Interleukin-22 signaling pathway module

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).

MODULE:il22_signalingDRAFTSignaling Pathwaymodules/il22_signaling.yaml
interleukin-22-mediated signaling pathwayGO:0140865
GO:0140865
interleukin-22-mediated signaling pathway
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).
PMID:10875937
Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R.
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).
PMID:10954742
Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor.
Cloned human IL22 (IL-TIF) and demonstrated STAT3 activation and induction of acute-phase reactants in human hepatoma cells.
PMID:11481447
A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist.
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).
PMID:18675809
Crystal structure of the IL-22/IL-22R1 complex and its implications for the IL-22 signaling mechanism.
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.
PMID:20462497
Structure and mechanism of receptor sharing by the IL-10R2 common chain.
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.
Reactome:R-HSA-448480
IL22 binds IL22RA1:JAK1 receptor complex
Reactome reaction documenting high-affinity binding of secreted IL22 to the IL22RA1:JAK1 complex at the plasma membrane.
Reactome:R-HSA-448741
IL22RA2 binds IL22
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).
Reactome:R-HSA-8854645
IL22:IL22RA1:JAK1 binds IL10RB:TYK2
Reactome reaction documenting recruitment of IL10RB:TYK2 to the binary IL22:IL22RA1:JAK1 complex.
Reactome:R-HSA-8987042
IL22:IL22RA1:JAK1:IL10RB:TYK2 phosphorylates JAK1,TYK2
Reactome reaction documenting reciprocal trans-phosphorylation of JAK1 and TYK2 in the assembled IL22 receptor complex.
Reactome:R-HSA-8987070
IL22:p-Y251,p-Y301-IL22RA1:p-JAK1:IL10RB:p-TYK2:STAT3 phosphorylates STAT3
Reactome reaction documenting JAK1/TYK2-mediated phosphorylation of STAT3 docked at phosphorylated IL22RA1 Y251/Y301.
file:genes/human/IL22/IL22-ai-review.yaml
Human IL22 gene review
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).
file:interpro/panther/PTHR48488/PTHR48488-review.yaml
PANTHER PTHR48488 (INTERLEUKIN-22) family review
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.
PANTHER:PTN009232695
PAINT node PTN009232695 for IL22
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.
PANTHER:PTN000466212
PAINT node PTN000466212 for IL22RA1, IL10RB, and IL22RA2
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.
PANTHER:PTN001562978
PAINT node PTN001562978 for JAK1 and TYK2
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.
PANTHER:PTN000210448
PAINT node PTN000210448 for STAT3
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.

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.

4Nodes
3Parts
0Variant Sets
0Variants
6Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:il22_signaling deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

4 gene-function check(s) reflected in core functions · 0 conflict(s) · 4 evidence or coverage gap(s) (12 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
il22_cytokine_ligand IL22
UniProtKB:Q9GZX6
Family Representative 		cytokine activity
GO:0005125 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
il22ra1_receptor_alpha IL22RA1
UniProtKB:Q8N6P7
Family Representative 		interleukin-22 receptor activity
GO:0042018 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
il10rb_receptor_beta IL10RB
UniProtKB:Q08334
Family Representative 		cytokine receptor activity
GO:0004896 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
jak1_tyrosine_kinase JAK1
UniProtKB:P23458
Family Representative 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tyk2_tyrosine_kinase TYK2
UniProtKB:P29597
Family Representative 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
stat3_transcription_factor STAT3
UniProtKB:P40763
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
il22_cytokine_ligand Interleukin-22 cytokine family
PANTHER:PTHR48488
Family 		cytokine activity
GO:0005125 		Family Supported
Family review supports GO:0005125 FAMILY_WIDE. Every member of PTHR48488 is a secreted cytokine ligand for the IL22RA1/IL10RB receptor complex.
il22ra1_receptor_alpha Interleukin-22 receptor subunit alpha-1 subfamily
PANTHER:PTHR20859:SF53
Family 		interleukin-22 receptor activity
GO:0042018 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR20859:SF53.
il10rb_receptor_beta Interleukin-10 receptor subunit beta subfamily
PANTHER:PTHR20859:SF50
Family 		cytokine receptor activity
GO:0004896 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR20859:SF50.
jak1_tyrosine_kinase Tyrosine-protein kinase JAK1 subfamily
PANTHER:PTHR45807:SF5
Family 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Family Supported
Family review supports GO:0004715 FAMILY_WIDE. Shown directly for JAK1, JAK2, JAK3, TYK2 and Hopscotch. The JH1 catalytic site (jh1_ptk_catalytic) is intact in every full-length member checked, so it is core for all four vertebrate subfamilies, the teleost SF2 and hop. It does not apply to the short kinase-domain fragments the HMM also captures in nematodes and fungi. These are not JAKs, and the residue site shows what one of them looks like.
tyk2_tyrosine_kinase Non-receptor tyrosine-protein kinase TYK2 subfamily
PANTHER:PTHR45807:SF6
Family 		non-membrane spanning protein tyrosine kinase activity
GO:0004715 		Family Supported
Family review supports GO:0004715 FAMILY_WIDE. Shown directly for JAK1, JAK2, JAK3, TYK2 and Hopscotch. The JH1 catalytic site (jh1_ptk_catalytic) is intact in every full-length member checked, so it is core for all four vertebrate subfamilies, the teleost SF2 and hop. It does not apply to the short kinase-domain fragments the HMM also captures in nematodes and fungi. These are not JAKs, and the residue site shows what one of them looks like.
stat3_transcription_factor Signal transducer and activator of transcription 3 subfamily
PANTHER:PTHR11801:SF2
Family 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Family Supported
Family review supports GO:0000981 FAMILY_WIDE. Sequence-specific, signal-dependent DNA-binding transcription factor activity is the defining STAT activity and is shown for vertebrate, Drosophila, C. elegans (STA-1) and Dictyostelium STATs, all of which keep the STAT DNA-binding domain. The exceptions are the plant STAT-type linker-SH2 proteins, which lack that domain. C. elegans STA-2 (SF49) is an unresolved case rather than an exception: it regulates antimicrobial-peptide transcription but keeps only the DNA-binding-domain fold, and sequence-specific binding is undemonstrated, so its gene review marks GO:0000978 over-annotated and generalises this term to GO:0140110 transcription regulator activity, without asserting that either is wrong.

Gene-review completeness (4/6 grounded genes reviewed)

1 complete review(s) · 3 with deep research · 2 missing review · 1 reviewed but lacking deep research

Gene Review Complete Deep research
IL22 Q9GZX6 ✓ ✓ ✓
JAK1 P23458 ✓ 331/332 ✓
IL10RB Q08334 ✗ — —
IL22RA1 Q8N6P7 ✗ — —
STAT3 P40763 ✓ 454/456 ✓
TYK2 P29597 ✓ 147/150 ✗

Details

Context
bony vertebratesNCBITaxon:117571
extracellular regionGO:0005576 plasma membraneGO:0005886 cytosolGO:0005829 nucleusGO:0005634
Interleukin-22 signaling pathwaySignaling Pathwayil22_signaling
interleukin-22-mediated signaling pathwayGO:0140865
Context
bony vertebratesNCBITaxon:117571
extracellular regionGO:0005576 plasma membraneGO:0005886 cytosolGO:0005829 nucleusGO:0005634

Connections

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.
PMID:10875937
IL22 binding to the IL22RA1/IL10RB receptor complex initiates intracellular JAK-STAT signaling.
Reactome:R-HSA-8987042
Reactome reaction documenting reciprocal JAK1 and TYK2 phosphorylation in the IL22 receptor complex.
Activated JAK1 and TYK2 phosphorylate STAT3 on Y705 at the IL22RA1 cytoplasmic domain, driving STAT3 dimerization, nuclear translocation, and epithelial barrier defense gene expression.
PMID:10875937
IL22 stimulation activates STAT3 tyrosine phosphorylation and transcriptional signaling in target cells.
Reactome:R-HSA-8987070
Reactome reaction documenting STAT3 phosphorylation at the activated IL22 receptor complex.
Part 1: il22 receptor complex assembly
IL22 engages the IL22RA1/IL10RB receptor complexRegulatory Stepil22_engages_receptor_complex

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

IL22 cytokine ligand
il22_cytokine_ligand
Participant: Family: Interleukin-22 cytokine family
Family:
Interleukin-22 cytokine familyPANTHER:PTHR48488
Representative Members: IL22UniProtKB:Q9GZX6

Function

cytokine activityGO:0005125

Processes

interleukin-22-mediated signaling pathwayGO:0140865

Locations

extracellular regionGO:0005576

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.

PMID:10875937
Identified human IL22 as the secreted cytokine agonist for the IL22RA1/IL10RB receptor complex.
PMID:18675809
Crystal structure of the human IL22:IL22RA1 complex defining the high-affinity receptor-binding interface.
file:genes/human/IL22/IL22-ai-review.yaml
Human IL22 review curates GO:0005125 (cytokine activity) and GO:0140865 (interleukin-22-mediated signaling pathway) as core functions.
file:interpro/panther/PTHR48488/PTHR48488-review.yaml
PTHR48488 family review assesses PTN009232695 and recommends GO:0005125 (asserted there) and GO:0140865 (not asserted there) as family-wide terms.
IL22RA1 receptor alpha-1 subunit
il22ra1_receptor_alpha
Participant: Family: Interleukin-22 receptor subunit alpha-1 subfamily
Family:
Interleukin-22 receptor subunit alpha-1 subfamilyPANTHER:PTHR20859:SF53
Representative Members: IL22RA1UniProtKB:Q8N6P7

Function

interleukin-22 receptor activityGO:0042018

Processes

interleukin-22-mediated signaling pathwayGO:0140865

Locations

plasma membraneGO:0005886

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.

PMID:10875937
Demonstrated that IL22RA1 (IL-22R) functions together with CRF2-4 (IL10RB) to enable IL22 signaling, supporting interleukin-22 receptor activity (GO:0042018).
PMID:11481447
Describes IL22 as binding to and signaling through the class II cytokine receptor heterodimer IL-22RA1/CRF2-4.
PMID:18675809
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.
IL10RB shared receptor beta subunit
il10rb_receptor_beta
Participant: Family: Interleukin-10 receptor subunit beta subfamily
Family:
Interleukin-10 receptor subunit beta subfamilyPANTHER:PTHR20859:SF50
Representative Members: IL10RBUniProtKB:Q08334

Function

cytokine receptor activityGO:0004896

Processes

interleukin-22-mediated signaling pathwayGO:0140865

Locations

plasma membraneGO:0005886

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.

PMID:10875937
Demonstrated that CRF2-4 (IL10RB) is required as the second signaling chain of the functional IL22 receptor complex.
PMID:20462497
Defined the structural interface between IL10RB and the IL22:IL22RA1 complex.
Part 2: jak1 and tyk2 kinase activation
JAK1 and TYK2 trans-phosphorylation and IL22RA1 phosphorylationRegulatory Stepil22_jak1_tyk2_activation

Juxtaposed JAK1 (on IL22RA1) and TYK2 (on IL10RB) trans-phosphorylate and phosphorylate cytoplasmic tyrosines on IL22RA1 (Y251, Y301), enabling STAT3 recruitment and activation.

Annotons

JAK1 non-receptor tyrosine kinase
jak1_tyrosine_kinase
Participant: Family: Tyrosine-protein kinase JAK1 subfamily
Family:
Tyrosine-protein kinase JAK1 subfamilyPANTHER:PTHR45807:SF5
Representative Members: JAK1UniProtKB:P23458

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

Locations

cytosolGO:0005829 plasma membraneGO:0005886

IL22RA1-associated Janus kinase that phosphorylates IL22RA1 cytoplasmic tyrosines and activates STAT3 upon ternary receptor complex assembly.

Reactome:R-HSA-8987042
Reactome reaction documenting JAK1 and TYK2 trans-activation in the IL22 receptor complex.
Reactome:R-HSA-8987070
Reactome reaction documenting JAK1/TYK2-mediated STAT3 phosphorylation at the activated IL22 receptor complex.
TYK2 non-receptor tyrosine kinase
tyk2_tyrosine_kinase
Participant: Family: Non-receptor tyrosine-protein kinase TYK2 subfamily
Family:
Non-receptor tyrosine-protein kinase TYK2 subfamilyPANTHER:PTHR45807:SF6
Representative Members: TYK2UniProtKB:P29597

Function

non-membrane spanning protein tyrosine kinase activityGO:0004715

Locations

cytosolGO:0005829 plasma membraneGO:0005886

IL10RB-associated Janus kinase brought into the ternary IL22 receptor complex to trans-activate with JAK1 and promote STAT3 phosphorylation.

Reactome:R-HSA-8854645
IL10RB:TYK2 is recruited to the IL22:IL22RA1:JAK1 complex.
Reactome:R-HSA-8987042
TYK2 and JAK1 reciprocally phosphorylate within the assembled IL22 receptor complex.
Part 3: stat3 epithelial barrier and acute-phase transcriptional output
STAT3 nuclear translocation and epithelial barrier transcriptional outputRegulatory Stepil22_stat3_barrier_output

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

STAT3 transcription factor
stat3_transcription_factor
Participant: Family: Signal transducer and activator of transcription 3 subfamily
Family:
Signal transducer and activator of transcription 3 subfamilyPANTHER:PTHR11801:SF2
Representative Members: STAT3UniProtKB:P40763

Function

DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981

Locations

cytosolGO:0005829 nucleusGO:0005634

Primary transcriptional effector of IL22 signaling in epithelial cells and hepatocytes that activates antimicrobial peptide, acute-phase reactant, and tissue regeneration gene programs.

PMID:10875937
Demonstrated rapid STAT3 activation in cells expressing IL22RA1 and IL10RB upon IL22 stimulation.
PMID:10954742
Demonstrated IL22-induced STAT3 activation and acute-phase protein expression in human hepatoma cells.