node PTN009232695 for IL22 statement: >- Local PAINT IBD node in PTHR48488 (node taxon NCBITaxon:117571 Euteleostomi) asserting C:GO:0005576 (seeds MGI:MGI:1355307 and RGD:1561292; date 20260601), F:GO:0005125 and P:GO:0050728 (seed MGI:MGI:1355307; date 20241010). No human seed. - source_id: PANTHER:PTN000466212 title: PAINT node PTN000466212 for IL22RA1, IL10RB, and IL22RA2 statement: >- Local PAINT IBD node in PTHR20859 (node taxon not recorded in paint.tsv) asserting C:GO:0005886, F:GO:0004896, and P:GO:0019221 (all dated 20260828). Human IL22RA1 (UniProtKB:Q8N6P7) seeds only C:GO:0005886; human IL10RB (UniProtKB:Q08334) seeds only P:GO:0019221; F:GO:0004896 is seeded by other family members, including human IL22RA2 (UniProtKB:Q969J5) but neither IL22RA1 nor IL10RB. - source_id: PANTHER:PTN001562978 title: PAINT node PTN001562978 for JAK1 and TYK2 statement: >- Local PAINT IBD node in PTHR45807 (node taxon NCBITaxon:33213 Bilateria) asserting C:GO:0005829, F:GO:0004715, F:GO:0005126, P:GO:0007259, P:GO:0019221, P:GO:0030154, and P:GO:0035556 (dates 20230112 to 20260828). Human JAK1 (UniProtKB:P23458) seeds F:GO:0004715, P:GO:0007259, and P:GO:0019221; human TYK2 (UniProtKB:P29597) seeds the same three plus F:GO:0005126. - source_id: PANTHER:PTN000210448 title: PAINT node PTN000210448 for STAT3 statement: >- Local PAINT IBD node in PTHR11801 (node taxon NCBITaxon:2759 Eukaryota) asserting C:GO:0005634, C:GO:0005737 (20260528), F:GO:0000978 (20251218), F:GO:0000981 (20240729), and P:GO:0006357 (20260828); human STAT3 (UniProtKB:P40763) is a seed for all five. notes: >- Three-step class II cytokine receptor JAK-STAT signaling module modeling Interleukin-22 (family PTHR48488) signaling through the heterodimeric IL22RA1 (PTHR20859:SF53) and IL10RB (PTHR20859:SF50) receptor complex. Boundary: the soluble decoy receptor IL22RA2 (IL-22BP, PTHR20859:SF51; representative UniProtKB:Q969J5) binds IL22 and neutralizes IL22-induced signaling (PMID:11481447, Reactome:R-HSA-448741). It is a negative regulator of the receptor-engagement step, not a participant in it, so it is excluded from the module parts rather than modelled inside the positive step; it is a candidate for a separate regulatory node acting on il22_engages_receptor_complex with a NEGATIVELY_REGULATES connection if pathway regulation is added later. The IL22RA1 receptor annoton uses the specific GO:0042018 (interleukin-22 receptor activity, an is_a child of GO:0004896). Its PAINT node PTN000466212 asserts the parent GO:0004896, which human IL22RA1 does not seed; the more specific term is kept on the step and the mismatch is recorded here. The shared IL10RB chain keeps GO:0004896. Per ligand-in-signaling conventions (projects/LIGANDS_IN_SIGNALING.md), the IL22 ligand annoton uses FAMILY selector PANTHER:PTHR48488 and molecular function GO:0005125 (cytokine activity, an is_a child of GO:0048018 receptor ligand activity) rather than the receptor-binding term GO:0045518 (interleukin-22 receptor binding), resolving the Category A gap where GO:0140865 was annotated to IL22RA1, IL10RB, and IL22RA2 in GOA but had zero annotations on IL22 itself in human or mouse. module: id: il22_signaling label: Interleukin-22 signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: interleukin-22-mediated signaling pathway term: id: GO:0140865 label: interleukin-22-mediated signaling pathway description: >- Series of molecular signals initiated by secreted IL22 binding to the heterodimeric IL22RA1/IL10RB receptor complex on epithelial and hepatic target cells, activating JAK1/TYK2 and STAT3 to drive barrier defense and regeneration. context: taxa: - preferred_term: bony vertebrates term: id: NCBITaxon:117571 label: Euteleostomi cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus parts: - order: 1 role: il22 receptor complex assembly node: id: il22_engages_receptor_complex label: IL22 engages the IL22RA1/IL10RB receptor complex module_type: REGULATORY_STEP description: >- Secreted IL22 binds the epithelial transmembrane receptor chain IL22RA1, and the binary IL22:IL22RA1 complex then recruits the shared class II cytokine receptor subunit IL10RB into a ternary signaling complex. annotons: - id: il22_cytokine_ligand label: IL22 cytokine ligand participant: selector_type: FAMILY family: preferred_term: Interleukin-22 cytokine family term: id: PANTHER:PTHR48488 label: INTERLEUKIN-22 representative_members: - preferred_term: IL22 term: id: UniProtKB:Q9GZX6 label: Interleukin-22 ancestral_nodes: - preferred_term: PAINT node PTN009232695 in PTHR48488 term: id: PANTHER:PTN009232695 label: PTN009232695 description: >- PAINT node in PTHR48488 with node taxon NCBITaxon:117571 (Euteleostomi), asserting C:GO:0005576 (seeds MGI:MGI:1355307 and RGD:1561292), F:GO:0005125 and P:GO:0050728 (seed MGI:MGI:1355307). Human IL22 (UniProtKB:Q9GZX6) is not a seed; it inherits these terms by IBA. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN009232695 in PTHR48488, recorded in interpro/panther/PTHR48488/PTHR48488-paint.tsv. function: preferred_term: cytokine activity term: id: GO:0005125 label: cytokine activity processes: - preferred_term: interleukin-22-mediated signaling pathway term: id: GO:0140865 label: interleukin-22-mediated signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Secreted six-helix-bundle IL-10-family cytokine ligand that binds IL22RA1 and recruits IL10RB on non-hematopoietic epithelial and hepatic cells to initiate JAK1/TYK2-STAT3 signaling. evidence: - source_id: PMID:10875937 statement: >- Identified human IL22 as the secreted cytokine agonist for the IL22RA1/IL10RB receptor complex. - source_id: PMID:18675809 statement: >- Crystal structure of the human IL22:IL22RA1 complex defining the high-affinity receptor-binding interface. - source_id: file:genes/human/IL22/IL22-ai-review.yaml statement: >- Human IL22 review curates GO:0005125 (cytokine activity) and GO:0140865 (interleukin-22-mediated signaling pathway) as core functions. - source_id: file:interpro/panther/PTHR48488/PTHR48488-review.yaml statement: >- PTHR48488 family review assesses PTN009232695 and recommends GO:0005125 (asserted there) and GO:0140865 (not asserted there) as family-wide terms. - id: il22ra1_receptor_alpha label: IL22RA1 receptor alpha-1 subunit participant: selector_type: FAMILY family: preferred_term: Interleukin-22 receptor subunit alpha-1 subfamily term: id: PANTHER:PTHR20859:SF53 label: INTERLEUKIN-22 RECEPTOR SUBUNIT ALPHA-1 representative_members: - preferred_term: IL22RA1 term: id: UniProtKB:Q8N6P7 label: Interleukin-22 receptor subunit alpha-1 ancestral_nodes: - preferred_term: PAINT node PTN000466212 in PTHR20859 term: id: PANTHER:PTN000466212 label: PTN000466212 description: >- PAINT node in PTHR20859 (node taxon not recorded in paint.tsv) asserting C:GO:0005886, F:GO:0004896, and P:GO:0019221. Human IL22RA1 (UniProtKB:Q8N6P7) seeds only C:GO:0005886. F:GO:0004896 is seeded by other members (including human IL22RA2, UniProtKB:Q969J5) and is the parent of the GO:0042018 used on this step. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN000466212 in PTHR20859, recorded in interpro/panther/PTHR20859/PTHR20859-paint.tsv. function: preferred_term: interleukin-22 receptor activity term: id: GO:0042018 label: interleukin-22 receptor activity processes: - preferred_term: interleukin-22-mediated signaling pathway term: id: GO:0140865 label: interleukin-22-mediated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- High-affinity transmembrane receptor chain restricted to non-hematopoietic epithelial and hepatic cells that binds IL22, associates with JAK1, and provides both coil-coil and phosphotyrosine (Y251, Y301) docking sites for STAT3. evidence: - source_id: PMID:10875937 statement: >- Demonstrated that IL22RA1 (IL-22R) functions together with CRF2-4 (IL10RB) to enable IL22 signaling, supporting interleukin-22 receptor activity (GO:0042018). - source_id: PMID:11481447 statement: >- Describes IL22 as binding to and signaling through the class II cytokine receptor heterodimer IL-22RA1/CRF2-4. - source_id: PMID:18675809 statement: >- IL22 signaling proceeds by sequential binding of IL22 to IL-22R1 and then of the binary complex to IL-10R2; the crystal structure defines the IL22:IL22RA1 interface. - id: il10rb_receptor_beta label: IL10RB shared receptor beta subunit participant: selector_type: FAMILY family: preferred_term: Interleukin-10 receptor subunit beta subfamily term: id: PANTHER:PTHR20859:SF50 label: INTERLEUKIN-10 RECEPTOR SUBUNIT BETA representative_members: - preferred_term: IL10RB term: id: UniProtKB:Q08334 label: Interleukin-10 receptor subunit beta ancestral_nodes: - preferred_term: PAINT node PTN000466212 in PTHR20859 term: id: PANTHER:PTN000466212 label: PTN000466212 description: >- PAINT node in PTHR20859 (node taxon not recorded in paint.tsv) asserting C:GO:0005886, F:GO:0004896, and P:GO:0019221. Human IL10RB (UniProtKB:Q08334) seeds only P:GO:0019221; C:GO:0005886 and F:GO:0004896 are seeded by other members. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN000466212 in PTHR20859, recorded in interpro/panther/PTHR20859/PTHR20859-paint.tsv. function: preferred_term: cytokine receptor activity term: id: GO:0004896 label: cytokine receptor activity processes: - preferred_term: interleukin-22-mediated signaling pathway term: id: GO:0140865 label: interleukin-22-mediated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Shared class II cytokine receptor beta subunit (CRF2-4) recruited to the binary IL22:IL22RA1 complex that brings associated TYK2 into proximity with IL22RA1-bound JAK1. evidence: - source_id: PMID:10875937 statement: >- Demonstrated that CRF2-4 (IL10RB) is required as the second signaling chain of the functional IL22 receptor complex. - source_id: PMID:20462497 statement: >- Defined the structural interface between IL10RB and the IL22:IL22RA1 complex. - order: 2 role: jak1 and tyk2 kinase activation node: id: il22_jak1_tyk2_activation label: JAK1 and TYK2 trans-phosphorylation and IL22RA1 phosphorylation module_type: REGULATORY_STEP description: >- Juxtaposed JAK1 (on IL22RA1) and TYK2 (on IL10RB) trans-phosphorylate and phosphorylate cytoplasmic tyrosines on IL22RA1 (Y251, Y301), enabling STAT3 recruitment and activation. annotons: - id: jak1_tyrosine_kinase label: JAK1 non-receptor tyrosine kinase participant: selector_type: FAMILY family: preferred_term: Tyrosine-protein kinase JAK1 subfamily term: id: PANTHER:PTHR45807:SF5 label: TYROSINE-PROTEIN KINASE JAK1 representative_members: - preferred_term: JAK1 term: id: UniProtKB:P23458 label: Tyrosine-protein kinase JAK1 ancestral_nodes: - preferred_term: PAINT node PTN001562978 in PTHR45807 term: id: PANTHER:PTN001562978 label: PTN001562978 description: >- PAINT node in PTHR45807 (node taxon NCBITaxon:33213, Bilateria) asserting C:GO:0005829, F:GO:0004715, F:GO:0005126, P:GO:0007259, P:GO:0019221, P:GO:0030154, and P:GO:0035556. Human JAK1 (UniProtKB:P23458) seeds F:GO:0004715, P:GO:0007259, and P:GO:0019221. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN001562978 in PTHR45807, recorded in interpro/panther/PTHR45807/PTHR45807-paint.tsv. function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- IL22RA1-associated Janus kinase that phosphorylates IL22RA1 cytoplasmic tyrosines and activates STAT3 upon ternary receptor complex assembly. evidence: - source_id: Reactome:R-HSA-8987042 statement: >- Reactome reaction documenting JAK1 and TYK2 trans-activation in the IL22 receptor complex. - source_id: Reactome:R-HSA-8987070 statement: >- Reactome reaction documenting JAK1/TYK2-mediated STAT3 phosphorylation at the activated IL22 receptor complex. - id: tyk2_tyrosine_kinase label: TYK2 non-receptor tyrosine kinase participant: selector_type: FAMILY family: preferred_term: Non-receptor tyrosine-protein kinase TYK2 subfamily term: id: PANTHER:PTHR45807:SF6 label: NON-RECEPTOR TYROSINE-PROTEIN KINASE TYK2 representative_members: - preferred_term: TYK2 term: id: UniProtKB:P29597 label: Non-receptor tyrosine-protein kinase TYK2 ancestral_nodes: - preferred_term: PAINT node PTN001562978 in PTHR45807 term: id: PANTHER:PTN001562978 label: PTN001562978 description: >- PAINT node in PTHR45807 (node taxon NCBITaxon:33213, Bilateria) asserting C:GO:0005829, F:GO:0004715, F:GO:0005126, P:GO:0007259, P:GO:0019221, P:GO:0030154, and P:GO:0035556. Human TYK2 (UniProtKB:P29597) seeds F:GO:0004715, F:GO:0005126, P:GO:0007259, and P:GO:0019221. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN001562978 in PTHR45807, recorded in interpro/panther/PTHR45807/PTHR45807-paint.tsv. function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- IL10RB-associated Janus kinase brought into the ternary IL22 receptor complex to trans-activate with JAK1 and promote STAT3 phosphorylation. evidence: - source_id: Reactome:R-HSA-8854645 statement: >- IL10RB:TYK2 is recruited to the IL22:IL22RA1:JAK1 complex. - source_id: Reactome:R-HSA-8987042 statement: >- TYK2 and JAK1 reciprocally phosphorylate within the assembled IL22 receptor complex. - order: 3 role: stat3 epithelial barrier and acute-phase transcriptional output node: id: il22_stat3_barrier_output label: STAT3 nuclear translocation and epithelial barrier transcriptional output module_type: REGULATORY_STEP description: >- Tyrosine-phosphorylated STAT3 homodimerizes, translocates to the nucleus of target epithelial cells and hepatocytes, and activates transcription of antimicrobial peptides (S100A7/A8/A9, DEFB4A, REG3A/REG3G), mucins, acute-phase proteins (SAA, haptoglobin), and pro-regenerative survival genes. annotons: - id: stat3_transcription_factor label: STAT3 transcription factor participant: selector_type: FAMILY family: preferred_term: Signal transducer and activator of transcription 3 subfamily term: id: PANTHER:PTHR11801:SF2 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 representative_members: - preferred_term: STAT3 term: id: UniProtKB:P40763 label: Signal transducer and activator of transcription 3 ancestral_nodes: - preferred_term: PAINT node PTN000210448 in PTHR11801 term: id: PANTHER:PTN000210448 label: PTN000210448 description: >- PAINT node in PTHR11801 (node taxon NCBITaxon:2759, Eukaryota) asserting C:GO:0005634, C:GO:0005737, F:GO:0000978, F:GO:0000981, and P:GO:0006357. Human STAT3 (UniProtKB:P40763) is a seed for all five. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN000210448 in PTHR11801, recorded in interpro/panther/PTHR11801/PTHR11801-paint.tsv. function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- Primary transcriptional effector of IL22 signaling in epithelial cells and hepatocytes that activates antimicrobial peptide, acute-phase reactant, and tissue regeneration gene programs. evidence: - source_id: PMID:10875937 statement: >- Demonstrated rapid STAT3 activation in cells expressing IL22RA1 and IL10RB upon IL22 stimulation. - source_id: PMID:10954742 statement: >- Demonstrated IL22-induced STAT3 activation and acute-phase protein expression in human hepatoma cells. connections: - source: il22_engages_receptor_complex target: il22_jak1_tyk2_activation connection_type: CAUSES description: >- IL22-induced assembly of the ternary IL22:IL22RA1:IL10RB complex juxtaposes IL22RA1-associated JAK1 and IL10RB-associated TYK2 for reciprocal trans-phosphorylation and IL22RA1 Y251/Y301 phosphorylation. evidence: - source_id: PMID:10875937 statement: >- IL22 binding to the IL22RA1/IL10RB receptor complex initiates intracellular JAK-STAT signaling. - source_id: Reactome:R-HSA-8987042 statement: >- Reactome reaction documenting reciprocal JAK1 and TYK2 phosphorylation in the IL22 receptor complex. - source: il22_jak1_tyk2_activation target: il22_stat3_barrier_output connection_type: CAUSES description: >- Activated JAK1 and TYK2 phosphorylate STAT3 on Y705 at the IL22RA1 cytoplasmic domain, driving STAT3 dimerization, nuclear translocation, and epithelial barrier defense gene expression. evidence: - source_id: PMID:10875937 statement: >- IL22 stimulation activates STAT3 tyrosine phosphorylation and transcriptional signaling in target cells. - source_id: Reactome:R-HSA-8987070 statement: >- Reactome reaction documenting STAT3 phosphorylation at the activated IL22 receptor complex.