IL23R

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0009897 external side of plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: IL23R is a type I transmembrane receptor localized at the cell surface of immune cells. The extracellular domain faces outward and has been structurally resolved by X-ray crystallography and cryo-EM (PMID:29287995). IBA annotation based on phylogenetic inference from related cytokine receptors is consistent with experimental evidence. Reason: IL23R is experimentally confirmed at the cell surface (PMID:12023369). Its extracellular Ig-like and FNIII domains face the external side of the plasma membrane to engage IL-23. The IBA annotation is appropriate and consistent with direct evidence. Supporting Evidence: PMID:12023369 Anti-IL-12Rbeta1 and anti-IL-23R Abs block IL-23 responses of an NK cell line and Ba/F3 cells expressing the two receptor chains. PMID:29287995 IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain.
GO:0019221 cytokine-mediated signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: IL23R is a core component of the IL-23 cytokine signaling pathway. Upon IL-23 binding, it signals through JAK2/TYK2-STAT3 (PMID:12023369). This IBA is well-supported phylogenetically across the type I cytokine receptor family. Reason: This is a correct and appropriately general annotation. IL23R directly participates in IL-23-mediated cytokine signaling, its core function. The more specific term GO:0038155 (interleukin-23-mediated signaling pathway) is also annotated separately with IDA evidence. Supporting Evidence: PMID:12023369 IL-23 activates the same Jak-stat signaling molecules as IL-12: Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different DNA-binding stat complexes form in response to IL-23 compared with IL-12.
GO:0008284 positive regulation of cell population proliferation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IL-23 signaling through IL23R promotes proliferation of memory T cells and other immune cell populations (PMID:11114383, PMID:12023369). The IBA annotation is phylogenetically inferred from related cytokine receptors that promote cell proliferation. Reason: While IL-23 signaling does promote proliferation of T cells and NK-like T cells, this is a downstream consequence of cytokine receptor signaling rather than a core molecular function of IL23R itself. The term is accurate but represents a broad biological outcome rather than the receptor's primary role. Supporting Evidence: PMID:11114383 IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low)) T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population.
GO:0019955 cytokine binding	IBA GO_REF:0000033	ACCEPT	Summary: IL23R binds IL-23 via its N-terminal Ig-like domain. Crystal structures confirm direct binding of IL23R to the p19 subunit of IL-23 (PMID:29287995). The IBA at the level of cytokine binding is correct but more specific terms exist. Reason: IL23R does bind IL-23, a cytokine. While more specific terms (GO:0042019 interleukin-23 binding, GO:0042020 interleukin-23 receptor activity) are also annotated, this broader IBA annotation captures the general cytokine-binding function appropriately at the family level. Supporting Evidence: PMID:12023369 Human IL-23, but not IL-12, exhibits detectable affinity for human IL-23R. PMID:29287995 IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain.
GO:0004925 prolactin receptor activity	IBA GO_REF:0000033	REMOVE	Summary: This annotation infers prolactin receptor activity for IL23R based on phylogenetic relationship to the prolactin receptor (PRLR). While IL23R and PRLR are both type I cytokine receptors, IL23R does not bind prolactin and has no demonstrated prolactin receptor activity. Reason: This is an erroneous IBA annotation. IL23R is in the same broad type I cytokine receptor superfamily as PRLR, but it does not bind prolactin. IL23R specifically binds IL-23 through its p19 subunit (PMID:29287995). The phylogenetic inference is too broad here, incorrectly transferring a ligand-specific function across distantly related receptors with different ligand specificities. Supporting Evidence: PMID:12023369 Human IL-23, but not IL-12, exhibits detectable affinity for human IL-23R.
GO:0005143 interleukin-12 receptor binding	IBA GO_REF:0000033	ACCEPT	Summary: IL23R contributes to IL-12 receptor binding in the sense that IL-23 shares the p40 subunit with IL-12 and IL23R pairs with IL12RB1 (the shared IL-12 receptor chain). The IBA annotation with contributes_to qualifier reflects that IL23R is part of a complex that engages IL-12-family cytokine receptor components. Reason: The contributes_to qualifier is appropriate. IL23R pairs with IL12RB1 to form the functional receptor, and IL-23 shares the p40/IL12B subunit with IL-12. This means IL23R contributes to a complex that has IL-12 receptor binding capacity through the shared IL12RB1 chain. The IBA annotation correctly captures this relationship. Supporting Evidence: PMID:12023369 Like IL-12, IL-23 binds to the IL-12R subunit IL-12Rbeta1. However, it does not use IL-12Rbeta2.
GO:0042019 interleukin-23 binding	IBA GO_REF:0000033	ACCEPT	Summary: IL23R contributes to IL-23 binding as part of the IL23R:IL12RB1 heterodimer. IL23R binds IL-23 p19 directly, while IL12RB1 engages p40 (PMID:29287995). The contributes_to qualifier reflects that full IL-23 binding requires both receptor chains. Reason: The IBA annotation with contributes_to is correct. IL23R directly binds the p19 subunit of IL-23, but the full high-affinity binding of IL-23 requires both IL23R and IL12RB1. This is confirmed by structural studies. Supporting Evidence: PMID:29287995 IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. PMID:12023369 Human IL-23, but not IL-12, exhibits detectable affinity for human IL-23R.
GO:0072536 interleukin-23 receptor complex	IBA GO_REF:0000033	ACCEPT	Summary: IL23R is a defining component of the interleukin-23 receptor complex, which consists of IL23R and IL12RB1 together with bound IL-23 (PMID:12023369). The IBA annotation is fully consistent with experimental evidence. Reason: IL23R is the IL-23-specific subunit of the IL-23 receptor complex. This is its core localization when engaged in signaling. The annotation is also supported by IDA evidence from PMID:12023369. Supporting Evidence: PMID:12023369 IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness on cells expressing both subunits.
GO:0017046 peptide hormone binding	IBA GO_REF:0000033	REMOVE	Summary: This annotation infers peptide hormone binding for IL23R based on phylogenetic relationship to the prolactin receptor. IL-23 is a cytokine, not a classical peptide hormone, and IL23R does not bind peptide hormones. Reason: This IBA is incorrectly transferred from the prolactin receptor. IL23R binds IL-23, which is a heterodimeric cytokine (p19/p40), not a peptide hormone. The more appropriate and already-annotated terms are cytokine binding (GO:0019955) and interleukin-23 binding (GO:0042019). This annotation should be removed as a propagation error from the prolactin receptor branch of the phylogeny. Supporting Evidence: PMID:12023369 Human IL-23, but not IL-12, exhibits detectable affinity for human IL-23R.
GO:0038161 prolactin signaling pathway	IEA GO_REF:0000108	REMOVE	Summary: This IEA annotation is derived by logical inference from the erroneous IBA annotation of prolactin receptor activity (GO:0004925). IL23R does not participate in prolactin signaling. Reason: This is a cascade error. The IBA annotation of prolactin receptor activity for IL23R is incorrect (IL23R does not bind prolactin), and this IEA was automatically inferred from that erroneous annotation. IL23R signals through the IL-23/JAK2/TYK2/STAT3 pathway, not prolactin signaling. Supporting Evidence: PMID:12023369 IL-23 activates the same Jak-stat signaling molecules as IL-12: Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different DNA-binding stat complexes form in response to IL-23 compared with IL-12.
GO:0002376 immune system process	IEA GO_REF:0000043	ACCEPT	Summary: IL23R is annotated to the Immunity keyword in UniProt, from which this IEA is derived. IL23R is indeed a core component of the immune system, functioning in innate and adaptive immunity through IL-23 signaling. Reason: While very broad, this IEA is correct. IL23R functions exclusively in the immune system, driving Th17/type 17 immune responses. More specific immune process annotations exist alongside this one. Supporting Evidence: PMID:12023369 IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness on cells expressing both subunits.
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation of IL23R to the plasma membrane based on automated mapping from UniProt subcellular location. IL23R is a single-pass type I transmembrane protein localized to the plasma membrane (PMID:12023369). Reason: Correct. IL23R is a transmembrane receptor at the plasma membrane. This is also supported by multiple TAS and IDA annotations for the same term. Supporting Evidence: PMID:12023369 IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness on cells expressing both subunits.
GO:0006954 inflammatory response	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: IEA from UniProt Inflammatory response keyword. IL-23 signaling through IL23R is a major driver of inflammatory responses, particularly in autoimmune and autoinflammatory diseases. Reason: While IL-23 signaling is strongly linked to inflammatory responses and IL23R variants are associated with inflammatory bowel disease and psoriasis, the inflammatory response is a downstream consequence of IL-23-mediated Th17 activation rather than the core molecular function of IL23R. The annotation is not wrong but is peripheral. Supporting Evidence: PMID:16482511 These data support the role of IL-23 in inflammation through stimulating IL-17 production by T lymphocytes, and importantly indicate a novel regulatory function for IL-12 by specifically suppressing IL-17 secretion.
GO:0045087 innate immune response	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: IEA from UniProt Innate immunity keyword. IL23R is expressed on innate immune cells including gamma-delta T cells, ILC3s, and NKT cells, and IL-23 signaling plays a role in innate immune defense. Reason: IL23R is expressed on innate immune cells and IL-23 signaling contributes to innate immunity. However, the primary role of IL23R is as a cytokine receptor that transduces IL-23 signals; the innate immune response is a downstream biological context. The annotation is acceptable but not core. Supporting Evidence: PMID:12023369 The ability of cells to respond to IL-23 or IL-12 correlates with expression of IL-23R or IL-12Rbeta2, respectively.
GO:0005515 protein binding	IPI PMID:12023369 A receptor for the heterodimeric cytokine IL-23 is composed ...	MARK AS OVER ANNOTATED	Summary: IPI from IntAct, based on co-immunoprecipitation of IL23R with JAK2 (UniProtKB:Q62120) and IL-23A/p19 (UniProtKB:Q9NPF7). These are well-characterized interactions central to IL23R function. Reason: Per curation guidelines, protein binding is uninformative. The interaction with JAK2 reflects IL23R's signaling function (captured by cytokine receptor activity GO:0004896) and the interaction with IL-23A reflects ligand binding (captured by interleukin-23 binding GO:0042019). More specific molecular function terms are already present. Supporting Evidence: PMID:12023369 IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with stat3.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: IPI from a high-throughput proteome-scale interactome mapping study (Rolland et al. 2014). The interacting partner is C1D (UniProtKB:Q13901), a nuclear matrix protein involved in DNA damage response. Reason: The interaction with C1D is from a high-throughput Y2H screen and its biological relevance to IL23R function is unclear. Additionally, protein binding is uninformative per curation guidelines. The interaction has not been validated in the context of IL-23 signaling. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions.
GO:0005886 plasma membrane	IPI PMID:11114383 Novel p19 protein engages IL-12p40 to form a cytokine, IL-23...	ACCEPT	Summary: ComplexPortal annotation of the mature IL23R chain to the plasma membrane. IL-23 receptor complex is on the cell surface where it binds extracellular IL-23. Oppmann et al. (2000) described IL-23 and its receptor biology. Reason: IL23R is a type I transmembrane receptor at the plasma membrane. Multiple lines of evidence support this localization. Supporting Evidence: PMID:12023369 IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness on cells expressing both subunits.
GO:0006955 immune response	NAS PMID:19088061 IL-23 modulates CD56+/CD3- NK cell and CD56+/CD3+ NK-like T ...	KEEP AS NON CORE	Summary: NAS annotation from ComplexPortal. Van de Wetering et al. (2009) showed IL-23 modulates NK and NK-like T cell function as part of the immune response. IL23R mediates immune cell activation. Reason: Correct but very broad. Immune response is a general consequence of IL-23 signaling through IL23R. More specific immune process annotations are present. Supporting Evidence: PMID:19088061 Our findings show that IL-23 and IL-18 synergistically elicit IFN-gamma production in NK-like T cells but not in NK cells.
GO:0032729 positive regulation of type II interferon production	IDA PMID:12023369 A receptor for the heterodimeric cytokine IL-23 is composed ...	ACCEPT	Summary: ComplexPortal IDA annotation. Parham et al. (2002) showed that IL-23 signaling through IL23R promotes IFN-gamma (type II interferon) production, similar to but distinct from IL-12 responses. Reason: IL-23 signaling through IL23R promotes IFN-gamma production in T cells and NK cells. This is a well-established downstream effect of IL-23 receptor engagement, supported by the original characterization paper and confirmed in multiple cell types. Supporting Evidence: PMID:12023369 IL-23 activates the same Jak-stat signaling molecules as IL-12: Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different DNA-binding stat complexes form in response to IL-23 compared with IL-12. PMID:11114383 Similar to IL-12, human IL-23 stimulates IFN-gamma production and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cells.
GO:0032740 positive regulation of interleukin-17 production	NAS PMID:16482511 Divergent effects of IL-12 and IL-23 on the production of IL...	ACCEPT	Summary: ComplexPortal NAS annotation. Hoeve et al. (2006) demonstrated that IL-23, in contrast to IL-12, enhances IL-17 secretion by human T cells. This is the defining function of IL-23 in Th17 biology. Reason: Promotion of IL-17 production is one of the most important downstream effects of IL-23 signaling through IL23R. This is the basis for the IL-23/Th17 axis that drives autoimmune inflammation. Supporting Evidence: PMID:16482511 These data support the role of IL-23 in inflammation through stimulating IL-17 production by T lymphocytes, and importantly indicate a novel regulatory function for IL-12 by specifically suppressing IL-17 secretion.
GO:0042102 positive regulation of T cell proliferation	IDA PMID:11114383 Novel p19 protein engages IL-12p40 to form a cytokine, IL-23...	ACCEPT	Summary: ComplexPortal IDA annotation. Oppmann et al. (2000) showed that IL-23 uniquely stimulates memory T cell proliferation, a property not shared with IL-12. Reason: IL-23 signaling through IL23R drives T cell proliferation, particularly of memory T cells. This is a well-established downstream effect directly demonstrated in the discovery paper for IL-23. Supporting Evidence: PMID:11114383 IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low)) T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population.
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT	IDA PMID:12023369 A receptor for the heterodimeric cytokine IL-23 is composed ...	ACCEPT	Summary: ComplexPortal IDA annotation. Parham et al. (2002) demonstrated that IL-23 binding to IL23R activates JAK2, TYK2, and STAT1/3/4/5 signaling, with predominant STAT3 activation. Reason: This is a core function of IL23R. Upon IL-23 binding, IL23R constitutively associates with JAK2 and activates JAK-STAT signaling. This annotation accurately describes that IL23R positively regulates JAK-STAT signaling. Supporting Evidence: PMID:12023369 IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with stat3.
GO:0051142 positive regulation of NK T cell proliferation	NAS PMID:19088061 IL-23 modulates CD56+/CD3- NK cell and CD56+/CD3+ NK-like T ...	KEEP AS NON CORE	Summary: ComplexPortal NAS annotation. Van de Wetering et al. (2009) showed that IL-23 modulates NK-like T cell function, including promoting IFN-gamma production and CD56 upregulation. Reason: IL-23 does modulate NKT cell function, but the primary evidence from van de Wetering et al. focuses more on cytokine production than proliferation per se. The annotation is plausible but represents a secondary cell-type-specific effect rather than a core function of IL23R. Supporting Evidence: PMID:19088061 Our findings show that IL-23 and IL-18 synergistically elicit IFN-gamma production in NK-like T cells but not in NK cells.
GO:2000318 positive regulation of T-helper 17 type immune response	NAS PMID:16482511 Divergent effects of IL-12 and IL-23 on the production of IL...	ACCEPT	Summary: ComplexPortal NAS annotation. IL-23 is the key cytokine for maintaining and expanding Th17 responses. Hoeve et al. (2006) demonstrated IL-23 promotes IL-17 production by T cells. Reason: Promotion of Th17 responses is the defining biological role of IL-23 signaling through IL23R. IL-23 is essential for stabilizing the Th17 lineage and maintaining IL-17 production. Supporting Evidence: PMID:16482511 These data support the role of IL-23 in inflammation through stimulating IL-17 production by T lymphocytes, and importantly indicate a novel regulatory function for IL-12 by specifically suppressing IL-17 secretion.
GO:0032819 positive regulation of natural killer cell proliferation	TAS PMID:19088061 IL-23 modulates CD56+/CD3- NK cell and CD56+/CD3+ NK-like T ...	KEEP AS NON CORE	Summary: BHF-UCL TAS annotation. Van de Wetering et al. (2009) examined IL-23 effects on NK and NKT cells, showing differential modulation compared to IL-12. Reason: IL-23 effects on NK cell proliferation are less well established than its effects on T cells. Van de Wetering et al. showed IL-23 modulates NK cell function but the proliferative effects were more pronounced for NKT cells. This is a secondary, cell-type-specific effect. Supporting Evidence: PMID:19088061 Our findings show that IL-23 and IL-18 synergistically elicit IFN-gamma production in NK-like T cells but not in NK cells.
GO:0051135 positive regulation of NK T cell activation	TAS PMID:19088061 IL-23 modulates CD56+/CD3- NK cell and CD56+/CD3+ NK-like T ...	KEEP AS NON CORE	Summary: BHF-UCL TAS annotation. Van de Wetering et al. (2009) showed IL-23 activates NKT cells, synergizing with IL-18 for IFN-gamma production and upregulating CD56. Reason: IL-23 does activate NKT cells, but this represents one of several cell types responsive to IL-23. The primary role of IL23R in Th17 biology is more central. Supporting Evidence: PMID:19088061 IL-23 and IL-18 synergistically elicit IFN-gamma production in NK-like T cells but not in NK cells. In contrast, IL-12 together with IL-18-induced secretion of IFN-gamma in both populations.
GO:0097696 cell surface receptor signaling pathway via STAT	TAS PMID:19088061 IL-23 modulates CD56+/CD3- NK cell and CD56+/CD3+ NK-like T ...	ACCEPT	Summary: BHF-UCL TAS annotation. IL23R signals through the JAK-STAT pathway, predominantly activating STAT3 (PMID:12023369). This annotation is consistent with the well-established signaling mechanism. Reason: STAT signaling is a core downstream pathway of IL23R. Upon IL-23 binding, IL23R activates STAT3 and to a lesser extent STAT4. This is well supported by the original receptor characterization. Supporting Evidence: PMID:12023369 IL-23 activates the same Jak-stat signaling molecules as IL-12: Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different DNA-binding stat complexes form in response to IL-23 compared with IL-12.
GO:0007259 cell surface receptor signaling pathway via JAK-STAT	IC PMID:12023369 A receptor for the heterodimeric cytokine IL-23 is composed ...	ACCEPT	Summary: BHF-UCL IC annotation inferred from IL-23 binding (GO:0042019). Parham et al. (2002) directly demonstrated JAK2/TYK2 and STAT activation by IL-23 through IL23R. Reason: JAK-STAT signaling is the canonical signaling mechanism of IL23R. IL23R constitutively associates with JAK2, and IL-23 binding activates JAK2/TYK2 leading to STAT3/STAT4 phosphorylation. This is a core biological process annotation. Supporting Evidence: PMID:12023369 IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with stat3.
GO:0004896 cytokine receptor activity	IDA PMID:29287995 Structural Activation of Pro-inflammatory Human Cytokine IL-...	ACCEPT	Summary: UniProt IDA annotation. Bloch et al. (2018) solved the crystal structure of IL-23 bound to IL23R, demonstrating it is a functional cytokine receptor that binds IL-23 via its N-terminal Ig domain and enables signaling. Reason: Cytokine receptor activity is the core molecular function of IL23R. The structural data from Bloch et al. provides direct evidence that IL23R functions as a cytokine receptor. A more specific annotation (GO:0042020 interleukin-23 receptor activity) also exists. Deep research confirms IL23R as the signaling chain of the IL-23 receptor complex with JAK2/TYK2 coupling (IL23R-deep-research-falcon.md). Supporting Evidence: PMID:29287995 IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. file:human/IL23R/IL23R-deep-research-falcon.md IL23R is the signaling chain of the IL-23 receptor complex. Upon IL-23 binding, IL23R:IL12RB1 engagement triggers JAK2/TYK2 activation, predominantly STAT3 signaling.
GO:0009986 cell surface	IDA PMID:12023369 A receptor for the heterodimeric cytokine IL-23 is composed ...	ACCEPT	Summary: UniProt IDA annotation. Parham et al. (2002) demonstrated IL23R at the cell surface using anti-IL23R antibodies that block IL-23 responses in NK cells and Ba/F3 cells. Reason: IL23R is a cell surface receptor. Antibody blocking experiments in the original characterization paper confirm cell surface localization. Supporting Evidence: PMID:12023369 Anti-IL-12Rbeta1 and anti-IL-23R Abs block IL-23 responses of an NK cell line and Ba/F3 cells expressing the two receptor chains.
GO:0038155 interleukin-23-mediated signaling pathway	IDA PMID:29287995 Structural Activation of Pro-inflammatory Human Cytokine IL-...	ACCEPT	Summary: UniProt IDA annotation. Bloch et al. (2018) provided structural and functional evidence that IL23R directly mediates IL-23 signaling by binding IL-23 p19 and restructuring it to enable IL12RB1 recruitment. Reason: This is the most specific and accurate biological process annotation for IL23R. The interleukin-23-mediated signaling pathway is the primary biological process in which IL23R functions. Supporting Evidence: PMID:29287995 IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8950269	ACCEPT	Summary: Reactome TAS annotation from the IL-23 signaling pathway model (STAT3/STAT4 phosphorylation step). IL23R is part of the plasma membrane receptor complex in IL-23 signaling. Reason: Correct. IL23R is a transmembrane receptor at the plasma membrane. The Reactome pathway model accurately places IL23R at the plasma membrane.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8952749	ACCEPT	Summary: Reactome TAS annotation from the STAT4 binding step in IL-23 signaling. Duplicate plasma membrane annotation from a different Reactome reaction. Reason: Correct but redundant with other plasma membrane annotations. IL23R is a plasma membrane receptor.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8952823	ACCEPT	Summary: Reactome TAS annotation from the STAT dissociation step in IL-23 signaling. Duplicate plasma membrane annotation from a different Reactome reaction. Reason: Correct but redundant with other plasma membrane annotations.
GO:0043235 receptor complex	IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm...	ACCEPT	Summary: MGI IDA annotation citing Ghai et al. (2013), a paper about PX-FERM protein-mediated endosomal trafficking. The paper identifies SNX17 binding to NPxY/NxxY motifs in various transmembrane cargos. IL23R may be among the putative cargo molecules identified. Reason: IL23R forms part of a receptor complex (the IL-23 receptor complex with IL12RB1). While the cited paper focuses on endosomal trafficking rather than receptor complex assembly per se, the annotation to receptor complex is correct -- IL23R is indeed part of a receptor complex. This is also more specifically captured by GO:0072536 (interleukin-23 receptor complex). Supporting Evidence: PMID:12023369 IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness on cells expressing both subunits.
GO:2000318 positive regulation of T-helper 17 type immune response	ISS GO_REF:0000024	ACCEPT	Summary: BHF-UCL ISS annotation transferred from mouse IL23R (Q9EQ14). IL-23 signaling through IL23R is essential for Th17 immune responses in both human and mouse. Reason: The Th17 response is the defining biological role of IL-23/IL23R signaling. The ISS transfer from mouse is well supported by human evidence including IL-23-driven IL-17 production and the protective effect of IL23R R381Q in autoimmune disease. Supporting Evidence: PMID:16482511 These data support the role of IL-23 in inflammation through stimulating IL-17 production by T lymphocytes, and importantly indicate a novel regulatory function for IL-12 by specifically suppressing IL-17 secretion.
GO:2000330 positive regulation of T-helper 17 cell lineage commitment	ISS GO_REF:0000024	ACCEPT	Summary: BHF-UCL ISS annotation transferred from mouse IL23R (Q9EQ14). IL-23 signaling is critical for Th17 lineage commitment and maintenance, distinct from Th17 differentiation initiation (which requires IL-6 and TGF-beta). Reason: IL-23 signaling through IL23R stabilizes and maintains Th17 cell identity. While IL-6/TGF-beta initiate Th17 differentiation, IL-23 is required for terminal Th17 commitment and function. This is well supported by mouse knockout studies and human genetic data. Supporting Evidence: PMID:16482511 These data support the role of IL-23 in inflammation through stimulating IL-17 production by T lymphocytes, and importantly indicate a novel regulatory function for IL-12 by specifically suppressing IL-17 secretion.
GO:0032693 negative regulation of interleukin-10 production	IMP PMID:16751425 IL-23 is increased in dendritic cells in multiple sclerosis ...	KEEP AS NON CORE	Summary: BHF-UCL IMP annotation. Vaknin-Dembinsky et al. (2006) showed that IL-23 suppression in dendritic cells from MS patients leads to increased IL-10 production, implying IL-23 signaling negatively regulates IL-10 production. Reason: IL-23 signaling does suppress IL-10 production, which is consistent with its pro-inflammatory role. However, IL-10 regulation is a downstream effect of IL-23 signaling rather than a core function of the IL-23 receptor itself. The evidence is from dendritic cells where IL-23 antisense oligos increased IL-10 output. Supporting Evidence: PMID:16751425 increased IL-10 and decreased TNF-alpha production
GO:0032725 positive regulation of granulocyte macrophage colony-stimulating factor production	IC PMID:20027291 Salmonella induced IL-23 and IL-1beta allow for IL-12 produc...	KEEP AS NON CORE	Summary: BHF-UCL IC annotation inferred from IL-23 binding. Van de Wetering et al. (2009, PMID:20027291) showed Salmonella-induced IL-23 and IL-1beta drive IFN-gamma and GM-CSF production through CD56+ cells. Reason: GM-CSF production is a downstream consequence of IL-23 signaling in the context of bacterial infection. It is not a core function of IL23R but rather one of several cytokines induced by IL-23 pathway activation. Supporting Evidence: PMID:20027291 The findings implicate a positive feedback loop in which IL-23 can enhance its release via induction of IFN-gamma and GM-CSF.
GO:0032729 positive regulation of type II interferon production	TAS PMID:19088061 IL-23 modulates CD56+/CD3- NK cell and CD56+/CD3+ NK-like T ...	ACCEPT	Summary: BHF-UCL TAS annotation. Van de Wetering et al. (2009) showed IL-23 promotes IFN-gamma production in NKT cells synergistically with IL-18. Reason: IFN-gamma production is a well-established downstream effect of IL-23 signaling through IL23R, demonstrated in multiple cell types. This TAS annotation provides additional evidence line for the same GO term. Supporting Evidence: PMID:19088061 Our findings show that IL-23 and IL-18 synergistically elicit IFN-gamma production in NK-like T cells but not in NK cells.
GO:0032729 positive regulation of type II interferon production	IC PMID:20027291 Salmonella induced IL-23 and IL-1beta allow for IL-12 produc...	ACCEPT	Summary: BHF-UCL IC annotation inferred from IL-23 binding. Van de Wetering et al. (2009) showed Salmonella-induced IL-23 drives IFN-gamma production through CD56+ cells. Reason: Consistent with the IDA and TAS annotations for the same term. IL-23 signaling promotes IFN-gamma production across multiple cell types and experimental contexts. Supporting Evidence: PMID:20027291 IFN-gamma production in human CD56(+) cells in an IL-23 and IL-1beta-dependent but IL-12-independent manner.
GO:0032735 positive regulation of interleukin-12 production	IDA PMID:20027291 Salmonella induced IL-23 and IL-1beta allow for IL-12 produc...	KEEP AS NON CORE	Summary: BHF-UCL IDA annotation. Van de Wetering et al. (2009) showed that Salmonella-induced IL-23 drives a feedback loop where IL-23-stimulated IFN-gamma enables monocytes to produce IL-12. Reason: IL-12 production is an indirect downstream effect of IL-23 signaling through an IFN-gamma feedback loop in the context of Salmonella infection. This is not a direct function of IL23R but rather a consequence of the immune amplification circuit. Supporting Evidence: PMID:20027291 Salmonella induced IL-23 and IL-1beta allow for IL-12 production by monocytes and Mphi1 through induction of IFN-gamma in CD56 NK/NK-like T cells.
GO:0032740 positive regulation of interleukin-17 production	IC PMID:17888176 IL-23 induces human osteoclastogenesis via IL-17 in vitro, a...	ACCEPT	Summary: BHF-UCL IC annotation inferred from IL-23 binding. Yago et al. (2007) showed IL-23 elevated the ratio of IL-17 to IFN-gamma production in activated T cells. Reason: IL-17 induction is the hallmark downstream effect of IL-23 signaling through IL23R, central to the IL-23/Th17 axis. Multiple independent studies confirm this. Supporting Evidence: PMID:17888176 we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23.
GO:0042102 positive regulation of T cell proliferation	IC PMID:12023369 A receptor for the heterodimeric cytokine IL-23 is composed ...	ACCEPT	Summary: BHF-UCL IC annotation inferred from IL-23 binding. Parham et al. (2002) showed IL-23 stimulates T cell responses through IL23R. Reason: T cell proliferation is a direct consequence of IL-23 receptor engagement. The original IL23R characterization paper demonstrated this activity. Supporting Evidence: PMID:12023369 Human and mouse IL-23 exhibit some activities similar to IL-12, but differ in their capacities to stimulate particular populations of memory T cells.
GO:0042104 positive regulation of activated T cell proliferation	IC PMID:11114383 Novel p19 protein engages IL-12p40 to form a cytokine, IL-23...	ACCEPT	Summary: BHF-UCL IC annotation inferred from IL-23 binding. Oppmann et al. (2000) showed IL-23 uniquely stimulates memory (activated) T cell proliferation. Reason: IL-23 uniquely stimulates memory T cell proliferation, distinguishing it from IL-12. This is one of the defining biological activities of IL-23 signaling. Supporting Evidence: PMID:11114383 IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low)) T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population.
GO:0045672 positive regulation of osteoclast differentiation	IC PMID:17888176 IL-23 induces human osteoclastogenesis via IL-17 in vitro, a...	KEEP AS NON CORE	Summary: BHF-UCL IC annotation inferred from IL-23 binding. Yago et al. (2007) showed IL-23 induces human osteoclastogenesis via IL-17 in vitro. Reason: IL-23-driven osteoclast differentiation occurs indirectly through IL-17 induction. This is a secondary downstream effect relevant to rheumatoid arthritis pathology but not a core function of IL23R. Supporting Evidence: PMID:17888176 This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC).
GO:0050829 defense response to Gram-negative bacterium	IC PMID:15114670 Commensal Gram-negative bacteria prime human dendritic cells...	KEEP AS NON CORE	Summary: BHF-UCL IC annotation inferred from IL-23 binding. Smits et al. (2004) showed Gram-negative bacteria prime dendritic cells for enhanced IL-23 production, which drives Th1 development. Reason: IL-23 is produced in response to Gram-negative bacteria and contributes to defense through Th17/Th1 activation. However, the defense response is a broad biological outcome rather than a core function of IL23R. The cited paper is about IL-23 production by DCs, not IL23R function per se. Supporting Evidence: PMID:15114670 all Gram-negative bacteria (GnB) primed moDC for enhanced Th1 cell development, which was dependent on IL-12 and an additional unidentified cofactor.
GO:0072536 interleukin-23 receptor complex	IDA PMID:12023369 A receptor for the heterodimeric cytokine IL-23 is composed ...	ACCEPT	Summary: BHF-UCL IDA annotation. Parham et al. (2002) directly demonstrated that IL23R pairs with IL12RB1 to form the IL-23 receptor complex. Reason: This is a core component annotation. IL23R is a defining subunit of the interleukin-23 receptor complex, directly demonstrated in the original receptor characterization paper. Supporting Evidence: PMID:12023369 IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness on cells expressing both subunits.
GO:0002230 positive regulation of defense response to virus by host	IDA PMID:12421946 Regulation of virus-induced IL-12 and IL-23 expression in hu...	KEEP AS NON CORE	Summary: BHF-UCL IDA annotation. Pirhonen et al. (2002) showed that human macrophages produce IL-23 in response to viral infection (Sendai virus), and IL-23 enhances IFN-gamma production by NK cells, promoting antiviral defense. Reason: IL-23 signaling contributes to antiviral defense through IFN-gamma promotion in NK cells. However, the cited paper primarily demonstrates IL-23 production by macrophages rather than direct IL23R-mediated antiviral activity. This is a downstream consequence of IL-23 signaling rather than a core function. Supporting Evidence: PMID:12421946 Sendai virus stimulates the expression of p19 and p40 mRNAs in macrophages.
GO:0002827 positive regulation of T-helper 1 type immune response	IDA PMID:15114670 Commensal Gram-negative bacteria prime human dendritic cells...	KEEP AS NON CORE	Summary: BHF-UCL IDA annotation. Smits et al. (2004) showed Gram-negative bacteria prime dendritic cells for IL-23 production that enhances Th1 development. Reason: IL-23 can promote Th1 responses, but the primary role of IL-23/IL23R signaling is in Th17 biology. Th1 promotion is a secondary effect, partly mediated through IFN-gamma induction. The cited paper is primarily about DC biology rather than IL23R function directly. Supporting Evidence: PMID:15114670 GnB-matured moDC expressed elevated levels of p19 and p28 mRNA, the critical subunits of IL-23 and IL-27, respectively, suggesting that the IL-12 family members may jointly be responsible for their Th1-driving capacity.
GO:0001916 positive regulation of T cell mediated cytotoxicity	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: BHF-UCL ISS annotation transferred from mouse IL23R (Q9EQ14). IL-23 may promote cytotoxic T cell function, but this is not a well-characterized primary activity of IL23R. Reason: T cell mediated cytotoxicity is a downstream immune effector function that may be enhanced by IL-23 signaling, but it is not a core function of IL23R. The ISS transfer from mouse is reasonable but represents a peripheral activity.
GO:0002230 positive regulation of defense response to virus by host	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: BHF-UCL ISS annotation transferred from mouse IL23R (Q9EQ14). Consistent with the IDA annotation from PMID:12421946 showing IL-23 contributes to antiviral defense. Reason: Duplicate evidence line for the same annotation also supported by IDA from PMID:12421946. Antiviral defense is not a core function of IL23R.
GO:0002827 positive regulation of T-helper 1 type immune response	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: BHF-UCL ISS annotation transferred from mouse IL23R (Q9EQ14). Consistent with IDA annotation from PMID:15114670. Reason: Duplicate evidence line. Th1 promotion is a secondary effect of IL-23 signaling. The primary axis is Th17.
GO:0043382 positive regulation of memory T cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: BHF-UCL ISS annotation transferred from mouse IL23R (Q9EQ14). IL-23 uniquely stimulates memory T cells (PMID:11114383), which is consistent with a role in memory T cell differentiation. Reason: IL-23 does preferentially act on memory T cells, but memory T cell differentiation is a downstream consequence of IL-23 signaling. The primary role of IL23R is in Th17 maintenance and cytokine receptor signaling. Supporting Evidence: PMID:11114383 IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low)) T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population.
GO:0005143 interleukin-12 receptor binding	IPI PMID:12023369 A receptor for the heterodimeric cytokine IL-23 is composed ...	ACCEPT	Summary: BHF-UCL IPI annotation with contributes_to qualifier. IL23R pairs with IL12RB1 (the shared IL-12 receptor beta 1 chain), contributing to a complex that has IL-12 receptor binding capacity through the p40 subunit. Reason: The contributes_to qualifier is appropriate. IL23R forms a complex with IL12RB1 where p40 (shared with IL-12) binds IL12RB1. IL23R contributes to the overall IL-12 receptor binding capacity of the complex. Supporting Evidence: PMID:12023369 Like IL-12, IL-23 binds to the IL-12R subunit IL-12Rbeta1.
GO:0042019 interleukin-23 binding	IPI PMID:12023369 A receptor for the heterodimeric cytokine IL-23 is composed ...	ACCEPT	Summary: BHF-UCL IPI annotation with contributes_to qualifier. Parham et al. (2002) showed IL-23 has detectable affinity for IL23R alone, but full binding requires the IL23R:IL12RB1 heterodimer. Reason: The contributes_to qualifier is correct. IL23R directly binds the p19 subunit, while IL12RB1 binds the p40 subunit. Together they form the complete IL-23 binding site. Supporting Evidence: PMID:12023369 Human IL-23, but not IL-12, exhibits detectable affinity for human IL-23R.
GO:0042020 interleukin-23 receptor activity	IDA PMID:12023369 A receptor for the heterodimeric cytokine IL-23 is composed ...	ACCEPT	Summary: BHF-UCL IDA annotation with contributes_to qualifier. Parham et al. (2002) demonstrated that IL23R pairs with IL12RB1 to form the functional IL-23 receptor, conferring IL-23 responsiveness. Reason: This is the most specific molecular function annotation for IL23R. The contributes_to qualifier is appropriate because full IL-23 receptor activity requires both IL23R and IL12RB1 subunits. IL23R alone has partial activity; the heterodimer is needed for full signaling. Supporting Evidence: PMID:12023369 IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness on cells expressing both subunits.
GO:0032496 response to lipopolysaccharide	IDA PMID:12023369 A receptor for the heterodimeric cytokine IL-23 is composed ...	KEEP AS NON CORE	Summary: BHF-UCL IDA annotation. Parham et al. (2002) studied IL23R expression and response in cells stimulated with LPS and other stimuli. IL23R expression may be upregulated by LPS in certain immune cell types. Reason: Response to LPS is a stimulus-response annotation that reflects IL23R expression regulation rather than IL23R's core signaling function. LPS can induce IL-23 production and modulate IL23R expression, but this represents the inflammatory context rather than the receptor's primary activity. Supporting Evidence: PMID:12023369 The ability of cells to respond to IL-23 or IL-12 correlates with expression of IL-23R or IL-12Rbeta2, respectively.
GO:0032729 positive regulation of type II interferon production	IDA PMID:11114383 Novel p19 protein engages IL-12p40 to form a cytokine, IL-23...	ACCEPT	Summary: BHF-UCL IDA annotation. Oppmann et al. (2000) showed IL-23 promotes IFN-gamma production in activated T cells. Reason: IFN-gamma promotion is a well-established downstream effect of IL-23 signaling through IL23R, demonstrated in the original IL-23 discovery paper. Supporting Evidence: PMID:11114383 Similar to IL-12, human IL-23 stimulates IFN-gamma production and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cells.
GO:0034341 response to type II interferon	IDA PMID:12023369 A receptor for the heterodimeric cytokine IL-23 is composed ...	KEEP AS NON CORE	Summary: BHF-UCL IDA annotation. Parham et al. (2002) showed that IFN-gamma can modulate IL23R expression and the ability of cells to respond to IL-23. Reason: Response to IFN-gamma reflects transcriptional regulation of IL23R expression rather than a core function of IL23R itself. IFN-gamma upregulates IL23R in some contexts, but this is a regulatory input not a core activity. Supporting Evidence: PMID:12023369 The ability of cells to respond to IL-23 or IL-12 correlates with expression of IL-23R or IL-12Rbeta2, respectively.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-447130	ACCEPT	Summary: Reactome TAS annotation from the IL-23 binding reaction in the Reactome pathway model. IL23R is located at the plasma membrane. Reason: Correct. Duplicate plasma membrane annotation from a different Reactome pathway step.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6790022	ACCEPT	Summary: Reactome TAS annotation from the STAT3-upregulated plasma membrane proteins pathway. IL23R is at the plasma membrane. Reason: Correct. IL23R is a plasma membrane protein. This Reactome step captures IL23R in the context of STAT3-regulated expression.

Core Functions

IL23R is the IL-23-specific subunit of the heterodimeric IL-23 receptor. It binds IL-23 p19 through its N-terminal Ig domain and pairs with IL12RB1 (which binds IL-12 p40) to form the signaling-competent receptor complex. Upon IL-23 binding, IL23R constitutively associates with JAK2 and recruits STAT3, activating the JAK2/TYK2-STAT3 cascade that drives Th17 gene expression programs.

Molecular Function:

interleukin-23 receptor activity

Directly Involved In:

interleukin-23-mediated signaling pathway positive regulation of T-helper 17 type immune response

In Complex:

interleukin-23 receptor complex

Supporting Evidence:

PMID:12023369
IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with stat3.
PMID:29287995
IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain.

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on inter-ontology links

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11114383

Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12

IL-23 uniquely stimulates memory T cell proliferation and promotes IFN-gamma production in activated T cells.

"IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low)) T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population. Similar to IL-12, human IL-23 stimulates IFN-gamma production and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cells."

PMID:12023369

A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.

Identified IL23R as the IL-23-specific receptor subunit. IL23R pairs with IL12RB1 to form the functional IL-23 receptor. IL23R constitutively associates with JAK2 and, upon IL-23 binding, recruits STAT3. IL-23 activates JAK2, TYK2, STAT1, STAT3, STAT4, and STAT5 but with weaker STAT4 activation than IL-12. IL23R is expressed on NK cells, T cells, monocytes, and dendritic cells.

"IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness on cells expressing both subunits. Human IL-23, but not IL-12, exhibits detectable affinity for human IL-23R."

PMID:12421946

Regulation of virus-induced IL-12 and IL-23 expression in human macrophages

Sendai virus induces IL-23 production in macrophages, promoting IFN-gamma production in NK cells for antiviral defense.

"Sendai virus stimulates the expression of p19 and p40 mRNAs in macrophages. Furthermore, it enhances p35 mRNA expression and the production of IL-12. Influenza A virus, in contrast, fails to stimulate IL-12 or IL-23 expression in macrophages. IL-12 and IL-23 contribute to the IFN-gamma-inducing activity that cell culture supernatant from Sendai virus-infected macrophages show in NK-92 cells."

PMID:15114670

Commensal Gram-negative bacteria prime human dendritic cells for enhanced IL-23 and IL-27 expression and enhanced Th1 development

Gram-negative bacteria prime dendritic cells for enhanced IL-23 production, driving Th1 development.

"all Gram-negative bacteria (GnB) primed moDC for enhanced Th1 cell development, which was dependent on IL-12 and an additional unidentified cofactor. Strikingly, GnB-matured moDC expressed elevated levels of p19 and p28 mRNA, the critical subunits of IL-23 and IL-27, respectively, suggesting that the IL-12 family members may jointly be responsible for their Th1-driving capacity."

PMID:16482511

Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells.

IL-23 enhances IL-17 secretion by human T cells while IL-12 specifically inhibits IL-17 production, establishing divergent roles in Th17 biology.

"IL-23 enhanced IL-17 secretion, as did IL-2, IL-15, IL-18 and IL-21. In contrast, IL-12 mediated specific inhibition of IL-17 production. These data support the role of IL-23 in inflammation through stimulating IL-17 production by T lymphocytes, and importantly indicate a novel regulatory function for IL-12 by specifically suppressing IL-17 secretion."

PMID:16751425

IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production

IL-23 suppression in dendritic cells increases IL-10 and decreases TNF-alpha production.

"Inhibition of IL-23 and IL-12 was associated with increased IL-10 and decreased TNF-alpha production. Furthermore, transfected DCs were poor allostimulators in the MLR."

PMID:17068223

A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.

IL23R R381Q variant (rs11209026) is strongly protective against Crohn's disease and ulcerative colitis.

"An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis."

PMID:17888176

IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats

IL-23 promotes osteoclastogenesis via IL-17 induction and elevates IL-17/IFN-gamma ratio in activated T cells.

"This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction."

PMID:19088061

IL-23 modulates CD56+/CD3- NK cell and CD56+/CD3+ NK-like T cell function differentially from IL-12

IL-23 and IL-18 synergistically promote IFN-gamma production in NKT cells but not NK cells, supporting early immune activation.

"Our findings show that IL-23 and IL-18 synergistically elicit IFN-gamma production in NK-like T cells but not in NK cells. In contrast, IL-12 together with IL-18-induced secretion of IFN-gamma in both populations."

PMID:20027291

Salmonella induced IL-23 and IL-1beta allow for IL-12 production by monocytes and Mphi1 through induction of IFN-gamma in CD56 NK/NK-like T cells

Salmonella-induced IL-23 drives IFN-gamma and GM-CSF production through CD56+ cells, enabling monocyte IL-12 production.

"The findings implicate a positive feedback loop in which IL-23 can enhance its release via induction of IFN-gamma and GM-CSF. The IL-23 induced cytokines allow for the subsequent production of IL-12 and amplify the IFN-gamma production in the type-1 cytokine pathway."

PMID:23382219

Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.

PX-FERM proteins bind transmembrane cargos including cytokine receptors for endosomal sorting.

"the PX-FERM proteins share a promiscuous ability to bind a wide array of putative cargo molecules, including receptor tyrosine kinases, and propose a model for their coordinated molecular interactions with membrane, cargo, and regulatory proteins."

PMID:25416956

A proteome-scale map of the human interactome network.

High-throughput Y2H screen identifying ~14,000 binary protein-protein interactions including IL23R-C1D.

"Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. At equal quality, this map is ?30% larger than what is available from small-scale studies published in the literature in the last few decades."

PMID:29287995

Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1.

Crystal structure of IL-23 bound to IL23R reveals binding exclusively through the N-terminal Ig domain, which restructures p19 to enable IL12RB1 recruitment.

"revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rβ1 with high affinity."

Reactome:R-HSA-447130

Interleukin-23 binds interleukin-23 receptor

Reactome:R-HSA-6790022

Expression of STAT3-upregulated plasma membrane proteins

Reactome:R-HSA-8950269

STAT3, STAT4 are phosphorylated by p-JAK2, p-TYK2 in IL23:IL23 receptor

Reactome:R-HSA-8952749

STAT4 binds p-Y-IL23R in IL23:IL23 receptor

Reactome:R-HSA-8952823

p-Y693-STAT4, p-Y705-STAT3 dissociate from IL23:IL23 receptor

file:human/IL23R/IL23R-deep-research-falcon.md

Deep research report on IL23R

Deep Research

Falcon

(IL23R-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 18 citations 2026-02-14T14:24:14.379506

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan and verification
- Identity/domain check: IL23R encodes the human interleukin-23 receptor (UniProt Q5VWK5), a type I single-pass cytokine receptor of the IL-12/IL-23 receptor family. Domain architecture comprises an N-terminal Ig-like domain and fibronectin type III-like cytokine receptor modules, a single transmembrane helix, and a cytoplasmic tail containing tyrosine motifs for signaling; this conforms with the family/domain annotations provided and confirms we are addressing human IL23R (Homo sapiens) (audia2024theil23rand pages 2-5, garciadominguez2025theroleof pages 2-4, audia2024theil23rand pages 1-2).

Research report: IL23R (human) functional annotation

1) Key concepts and definitions (current understanding)
- Receptor composition and ligand recognition: IL-23 is a heterodimeric cytokine (p19 + p40). Its receptor is a heteromer of IL23R (the IL-23-specific chain) and IL12RB1 (the shared chain with IL-12). IL-23 first engages IL23R via p19, then recruits IL12RB1 through p40 to form the signaling-competent ternary complex (jairath2024il23inhibitionfor pages 1-2) (audia2024theil23rand pages 2-5).
- Subcellular localization: IL23R is a single-pass type I membrane glycoprotein on the plasma membrane of responsive immune cells (audia2024theil23rand pages 2-5, garciadominguez2025theroleof pages 2-4, audia2024theil23rand pages 1-2).
- Canonical signaling: IL23R associates with JAK2 and IL12RB1 with TYK2. Ligand engagement triggers JAK2/TYK2 activation and downstream STAT phosphorylation, with predominant activation of STAT3 in IL-23 signaling (contrast: IL-12 signals mainly via STAT4). Resulting transcriptional programs stabilize/expand Th17 and other IL-23-responsive populations (jairath2024il23inhibitionfor pages 1-2, audia2024theil23rand pages 2-5, garciadominguez2025theroleof pages 2-4).
- Cellular expression: IL23R is expressed on Th17 cells and multiple innate-like lymphocytes including γδ T cells, group 3 innate lymphoid cells (ILC3), and NKT cells; inducible/condition-specific expression is reported in certain myeloid contexts (lay2023useofnanobit pages 1-2, audia2024theil23rand pages 8-10, garciadominguez2025theroleof pages 2-4).

2) Recent developments and latest research (2023–2024 prioritized)
- Preformed receptor assemblies and signaling in living cells: Using NanoBiT/NanoBRET in HEK293 cells, pre-assembled IL23R:IL12RB1 heteromers were detected at the cell surface in the absence of ligand; IL‑23 binding to these preformed complexes induces STAT3 phosphorylation. Artificial high-affinity crosslinking can elicit ligand-independent signaling, underscoring the importance of receptor geometry/avidity (Lay et al., Br J Pharmacol, Jan 2023; URL: https://doi.org/10.1111/bph.16018) (lay2023useofnanobit pages 1-2).
- Structural insights into the extracellular assemblies: Cryo-EM models of complete extracellular IL-23:receptor assemblies reveal how IL-23 p19 engages IL23R and p40 engages IL12RB1, and how therapeutic antagonists (e.g., ustekinumab or designed binders) sterically disrupt assembly. These structures provide a framework for cytokine-specific antagonism within the IL‑12 family (bioRxiv, Mar 2024; URL: https://doi.org/10.1101/2023.03.13.532366) (bloch2024structuresofcomplete pages 20-27).
- Authoritative overview of IL‑23 biology and therapeutics: A 2024 Lancet review synthesizes basic and clinical advances, highlighting IL-23’s dominant role across several IMIDs, the receptor’s JAK2/TYK2 coupling, and clinical data showing high objective response rates with p19 inhibitors, alongside safety similar to placebo across indications (The Lancet, Oct 2024; URL: https://doi.org/10.1016/S0140-6736(24)01750-1) (jairath2024il23inhibitionfor pages 1-2).

3) Primary function and pathways
- Functional role: IL23R is the signaling chain of the IL‑23 receptor complex. Upon IL-23 binding, IL23R:IL12RB1 engagement triggers JAK2/TYK2 activation, predominantly STAT3 signaling, and reinforcement of Th17/IL-23-responsive programs (e.g., IL-17A/F, IL-22), also influencing innate-like lymphocytes (γδ T, ILC3, NKT) (jairath2024il23inhibitionfor pages 1-2, audia2024theil23rand pages 2-5, garciadominguez2025theroleof pages 2-4).
- Pathway placement: IL23R sits upstream of JAK2/TYK2→STAT3/STAT4 (mainly STAT3 for IL-23), integrating microbial and inflammatory cues into effector cytokine production that sustains type 17 immunity (jairath2024il23inhibitionfor pages 1-2, audia2024theil23rand pages 2-5, garciadominguez2025theroleof pages 2-4).

4) Structural and biophysical details
- Domain architecture: N-terminal Ig-like domain plus FNIII-like cytokine receptor modules for ligand binding and receptor assembly; single transmembrane helix; cytosolic tail with tyrosine motifs docking JAKs and STATs (audia2024theil23rand pages 2-5, garciadominguez2025theroleof pages 2-4).
- Ligand–receptor complex organization: Cryo-EM reconstructions of extracellular assemblies show p19:IL23R and p40:IL12RB1 interfaces and map where approved or experimental antagonists block assembly (bioRxiv 2024; URL above) (bloch2024structuresofcomplete pages 20-27).
- Stoichiometry/dynamics at the cell surface: Pre-assembled IL23R–IL12RB1 heteromers exist prior to ligand addition; high-affinity ligand binding (picomolar by NanoBRET) drives signaling, with receptor crosslinking geometry influencing basal activity (Br J Pharmacol 2023; URL above) (lay2023useofnanobit pages 1-2).

5) Expression, cellular and tissue context
- Immune cell expression: Prominent on Th17 cells; also on γδ T cells, ILC3, and NKT cells; inducible in some myeloid settings. These distributions align with IL‑23’s role in type‑17 immunity at barrier tissues (lay2023useofnanobit pages 1-2, audia2024theil23rand pages 8-10, garciadominguez2025theroleof pages 2-4).
- Disease-relevant contexts: IL23R+ ILC3s and Th17-lineage responses are enriched in inflamed mucosa and synovium across IMIDs, consistent with clinical efficacy of IL‑23 blockade (jairath2024il23inhibitionfor pages 1-2, audia2024theil23rand pages 8-10).

6) Human genetics and disease association
- Missense variant R381Q (rs11209026): A well-established protective allele for IMIDs, including Crohn’s disease and ulcerative colitis, with evidence for protection in psoriasis and ankylosing spondylitis in multiple populations; mechanistically, it reduces IL‑23R signaling and/or surface expression, dampening IL‑23–dependent IL‑17 production (2025 synthesis; prioritized here for mechanism) (pastras2025targetingtheil23 pages 6-7) (pastras2025targetingtheil23 pages 9-10, audia2024theil23rand pages 8-10, audia2024theil23rand pages 1-2).
- Other IL23R variants: Protective missense G149R (rs76418789) and V362I (rs41313262) that impair trafficking/stability or signaling; 3′ UTR/regulatory variant rs10889677 associated with risk in some ethnicities (e.g., CD in Caucasians, UC in Asians) via increased expression (pastras2025targetingtheil23 pages 9-10, pastras2025targetingtheil23 pages 6-7).
- Disease links: Multiple GWAS and follow-ups implicate IL23R in IBD, psoriasis, and ankylosing spondylitis; convergence on reduced IL‑23R signaling conferring protection across diseases underscores the pathway’s causal role (pastras2025targetingtheil23 pages 6-7, audia2024theil23rand pages 8-10, audia2024theil23rand pages 1-2).

7) Current applications and real-world implementations
- Therapeutic classes targeting the IL‑23 axis:
- Anti‑p40 (IL‑12/23) monoclonal antibody: ustekinumab, effective across psoriasis, PsA, and IBD; now complemented or surpassed by p19-selective agents in some settings (jairath2024il23inhibitionfor pages 1-2).
- Anti‑p19 monoclonal antibodies: guselkumab, risankizumab, tildrakizumab (dermatology/rheumatology) and mirikizumab, risankizumab, guselkumab (gastroenterology). Lancet 2024 highlights that p19 inhibitors generally show greater efficacy than p40 blockade and, in psoriasis, superiority over TNF inhibitors in achieving high-level responses with extended dosing intervals up to 12 weeks (jairath2024il23inhibitionfor pages 1-2).
- Quantitative efficacy and safety (selected 2023–2024 data):
- Psoriatic arthritis RCT meta-analysis (6 trials; guselkumab/risankizumab/tildrakizumab): ACR-linked musculoskeletal domains improved—resolution of enthesitis RR 1.50 (95% CI 1.34–1.67) and dactylitis RR 1.40 (95% CI 1.22–1.61) vs placebo at ~24 weeks; overall AEs RR 1.07 (95% CI 0.99–1.15), SAEs RR 0.78 (95% CI 0.52–1.15); elevated transaminases increased (RR 1.69, 95% CI 1.29–2.23) (Immunologic Research, Feb 2023; URL: https://doi.org/10.1007/s12026-023-09366-4) (huang2023efficacyandsafety pages 4-8).
- Across indications, pooled data summarized by The Lancet show objective improvement in >70% of psoriasis patients and up to ~50% in IBD with IL‑23 pathway inhibitors; serious AEs and infections comparable to placebo (The Lancet, Oct 2024; URL above) (jairath2024il23inhibitionfor pages 1-2).

8) Expert opinions and analysis (authoritative sources)
- The Lancet 2024 review positions IL‑23 as a hierarchically dominant cytokine across several IMIDs, explains differences in signaling bias versus IL‑12 (STAT3 vs STAT4 bias), and synthesizes comparative clinical performance and safety of p19 vs p40 agents, including practical considerations such as long dosing intervals and broad efficacy across organ systems (Oct 2024; URL above) (jairath2024il23inhibitionfor pages 1-2).

9) Statistics and data highlights
- Psoriatic arthritis: IL‑23 inhibitor RCT meta-analysis—enthesitis RR 1.50 and dactylitis RR 1.40 vs placebo; no increase in SAEs; elevated transaminases RR 1.69 (Immunologic Research, Feb 2023; URL above) (huang2023efficacyandsafety pages 4-8).
- Aggregate cross-indication outcomes: >70% objective improvement in psoriasis and up to ~50% in IBD with IL‑23 blockade; safety similar to placebo (The Lancet, Oct 2024; URL above) (jairath2024il23inhibitionfor pages 1-2).

10) Notes on ambiguity and verification
- The symbol IL23R is unambiguous in this context and maps to the human interleukin‑23 receptor, UniProt Q5VWK5 (Homo sapiens). Domain architecture and receptor family assignment (type I cytokine receptor with Ig-like and FNIII-like domains) in the cited literature match the UniProt description provided, confirming correct target identification (audia2024theil23rand pages 2-5, garciadominguez2025theroleof pages 2-4, audia2024theil23rand pages 1-2).

References (with URLs, publication dates)
- Jairath V, Acosta Felquer ML, Cho RJ. IL-23 inhibition for chronic inflammatory disease. The Lancet. Oct 2024. URL: https://doi.org/10.1016/S0140-6736(24)01750-1 (jairath2024il23inhibitionfor pages 1-2)
- Lay CS, Kilpatrick LE, Craggs PD, Hill SJ. Use of NanoBiT and NanoBRET to characterise interleukin‑23 receptor dimer formation in living cells. Br J Pharmacol. Jan 2023. URL: https://doi.org/10.1111/bph.16018 (lay2023useofnanobit pages 1-2)
- Bloch Y, Felix J, Merceron R, et al. Structures of complete extracellular receptor assemblies mediated by IL‑12 and IL‑23. bioRxiv. Mar 2024. URL: https://doi.org/10.1101/2023.03.13.532366 (bloch2024structuresofcomplete pages 20-27)
- Huang X, Shentu H, He Y, et al. Efficacy and safety of IL‑23 inhibitors in the treatment of psoriatic arthritis: a meta‑analysis based on randomized controlled trials. Immunologic Research. Feb 2023. URL: https://doi.org/10.1007/s12026-023-09366-4 (huang2023efficacyandsafety pages 4-8)
- Audia S, Brescia C, Dattilo V, et al. The IL‑23R and its genetic variants: a hitherto unforeseen bridge between the immune system and cancer development. Cancers. Dec 2024. URL: https://doi.org/10.3390/cancers17010055 (audia2024theil23rand pages 8-10, audia2024theil23rand pages 1-2, audia2024theil23rand pages 19-20, audia2024theil23rand pages 2-5)
- Pastras P, Aggeletopoulou I, Papantoniou K, Triantos C. Targeting the IL‑23 receptor gene: A promising approach in inflammatory bowel disease treatment. Int J Mol Sci. May 2025. URL: https://doi.org/10.3390/ijms26104775 (genetics overview; mechanism emphasis) (pastras2025targetingtheil23 pages 9-10, pastras2025targetingtheil23 pages 6-7)
- García‑Domínguez M. The Role of IL‑23 in the Development of Inflammatory Diseases. Biology. Mar 2025. URL: https://doi.org/10.3390/biology14040347 (structural/biological context) (garciadominguez2025theroleof pages 2-4)

Limitations
- Some genetics summaries (e.g., specific non‑R381Q variants) derive from 2025 reviews; core mechanisms and clinical data are anchored to 2023–2024 high‑quality sources where available. Future guideline updates and head‑to‑head trials will refine positioning among p19 inhibitors.

References

(audia2024theil23rand pages 2-5): Salvatore Audia, Carolina Brescia, Vincenzo Dattilo, Naomi Torchia, Francesco Trapasso, and Rosario Amato. The il-23r and its genetic variants: a hitherto unforeseen bridge between the immune system and cancer development. Cancers, 17:55, Dec 2024. URL: https://doi.org/10.3390/cancers17010055, doi:10.3390/cancers17010055. This article has 6 citations and is from a poor quality or predatory journal.
(garciadominguez2025theroleof pages 2-4): Mario García-Domínguez. The role of il-23 in the development of inflammatory diseases. Biology, 14:347, Mar 2025. URL: https://doi.org/10.3390/biology14040347, doi:10.3390/biology14040347. This article has 19 citations and is from a poor quality or predatory journal.
(audia2024theil23rand pages 1-2): Salvatore Audia, Carolina Brescia, Vincenzo Dattilo, Naomi Torchia, Francesco Trapasso, and Rosario Amato. The il-23r and its genetic variants: a hitherto unforeseen bridge between the immune system and cancer development. Cancers, 17:55, Dec 2024. URL: https://doi.org/10.3390/cancers17010055, doi:10.3390/cancers17010055. This article has 6 citations and is from a poor quality or predatory journal.
(jairath2024il23inhibitionfor pages 1-2): Vipul Jairath, Maria Laura Acosta Felquer, and Raymond Jaihyun Cho. Il-23 inhibition for chronic inflammatory disease. The Lancet, 404:1679-1692, Oct 2024. URL: https://doi.org/10.1016/s0140-6736(24)01750-1, doi:10.1016/s0140-6736(24)01750-1. This article has 29 citations and is from a highest quality peer-reviewed journal.
(lay2023useofnanobit pages 1-2): Charles S. Lay, Laura E. Kilpatrick, Peter D. Craggs, and Stephen J. Hill. Use of nanobit and nanobret to characterise interleukin‐23 receptor dimer formation in living cells. British Journal of Pharmacology, 180:1444-1459, Jan 2023. URL: https://doi.org/10.1111/bph.16018, doi:10.1111/bph.16018. This article has 5 citations and is from a highest quality peer-reviewed journal.
(audia2024theil23rand pages 8-10): Salvatore Audia, Carolina Brescia, Vincenzo Dattilo, Naomi Torchia, Francesco Trapasso, and Rosario Amato. The il-23r and its genetic variants: a hitherto unforeseen bridge between the immune system and cancer development. Cancers, 17:55, Dec 2024. URL: https://doi.org/10.3390/cancers17010055, doi:10.3390/cancers17010055. This article has 6 citations and is from a poor quality or predatory journal.
(bloch2024structuresofcomplete pages 20-27): Yehudi Bloch, Jan Felix, Romain Merceron, Mathias Provost, Royan Alipour Symakani, Robin De Backer, Elisabeth Lambert, and Savvas N. Savvides. Structures of complete extracellular receptor assemblies mediated by il-12 and il-23. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2023.03.13.532366, doi:10.1101/2023.03.13.532366. This article has 8 citations and is from a poor quality or predatory journal.
(pastras2025targetingtheil23 pages 6-7): Ploutarchos Pastras, Ioanna Aggeletopoulou, Konstantinos Papantoniou, and Christos Triantos. Targeting the il-23 receptor gene: a promising approach in inflammatory bowel disease treatment. International Journal of Molecular Sciences, 26:4775, May 2025. URL: https://doi.org/10.3390/ijms26104775, doi:10.3390/ijms26104775. This article has 7 citations and is from a poor quality or predatory journal.
(pastras2025targetingtheil23 pages 9-10): Ploutarchos Pastras, Ioanna Aggeletopoulou, Konstantinos Papantoniou, and Christos Triantos. Targeting the il-23 receptor gene: a promising approach in inflammatory bowel disease treatment. International Journal of Molecular Sciences, 26:4775, May 2025. URL: https://doi.org/10.3390/ijms26104775, doi:10.3390/ijms26104775. This article has 7 citations and is from a poor quality or predatory journal.
(huang2023efficacyandsafety pages 4-8): Xiaojing Huang, Haojie Shentu, Yujing He, Haijia Lai, Chen Xu, Meiling Chen, and Haowei Zhu. Efficacy and safety of il-23 inhibitors in the treatment of psoriatic arthritis: a meta-analysis based on randomized controlled trials. Immunologic Research, 71:505-515, Feb 2023. URL: https://doi.org/10.1007/s12026-023-09366-4, doi:10.1007/s12026-023-09366-4. This article has 31 citations and is from a peer-reviewed journal.
(audia2024theil23rand pages 19-20): Salvatore Audia, Carolina Brescia, Vincenzo Dattilo, Naomi Torchia, Francesco Trapasso, and Rosario Amato. The il-23r and its genetic variants: a hitherto unforeseen bridge between the immune system and cancer development. Cancers, 17:55, Dec 2024. URL: https://doi.org/10.3390/cancers17010055, doi:10.3390/cancers17010055. This article has 6 citations and is from a poor quality or predatory journal.

Citations

lay2023useofnanobit pages 1-2
bloch2024structuresofcomplete pages 20-27
huang2023efficacyandsafety pages 4-8
garciadominguez2025theroleof pages 2-4
https://doi.org/10.1111/bph.16018
https://doi.org/10.1101/2023.03.13.532366
https://doi.org/10.1016/S0140-6736(24
https://doi.org/10.1007/s12026-023-09366-4
https://doi.org/10.3390/cancers17010055
https://doi.org/10.3390/ijms26104775
https://doi.org/10.3390/biology14040347
https://doi.org/10.3390/cancers17010055,
https://doi.org/10.3390/biology14040347,
https://doi.org/10.1016/s0140-6736(24
https://doi.org/10.1111/bph.16018,
https://doi.org/10.1101/2023.03.13.532366,
https://doi.org/10.3390/ijms26104775,
https://doi.org/10.1007/s12026-023-09366-4,

📄 View Raw YAML

id: Q5VWK5
gene_symbol: IL23R
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: IL23R encodes the interleukin-23 receptor, the IL-23-specific subunit
  of the heterodimeric IL-23 receptor complex. IL23R pairs with IL12RB1 to form the
  functional receptor for IL-23 (a p19/p40 heterodimeric cytokine). IL23R is a single-pass
  type I membrane glycoprotein containing an N-terminal Ig-like domain and two fibronectin
  type III domains in its extracellular region, a single transmembrane helix, and
  a cytoplasmic tail bearing tyrosine motifs that recruit JAK2 and STAT3. Upon IL-23
  binding, the receptor activates the JAK2/TYK2-STAT3/STAT4 signaling cascade, with
  predominant STAT3 activation distinguishing IL-23 signaling from IL-12 signaling.
  IL23R is expressed on Th17 cells, gamma-delta T cells, group 3 innate lymphoid cells,
  NKT cells, and NK cells, where it drives type 17 immune responses critical for mucosal
  immunity and defense against extracellular pathogens. The R381Q variant (rs11209026)
  in the cytoplasmic domain is strongly protective against inflammatory bowel disease
  and psoriasis, consistent with the causal role of IL-23 signaling in autoimmune
  inflammation.
alternative_products:
- name: 1 (IL-23R1)
  id: Q5VWK5-1
- name: 2 (IL-23R2-F2)
  id: Q5VWK5-2
  sequence_note: VSP_021993
- name: 3 (IL-23R3-F1)
  id: Q5VWK5-3
  sequence_note: VSP_021997, VSP_021998
- name: 4 (IL-23R2-F1)
  id: Q5VWK5-4
  sequence_note: VSP_021994, VSP_021995
- name: 5 (IL-23R3-F3)
  id: Q5VWK5-5
  sequence_note: VSP_021991, VSP_021999
- name: 6 (IL-23R6)
  id: Q5VWK5-6
  sequence_note: VSP_021992, VSP_021996
- name: 7 (IL-23R5)
  id: Q5VWK5-7
  sequence_note: VSP_021990
existing_annotations:
- term:
    id: GO:0009897
    label: external side of plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IL23R is a type I transmembrane receptor localized at the cell surface
      of immune cells. The extracellular domain faces outward and has been structurally
      resolved by X-ray crystallography and cryo-EM (PMID:29287995). IBA annotation
      based on phylogenetic inference from related cytokine receptors is consistent
      with experimental evidence.
    action: ACCEPT
    reason: IL23R is experimentally confirmed at the cell surface (PMID:12023369).
      Its extracellular Ig-like and FNIII domains face the external side of the plasma
      membrane to engage IL-23. The IBA annotation is appropriate and consistent with
      direct evidence.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: Anti-IL-12Rbeta1 and anti-IL-23R Abs block IL-23 responses
        of an NK cell line and Ba/F3 cells expressing the two receptor chains.
    - reference_id: PMID:29287995
      supporting_text: IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin
        domain.
- term:
    id: GO:0019221
    label: cytokine-mediated signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IL23R is a core component of the IL-23 cytokine signaling pathway. Upon
      IL-23 binding, it signals through JAK2/TYK2-STAT3 (PMID:12023369). This IBA
      is well-supported phylogenetically across the type I cytokine receptor family.
    action: ACCEPT
    reason: This is a correct and appropriately general annotation. IL23R directly
      participates in IL-23-mediated cytokine signaling, its core function. The more
      specific term GO:0038155 (interleukin-23-mediated signaling pathway) is also
      annotated separately with IDA evidence.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: 'IL-23 activates the same Jak-stat signaling molecules as IL-12:
        Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially
        weaker and different DNA-binding stat complexes form in response to IL-23
        compared with IL-12.'
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IL-23 signaling through IL23R promotes proliferation of memory T cells
      and other immune cell populations (PMID:11114383, PMID:12023369). The IBA annotation
      is phylogenetically inferred from related cytokine receptors that promote cell
      proliferation.
    action: KEEP_AS_NON_CORE
    reason: While IL-23 signaling does promote proliferation of T cells and NK-like
      T cells, this is a downstream consequence of cytokine receptor signaling rather
      than a core molecular function of IL23R itself. The term is accurate but represents
      a broad biological outcome rather than the receptor's primary role.
    supported_by:
    - reference_id: PMID:11114383
      supporting_text: IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low))
        T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population.
- term:
    id: GO:0019955
    label: cytokine binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IL23R binds IL-23 via its N-terminal Ig-like domain. Crystal structures
      confirm direct binding of IL23R to the p19 subunit of IL-23 (PMID:29287995).
      The IBA at the level of cytokine binding is correct but more specific terms
      exist.
    action: ACCEPT
    reason: IL23R does bind IL-23, a cytokine. While more specific terms (GO:0042019
      interleukin-23 binding, GO:0042020 interleukin-23 receptor activity) are also
      annotated, this broader IBA annotation captures the general cytokine-binding
      function appropriately at the family level.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: Human IL-23, but not IL-12, exhibits detectable affinity for
        human IL-23R.
    - reference_id: PMID:29287995
      supporting_text: IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin
        domain.
- term:
    id: GO:0004925
    label: prolactin receptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This annotation infers prolactin receptor activity for IL23R based on
      phylogenetic relationship to the prolactin receptor (PRLR). While IL23R and
      PRLR are both type I cytokine receptors, IL23R does not bind prolactin and has
      no demonstrated prolactin receptor activity.
    action: REMOVE
    reason: This is an erroneous IBA annotation. IL23R is in the same broad type I
      cytokine receptor superfamily as PRLR, but it does not bind prolactin. IL23R
      specifically binds IL-23 through its p19 subunit (PMID:29287995). The phylogenetic
      inference is too broad here, incorrectly transferring a ligand-specific function
      across distantly related receptors with different ligand specificities.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: Human IL-23, but not IL-12, exhibits detectable affinity for
        human IL-23R.
- term:
    id: GO:0005143
    label: interleukin-12 receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: IL23R contributes to IL-12 receptor binding in the sense that IL-23 shares
      the p40 subunit with IL-12 and IL23R pairs with IL12RB1 (the shared IL-12 receptor
      chain). The IBA annotation with contributes_to qualifier reflects that IL23R
      is part of a complex that engages IL-12-family cytokine receptor components.
    action: ACCEPT
    reason: The contributes_to qualifier is appropriate. IL23R pairs with IL12RB1
      to form the functional receptor, and IL-23 shares the p40/IL12B subunit with
      IL-12. This means IL23R contributes to a complex that has IL-12 receptor binding
      capacity through the shared IL12RB1 chain. The IBA annotation correctly captures
      this relationship.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: Like IL-12, IL-23 binds to the IL-12R subunit IL-12Rbeta1.
        However, it does not use IL-12Rbeta2.
- term:
    id: GO:0042019
    label: interleukin-23 binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: IL23R contributes to IL-23 binding as part of the IL23R:IL12RB1 heterodimer.
      IL23R binds IL-23 p19 directly, while IL12RB1 engages p40 (PMID:29287995). The
      contributes_to qualifier reflects that full IL-23 binding requires both receptor
      chains.
    action: ACCEPT
    reason: The IBA annotation with contributes_to is correct. IL23R directly binds
      the p19 subunit of IL-23, but the full high-affinity binding of IL-23 requires
      both IL23R and IL12RB1. This is confirmed by structural studies.
    supported_by:
    - reference_id: PMID:29287995
      supporting_text: IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin
        domain.
    - reference_id: PMID:12023369
      supporting_text: Human IL-23, but not IL-12, exhibits detectable affinity for
        human IL-23R.
- term:
    id: GO:0072536
    label: interleukin-23 receptor complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IL23R is a defining component of the interleukin-23 receptor complex,
      which consists of IL23R and IL12RB1 together with bound IL-23 (PMID:12023369).
      The IBA annotation is fully consistent with experimental evidence.
    action: ACCEPT
    reason: IL23R is the IL-23-specific subunit of the IL-23 receptor complex. This
      is its core localization when engaged in signaling. The annotation is also supported
      by IDA evidence from PMID:12023369.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness
        on cells expressing both subunits.
- term:
    id: GO:0017046
    label: peptide hormone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This annotation infers peptide hormone binding for IL23R based on phylogenetic
      relationship to the prolactin receptor. IL-23 is a cytokine, not a classical
      peptide hormone, and IL23R does not bind peptide hormones.
    action: REMOVE
    reason: This IBA is incorrectly transferred from the prolactin receptor. IL23R
      binds IL-23, which is a heterodimeric cytokine (p19/p40), not a peptide hormone.
      The more appropriate and already-annotated terms are cytokine binding (GO:0019955)
      and interleukin-23 binding (GO:0042019). This annotation should be removed as
      a propagation error from the prolactin receptor branch of the phylogeny.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: Human IL-23, but not IL-12, exhibits detectable affinity for
        human IL-23R.
- term:
    id: GO:0038161
    label: prolactin signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: This IEA annotation is derived by logical inference from the erroneous
      IBA annotation of prolactin receptor activity (GO:0004925). IL23R does not participate
      in prolactin signaling.
    action: REMOVE
    reason: This is a cascade error. The IBA annotation of prolactin receptor activity
      for IL23R is incorrect (IL23R does not bind prolactin), and this IEA was automatically
      inferred from that erroneous annotation. IL23R signals through the IL-23/JAK2/TYK2/STAT3
      pathway, not prolactin signaling.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: 'IL-23 activates the same Jak-stat signaling molecules as IL-12:
        Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially
        weaker and different DNA-binding stat complexes form in response to IL-23
        compared with IL-12.'
- term:
    id: GO:0002376
    label: immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IL23R is annotated to the Immunity keyword in UniProt, from which this
      IEA is derived. IL23R is indeed a core component of the immune system, functioning
      in innate and adaptive immunity through IL-23 signaling.
    action: ACCEPT
    reason: While very broad, this IEA is correct. IL23R functions exclusively in
      the immune system, driving Th17/type 17 immune responses. More specific immune
      process annotations exist alongside this one.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness
        on cells expressing both subunits.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation of IL23R to the plasma membrane based on automated mapping
      from UniProt subcellular location. IL23R is a single-pass type I transmembrane
      protein localized to the plasma membrane (PMID:12023369).
    action: ACCEPT
    reason: Correct. IL23R is a transmembrane receptor at the plasma membrane. This
      is also supported by multiple TAS and IDA annotations for the same term.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness
        on cells expressing both subunits.
- term:
    id: GO:0006954
    label: inflammatory response
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA from UniProt Inflammatory response keyword. IL-23 signaling through
      IL23R is a major driver of inflammatory responses, particularly in autoimmune
      and autoinflammatory diseases.
    action: KEEP_AS_NON_CORE
    reason: While IL-23 signaling is strongly linked to inflammatory responses and
      IL23R variants are associated with inflammatory bowel disease and psoriasis,
      the inflammatory response is a downstream consequence of IL-23-mediated Th17
      activation rather than the core molecular function of IL23R. The annotation
      is not wrong but is peripheral.
    supported_by:
    - reference_id: PMID:16482511
      supporting_text: These data support the role of IL-23 in inflammation through
        stimulating IL-17 production by T lymphocytes, and importantly indicate a
        novel regulatory function for IL-12 by specifically suppressing IL-17 secretion.
- term:
    id: GO:0045087
    label: innate immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA from UniProt Innate immunity keyword. IL23R is expressed on innate
      immune cells including gamma-delta T cells, ILC3s, and NKT cells, and IL-23
      signaling plays a role in innate immune defense.
    action: KEEP_AS_NON_CORE
    reason: IL23R is expressed on innate immune cells and IL-23 signaling contributes
      to innate immunity. However, the primary role of IL23R is as a cytokine receptor
      that transduces IL-23 signals; the innate immune response is a downstream biological
      context. The annotation is acceptable but not core.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: The ability of cells to respond to IL-23 or IL-12 correlates
        with expression of IL-23R or IL-12Rbeta2, respectively.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12023369
  review:
    summary: IPI from IntAct, based on co-immunoprecipitation of IL23R with JAK2 (UniProtKB:Q62120)
      and IL-23A/p19 (UniProtKB:Q9NPF7). These are well-characterized interactions
      central to IL23R function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation guidelines, protein binding is uninformative. The interaction
      with JAK2 reflects IL23R's signaling function (captured by cytokine receptor
      activity GO:0004896) and the interaction with IL-23A reflects ligand binding
      (captured by interleukin-23 binding GO:0042019). More specific molecular function
      terms are already present.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: IL-23R associates constitutively with Jak2 and in a ligand-dependent
        manner with stat3.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: IPI from a high-throughput proteome-scale interactome mapping study (Rolland
      et al. 2014). The interacting partner is C1D (UniProtKB:Q13901), a nuclear matrix
      protein involved in DNA damage response.
    action: MARK_AS_OVER_ANNOTATED
    reason: The interaction with C1D is from a high-throughput Y2H screen and its
      biological relevance to IL23R function is unclear. Additionally, protein binding
      is uninformative per curation guidelines. The interaction has not been validated
      in the context of IL-23 signaling.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: Here, we describe a systematic map of ?14,000 high-quality
        human binary protein-protein interactions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IPI
  original_reference_id: PMID:11114383
  review:
    summary: ComplexPortal annotation of the mature IL23R chain to the plasma membrane.
      IL-23 receptor complex is on the cell surface where it binds extracellular IL-23.
      Oppmann et al. (2000) described IL-23 and its receptor biology.
    action: ACCEPT
    reason: IL23R is a type I transmembrane receptor at the plasma membrane. Multiple
      lines of evidence support this localization.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness
        on cells expressing both subunits.
- term:
    id: GO:0006955
    label: immune response
  evidence_type: NAS
  original_reference_id: PMID:19088061
  review:
    summary: NAS annotation from ComplexPortal. Van de Wetering et al. (2009) showed
      IL-23 modulates NK and NK-like T cell function as part of the immune response.
      IL23R mediates immune cell activation.
    action: KEEP_AS_NON_CORE
    reason: Correct but very broad. Immune response is a general consequence of IL-23
      signaling through IL23R. More specific immune process annotations are present.
    supported_by:
    - reference_id: PMID:19088061
      supporting_text: Our findings show that IL-23 and IL-18 synergistically elicit
        IFN-gamma production in NK-like T cells but not in NK cells.
- term:
    id: GO:0032729
    label: positive regulation of type II interferon production
  evidence_type: IDA
  original_reference_id: PMID:12023369
  review:
    summary: ComplexPortal IDA annotation. Parham et al. (2002) showed that IL-23
      signaling through IL23R promotes IFN-gamma (type II interferon) production,
      similar to but distinct from IL-12 responses.
    action: ACCEPT
    reason: IL-23 signaling through IL23R promotes IFN-gamma production in T cells
      and NK cells. This is a well-established downstream effect of IL-23 receptor
      engagement, supported by the original characterization paper and confirmed in
      multiple cell types.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: 'IL-23 activates the same Jak-stat signaling molecules as IL-12:
        Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially
        weaker and different DNA-binding stat complexes form in response to IL-23
        compared with IL-12.'
    - reference_id: PMID:11114383
      supporting_text: Similar to IL-12, human IL-23 stimulates IFN-gamma production
        and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cells.
- term:
    id: GO:0032740
    label: positive regulation of interleukin-17 production
  evidence_type: NAS
  original_reference_id: PMID:16482511
  review:
    summary: ComplexPortal NAS annotation. Hoeve et al. (2006) demonstrated that IL-23,
      in contrast to IL-12, enhances IL-17 secretion by human T cells. This is the
      defining function of IL-23 in Th17 biology.
    action: ACCEPT
    reason: Promotion of IL-17 production is one of the most important downstream
      effects of IL-23 signaling through IL23R. This is the basis for the IL-23/Th17
      axis that drives autoimmune inflammation.
    supported_by:
    - reference_id: PMID:16482511
      supporting_text: These data support the role of IL-23 in inflammation through
        stimulating IL-17 production by T lymphocytes, and importantly indicate a
        novel regulatory function for IL-12 by specifically suppressing IL-17 secretion.
- term:
    id: GO:0042102
    label: positive regulation of T cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:11114383
  review:
    summary: ComplexPortal IDA annotation. Oppmann et al. (2000) showed that IL-23
      uniquely stimulates memory T cell proliferation, a property not shared with
      IL-12.
    action: ACCEPT
    reason: IL-23 signaling through IL23R drives T cell proliferation, particularly
      of memory T cells. This is a well-established downstream effect directly demonstrated
      in the discovery paper for IL-23.
    supported_by:
    - reference_id: PMID:11114383
      supporting_text: IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low))
        T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population.
- term:
    id: GO:0046427
    label: positive regulation of receptor signaling pathway via JAK-STAT
  evidence_type: IDA
  original_reference_id: PMID:12023369
  review:
    summary: ComplexPortal IDA annotation. Parham et al. (2002) demonstrated that
      IL-23 binding to IL23R activates JAK2, TYK2, and STAT1/3/4/5 signaling, with
      predominant STAT3 activation.
    action: ACCEPT
    reason: This is a core function of IL23R. Upon IL-23 binding, IL23R constitutively
      associates with JAK2 and activates JAK-STAT signaling. This annotation accurately
      describes that IL23R positively regulates JAK-STAT signaling.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: IL-23R associates constitutively with Jak2 and in a ligand-dependent
        manner with stat3.
- term:
    id: GO:0051142
    label: positive regulation of NK T cell proliferation
  evidence_type: NAS
  original_reference_id: PMID:19088061
  review:
    summary: ComplexPortal NAS annotation. Van de Wetering et al. (2009) showed that
      IL-23 modulates NK-like T cell function, including promoting IFN-gamma production
      and CD56 upregulation.
    action: KEEP_AS_NON_CORE
    reason: IL-23 does modulate NKT cell function, but the primary evidence from van
      de Wetering et al. focuses more on cytokine production than proliferation per
      se. The annotation is plausible but represents a secondary cell-type-specific
      effect rather than a core function of IL23R.
    supported_by:
    - reference_id: PMID:19088061
      supporting_text: Our findings show that IL-23 and IL-18 synergistically elicit
        IFN-gamma production in NK-like T cells but not in NK cells.
- term:
    id: GO:2000318
    label: positive regulation of T-helper 17 type immune response
  evidence_type: NAS
  original_reference_id: PMID:16482511
  review:
    summary: ComplexPortal NAS annotation. IL-23 is the key cytokine for maintaining
      and expanding Th17 responses. Hoeve et al. (2006) demonstrated IL-23 promotes
      IL-17 production by T cells.
    action: ACCEPT
    reason: Promotion of Th17 responses is the defining biological role of IL-23 signaling
      through IL23R. IL-23 is essential for stabilizing the Th17 lineage and maintaining
      IL-17 production.
    supported_by:
    - reference_id: PMID:16482511
      supporting_text: These data support the role of IL-23 in inflammation through
        stimulating IL-17 production by T lymphocytes, and importantly indicate a
        novel regulatory function for IL-12 by specifically suppressing IL-17 secretion.
- term:
    id: GO:0032819
    label: positive regulation of natural killer cell proliferation
  evidence_type: TAS
  original_reference_id: PMID:19088061
  review:
    summary: BHF-UCL TAS annotation. Van de Wetering et al. (2009) examined IL-23
      effects on NK and NKT cells, showing differential modulation compared to IL-12.
    action: KEEP_AS_NON_CORE
    reason: IL-23 effects on NK cell proliferation are less well established than
      its effects on T cells. Van de Wetering et al. showed IL-23 modulates NK cell
      function but the proliferative effects were more pronounced for NKT cells. This
      is a secondary, cell-type-specific effect.
    supported_by:
    - reference_id: PMID:19088061
      supporting_text: Our findings show that IL-23 and IL-18 synergistically elicit
        IFN-gamma production in NK-like T cells but not in NK cells.
- term:
    id: GO:0051135
    label: positive regulation of NK T cell activation
  evidence_type: TAS
  original_reference_id: PMID:19088061
  review:
    summary: BHF-UCL TAS annotation. Van de Wetering et al. (2009) showed IL-23 activates
      NKT cells, synergizing with IL-18 for IFN-gamma production and upregulating
      CD56.
    action: KEEP_AS_NON_CORE
    reason: IL-23 does activate NKT cells, but this represents one of several cell
      types responsive to IL-23. The primary role of IL23R in Th17 biology is more
      central.
    supported_by:
    - reference_id: PMID:19088061
      supporting_text: IL-23 and IL-18 synergistically elicit IFN-gamma production
        in NK-like T cells but not in NK cells. In contrast, IL-12 together with IL-18-induced
        secretion of IFN-gamma in both populations.
- term:
    id: GO:0097696
    label: cell surface receptor signaling pathway via STAT
  evidence_type: TAS
  original_reference_id: PMID:19088061
  review:
    summary: BHF-UCL TAS annotation. IL23R signals through the JAK-STAT pathway, predominantly
      activating STAT3 (PMID:12023369). This annotation is consistent with the well-established
      signaling mechanism.
    action: ACCEPT
    reason: STAT signaling is a core downstream pathway of IL23R. Upon IL-23 binding,
      IL23R activates STAT3 and to a lesser extent STAT4. This is well supported by
      the original receptor characterization.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: 'IL-23 activates the same Jak-stat signaling molecules as IL-12:
        Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially
        weaker and different DNA-binding stat complexes form in response to IL-23
        compared with IL-12.'
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: IC
  original_reference_id: PMID:12023369
  review:
    summary: BHF-UCL IC annotation inferred from IL-23 binding (GO:0042019). Parham
      et al. (2002) directly demonstrated JAK2/TYK2 and STAT activation by IL-23 through
      IL23R.
    action: ACCEPT
    reason: JAK-STAT signaling is the canonical signaling mechanism of IL23R. IL23R
      constitutively associates with JAK2, and IL-23 binding activates JAK2/TYK2 leading
      to STAT3/STAT4 phosphorylation. This is a core biological process annotation.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: IL-23R associates constitutively with Jak2 and in a ligand-dependent
        manner with stat3.
- term:
    id: GO:0004896
    label: cytokine receptor activity
  evidence_type: IDA
  original_reference_id: PMID:29287995
  review:
    summary: UniProt IDA annotation. Bloch et al. (2018) solved the crystal structure
      of IL-23 bound to IL23R, demonstrating it is a functional cytokine receptor
      that binds IL-23 via its N-terminal Ig domain and enables signaling.
    action: ACCEPT
    reason: Cytokine receptor activity is the core molecular function of IL23R. The
      structural data from Bloch et al. provides direct evidence that IL23R functions
      as a cytokine receptor. A more specific annotation (GO:0042020 interleukin-23
      receptor activity) also exists. Deep research confirms IL23R as the signaling
      chain of the IL-23 receptor complex with JAK2/TYK2 coupling (IL23R-deep-research-falcon.md).
    supported_by:
    - reference_id: PMID:29287995
      supporting_text: IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin
        domain.
    - reference_id: file:human/IL23R/IL23R-deep-research-falcon.md
      supporting_text: IL23R is the signaling chain of the IL-23 receptor complex.
        Upon IL-23 binding, IL23R:IL12RB1 engagement triggers JAK2/TYK2 activation,
        predominantly STAT3 signaling.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:12023369
  review:
    summary: UniProt IDA annotation. Parham et al. (2002) demonstrated IL23R at the
      cell surface using anti-IL23R antibodies that block IL-23 responses in NK cells
      and Ba/F3 cells.
    action: ACCEPT
    reason: IL23R is a cell surface receptor. Antibody blocking experiments in the
      original characterization paper confirm cell surface localization.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: Anti-IL-12Rbeta1 and anti-IL-23R Abs block IL-23 responses
        of an NK cell line and Ba/F3 cells expressing the two receptor chains.
- term:
    id: GO:0038155
    label: interleukin-23-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:29287995
  review:
    summary: UniProt IDA annotation. Bloch et al. (2018) provided structural and functional
      evidence that IL23R directly mediates IL-23 signaling by binding IL-23 p19 and
      restructuring it to enable IL12RB1 recruitment.
    action: ACCEPT
    reason: This is the most specific and accurate biological process annotation for
      IL23R. The interleukin-23-mediated signaling pathway is the primary biological
      process in which IL23R functions.
    supported_by:
    - reference_id: PMID:29287995
      supporting_text: IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin
        domain.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950269
  review:
    summary: Reactome TAS annotation from the IL-23 signaling pathway model (STAT3/STAT4
      phosphorylation step). IL23R is part of the plasma membrane receptor complex
      in IL-23 signaling.
    action: ACCEPT
    reason: Correct. IL23R is a transmembrane receptor at the plasma membrane. The
      Reactome pathway model accurately places IL23R at the plasma membrane.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952749
  review:
    summary: Reactome TAS annotation from the STAT4 binding step in IL-23 signaling.
      Duplicate plasma membrane annotation from a different Reactome reaction.
    action: ACCEPT
    reason: Correct but redundant with other plasma membrane annotations. IL23R is
      a plasma membrane receptor.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952823
  review:
    summary: Reactome TAS annotation from the STAT dissociation step in IL-23 signaling.
      Duplicate plasma membrane annotation from a different Reactome reaction.
    action: ACCEPT
    reason: Correct but redundant with other plasma membrane annotations.
- term:
    id: GO:0043235
    label: receptor complex
  evidence_type: IDA
  original_reference_id: PMID:23382219
  review:
    summary: MGI IDA annotation citing Ghai et al. (2013), a paper about PX-FERM protein-mediated
      endosomal trafficking. The paper identifies SNX17 binding to NPxY/NxxY motifs
      in various transmembrane cargos. IL23R may be among the putative cargo molecules
      identified.
    action: ACCEPT
    reason: IL23R forms part of a receptor complex (the IL-23 receptor complex with
      IL12RB1). While the cited paper focuses on endosomal trafficking rather than
      receptor complex assembly per se, the annotation to receptor complex is correct
      -- IL23R is indeed part of a receptor complex. This is also more specifically
      captured by GO:0072536 (interleukin-23 receptor complex).
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness
        on cells expressing both subunits.
- term:
    id: GO:2000318
    label: positive regulation of T-helper 17 type immune response
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: BHF-UCL ISS annotation transferred from mouse IL23R (Q9EQ14). IL-23 signaling
      through IL23R is essential for Th17 immune responses in both human and mouse.
    action: ACCEPT
    reason: The Th17 response is the defining biological role of IL-23/IL23R signaling.
      The ISS transfer from mouse is well supported by human evidence including IL-23-driven
      IL-17 production and the protective effect of IL23R R381Q in autoimmune disease.
    supported_by:
    - reference_id: PMID:16482511
      supporting_text: These data support the role of IL-23 in inflammation through
        stimulating IL-17 production by T lymphocytes, and importantly indicate a
        novel regulatory function for IL-12 by specifically suppressing IL-17 secretion.
- term:
    id: GO:2000330
    label: positive regulation of T-helper 17 cell lineage commitment
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: BHF-UCL ISS annotation transferred from mouse IL23R (Q9EQ14). IL-23 signaling
      is critical for Th17 lineage commitment and maintenance, distinct from Th17
      differentiation initiation (which requires IL-6 and TGF-beta).
    action: ACCEPT
    reason: IL-23 signaling through IL23R stabilizes and maintains Th17 cell identity.
      While IL-6/TGF-beta initiate Th17 differentiation, IL-23 is required for terminal
      Th17 commitment and function. This is well supported by mouse knockout studies
      and human genetic data.
    supported_by:
    - reference_id: PMID:16482511
      supporting_text: These data support the role of IL-23 in inflammation through
        stimulating IL-17 production by T lymphocytes, and importantly indicate a
        novel regulatory function for IL-12 by specifically suppressing IL-17 secretion.
- term:
    id: GO:0032693
    label: negative regulation of interleukin-10 production
  evidence_type: IMP
  original_reference_id: PMID:16751425
  review:
    summary: BHF-UCL IMP annotation. Vaknin-Dembinsky et al. (2006) showed that IL-23
      suppression in dendritic cells from MS patients leads to increased IL-10 production,
      implying IL-23 signaling negatively regulates IL-10 production.
    action: KEEP_AS_NON_CORE
    reason: IL-23 signaling does suppress IL-10 production, which is consistent with
      its pro-inflammatory role. However, IL-10 regulation is a downstream effect
      of IL-23 signaling rather than a core function of the IL-23 receptor itself.
      The evidence is from dendritic cells where IL-23 antisense oligos increased
      IL-10 output.
    supported_by:
    - reference_id: PMID:16751425
      supporting_text: increased IL-10 and decreased TNF-alpha production
- term:
    id: GO:0032725
    label: positive regulation of granulocyte macrophage colony-stimulating factor
      production
  evidence_type: IC
  original_reference_id: PMID:20027291
  review:
    summary: BHF-UCL IC annotation inferred from IL-23 binding. Van de Wetering et
      al. (2009, PMID:20027291) showed Salmonella-induced IL-23 and IL-1beta drive
      IFN-gamma and GM-CSF production through CD56+ cells.
    action: KEEP_AS_NON_CORE
    reason: GM-CSF production is a downstream consequence of IL-23 signaling in the
      context of bacterial infection. It is not a core function of IL23R but rather
      one of several cytokines induced by IL-23 pathway activation.
    supported_by:
    - reference_id: PMID:20027291
      supporting_text: The findings implicate a positive feedback loop in which IL-23
        can enhance its release via induction of IFN-gamma and GM-CSF.
- term:
    id: GO:0032729
    label: positive regulation of type II interferon production
  evidence_type: TAS
  original_reference_id: PMID:19088061
  review:
    summary: BHF-UCL TAS annotation. Van de Wetering et al. (2009) showed IL-23 promotes
      IFN-gamma production in NKT cells synergistically with IL-18.
    action: ACCEPT
    reason: IFN-gamma production is a well-established downstream effect of IL-23
      signaling through IL23R, demonstrated in multiple cell types. This TAS annotation
      provides additional evidence line for the same GO term.
    supported_by:
    - reference_id: PMID:19088061
      supporting_text: Our findings show that IL-23 and IL-18 synergistically elicit
        IFN-gamma production in NK-like T cells but not in NK cells.
- term:
    id: GO:0032729
    label: positive regulation of type II interferon production
  evidence_type: IC
  original_reference_id: PMID:20027291
  review:
    summary: BHF-UCL IC annotation inferred from IL-23 binding. Van de Wetering et
      al. (2009) showed Salmonella-induced IL-23 drives IFN-gamma production through
      CD56+ cells.
    action: ACCEPT
    reason: Consistent with the IDA and TAS annotations for the same term. IL-23 signaling
      promotes IFN-gamma production across multiple cell types and experimental contexts.
    supported_by:
    - reference_id: PMID:20027291
      supporting_text: IFN-gamma production in human CD56(+) cells in an IL-23 and
        IL-1beta-dependent but IL-12-independent manner.
- term:
    id: GO:0032735
    label: positive regulation of interleukin-12 production
  evidence_type: IDA
  original_reference_id: PMID:20027291
  review:
    summary: BHF-UCL IDA annotation. Van de Wetering et al. (2009) showed that Salmonella-induced
      IL-23 drives a feedback loop where IL-23-stimulated IFN-gamma enables monocytes
      to produce IL-12.
    action: KEEP_AS_NON_CORE
    reason: IL-12 production is an indirect downstream effect of IL-23 signaling through
      an IFN-gamma feedback loop in the context of Salmonella infection. This is not
      a direct function of IL23R but rather a consequence of the immune amplification
      circuit.
    supported_by:
    - reference_id: PMID:20027291
      supporting_text: Salmonella induced IL-23 and IL-1beta allow for IL-12 production
        by monocytes and Mphi1 through induction of IFN-gamma in CD56 NK/NK-like T
        cells.
- term:
    id: GO:0032740
    label: positive regulation of interleukin-17 production
  evidence_type: IC
  original_reference_id: PMID:17888176
  review:
    summary: BHF-UCL IC annotation inferred from IL-23 binding. Yago et al. (2007)
      showed IL-23 elevated the ratio of IL-17 to IFN-gamma production in activated
      T cells.
    action: ACCEPT
    reason: IL-17 induction is the hallmark downstream effect of IL-23 signaling through
      IL23R, central to the IL-23/Th17 axis. Multiple independent studies confirm
      this.
    supported_by:
    - reference_id: PMID:17888176
      supporting_text: we found the ratio of production levels of IL-17 to those of
        IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23.
- term:
    id: GO:0042102
    label: positive regulation of T cell proliferation
  evidence_type: IC
  original_reference_id: PMID:12023369
  review:
    summary: BHF-UCL IC annotation inferred from IL-23 binding. Parham et al. (2002)
      showed IL-23 stimulates T cell responses through IL23R.
    action: ACCEPT
    reason: T cell proliferation is a direct consequence of IL-23 receptor engagement.
      The original IL23R characterization paper demonstrated this activity.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: Human and mouse IL-23 exhibit some activities similar to IL-12,
        but differ in their capacities to stimulate particular populations of memory
        T cells.
- term:
    id: GO:0042104
    label: positive regulation of activated T cell proliferation
  evidence_type: IC
  original_reference_id: PMID:11114383
  review:
    summary: BHF-UCL IC annotation inferred from IL-23 binding. Oppmann et al. (2000)
      showed IL-23 uniquely stimulates memory (activated) T cell proliferation.
    action: ACCEPT
    reason: IL-23 uniquely stimulates memory T cell proliferation, distinguishing
      it from IL-12. This is one of the defining biological activities of IL-23 signaling.
    supported_by:
    - reference_id: PMID:11114383
      supporting_text: IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low))
        T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population.
- term:
    id: GO:0045672
    label: positive regulation of osteoclast differentiation
  evidence_type: IC
  original_reference_id: PMID:17888176
  review:
    summary: BHF-UCL IC annotation inferred from IL-23 binding. Yago et al. (2007)
      showed IL-23 induces human osteoclastogenesis via IL-17 in vitro.
    action: KEEP_AS_NON_CORE
    reason: IL-23-driven osteoclast differentiation occurs indirectly through IL-17
      induction. This is a secondary downstream effect relevant to rheumatoid arthritis
      pathology but not a core function of IL23R.
    supported_by:
    - reference_id: PMID:17888176
      supporting_text: This study demonstrates that IL-23 stimulates the differentiation
        of human osteoclasts from peripheral blood mononuclear cells (PBMC).
- term:
    id: GO:0050829
    label: defense response to Gram-negative bacterium
  evidence_type: IC
  original_reference_id: PMID:15114670
  review:
    summary: BHF-UCL IC annotation inferred from IL-23 binding. Smits et al. (2004)
      showed Gram-negative bacteria prime dendritic cells for enhanced IL-23 production,
      which drives Th1 development.
    action: KEEP_AS_NON_CORE
    reason: IL-23 is produced in response to Gram-negative bacteria and contributes
      to defense through Th17/Th1 activation. However, the defense response is a broad
      biological outcome rather than a core function of IL23R. The cited paper is
      about IL-23 production by DCs, not IL23R function per se.
    supported_by:
    - reference_id: PMID:15114670
      supporting_text: all Gram-negative bacteria (GnB) primed moDC for enhanced Th1
        cell development, which was dependent on IL-12 and an additional unidentified
        cofactor.
- term:
    id: GO:0072536
    label: interleukin-23 receptor complex
  evidence_type: IDA
  original_reference_id: PMID:12023369
  review:
    summary: BHF-UCL IDA annotation. Parham et al. (2002) directly demonstrated that
      IL23R pairs with IL12RB1 to form the IL-23 receptor complex.
    action: ACCEPT
    reason: This is a core component annotation. IL23R is a defining subunit of the
      interleukin-23 receptor complex, directly demonstrated in the original receptor
      characterization paper.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness
        on cells expressing both subunits.
- term:
    id: GO:0002230
    label: positive regulation of defense response to virus by host
  evidence_type: IDA
  original_reference_id: PMID:12421946
  review:
    summary: BHF-UCL IDA annotation. Pirhonen et al. (2002) showed that human macrophages
      produce IL-23 in response to viral infection (Sendai virus), and IL-23 enhances
      IFN-gamma production by NK cells, promoting antiviral defense.
    action: KEEP_AS_NON_CORE
    reason: IL-23 signaling contributes to antiviral defense through IFN-gamma promotion
      in NK cells. However, the cited paper primarily demonstrates IL-23 production
      by macrophages rather than direct IL23R-mediated antiviral activity. This is
      a downstream consequence of IL-23 signaling rather than a core function.
    supported_by:
    - reference_id: PMID:12421946
      supporting_text: Sendai virus stimulates the expression of p19 and p40 mRNAs
        in macrophages.
- term:
    id: GO:0002827
    label: positive regulation of T-helper 1 type immune response
  evidence_type: IDA
  original_reference_id: PMID:15114670
  review:
    summary: BHF-UCL IDA annotation. Smits et al. (2004) showed Gram-negative bacteria
      prime dendritic cells for IL-23 production that enhances Th1 development.
    action: KEEP_AS_NON_CORE
    reason: IL-23 can promote Th1 responses, but the primary role of IL-23/IL23R signaling
      is in Th17 biology. Th1 promotion is a secondary effect, partly mediated through
      IFN-gamma induction. The cited paper is primarily about DC biology rather than
      IL23R function directly.
    supported_by:
    - reference_id: PMID:15114670
      supporting_text: GnB-matured moDC expressed elevated levels of p19 and p28 mRNA,
        the critical subunits of IL-23 and IL-27, respectively, suggesting that the
        IL-12 family members may jointly be responsible for their Th1-driving capacity.
- term:
    id: GO:0001916
    label: positive regulation of T cell mediated cytotoxicity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: BHF-UCL ISS annotation transferred from mouse IL23R (Q9EQ14). IL-23 may
      promote cytotoxic T cell function, but this is not a well-characterized primary
      activity of IL23R.
    action: KEEP_AS_NON_CORE
    reason: T cell mediated cytotoxicity is a downstream immune effector function
      that may be enhanced by IL-23 signaling, but it is not a core function of IL23R.
      The ISS transfer from mouse is reasonable but represents a peripheral activity.
- term:
    id: GO:0002230
    label: positive regulation of defense response to virus by host
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: BHF-UCL ISS annotation transferred from mouse IL23R (Q9EQ14). Consistent
      with the IDA annotation from PMID:12421946 showing IL-23 contributes to antiviral
      defense.
    action: KEEP_AS_NON_CORE
    reason: Duplicate evidence line for the same annotation also supported by IDA
      from PMID:12421946. Antiviral defense is not a core function of IL23R.
- term:
    id: GO:0002827
    label: positive regulation of T-helper 1 type immune response
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: BHF-UCL ISS annotation transferred from mouse IL23R (Q9EQ14). Consistent
      with IDA annotation from PMID:15114670.
    action: KEEP_AS_NON_CORE
    reason: Duplicate evidence line. Th1 promotion is a secondary effect of IL-23
      signaling. The primary axis is Th17.
- term:
    id: GO:0043382
    label: positive regulation of memory T cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: BHF-UCL ISS annotation transferred from mouse IL23R (Q9EQ14). IL-23 uniquely
      stimulates memory T cells (PMID:11114383), which is consistent with a role in
      memory T cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: IL-23 does preferentially act on memory T cells, but memory T cell differentiation
      is a downstream consequence of IL-23 signaling. The primary role of IL23R is
      in Th17 maintenance and cytokine receptor signaling.
    supported_by:
    - reference_id: PMID:11114383
      supporting_text: IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low))
        T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population.
- term:
    id: GO:0005143
    label: interleukin-12 receptor binding
  evidence_type: IPI
  original_reference_id: PMID:12023369
  qualifier: contributes_to
  review:
    summary: BHF-UCL IPI annotation with contributes_to qualifier. IL23R pairs with
      IL12RB1 (the shared IL-12 receptor beta 1 chain), contributing to a complex
      that has IL-12 receptor binding capacity through the p40 subunit.
    action: ACCEPT
    reason: The contributes_to qualifier is appropriate. IL23R forms a complex with
      IL12RB1 where p40 (shared with IL-12) binds IL12RB1. IL23R contributes to the
      overall IL-12 receptor binding capacity of the complex.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: Like IL-12, IL-23 binds to the IL-12R subunit IL-12Rbeta1.
- term:
    id: GO:0042019
    label: interleukin-23 binding
  evidence_type: IPI
  original_reference_id: PMID:12023369
  qualifier: contributes_to
  review:
    summary: BHF-UCL IPI annotation with contributes_to qualifier. Parham et al. (2002)
      showed IL-23 has detectable affinity for IL23R alone, but full binding requires
      the IL23R:IL12RB1 heterodimer.
    action: ACCEPT
    reason: The contributes_to qualifier is correct. IL23R directly binds the p19
      subunit, while IL12RB1 binds the p40 subunit. Together they form the complete
      IL-23 binding site.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: Human IL-23, but not IL-12, exhibits detectable affinity for
        human IL-23R.
- term:
    id: GO:0042020
    label: interleukin-23 receptor activity
  evidence_type: IDA
  original_reference_id: PMID:12023369
  qualifier: contributes_to
  review:
    summary: BHF-UCL IDA annotation with contributes_to qualifier. Parham et al. (2002)
      demonstrated that IL23R pairs with IL12RB1 to form the functional IL-23 receptor,
      conferring IL-23 responsiveness.
    action: ACCEPT
    reason: This is the most specific molecular function annotation for IL23R. The
      contributes_to qualifier is appropriate because full IL-23 receptor activity
      requires both IL23R and IL12RB1 subunits. IL23R alone has partial activity;
      the heterodimer is needed for full signaling.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness
        on cells expressing both subunits.
- term:
    id: GO:0032496
    label: response to lipopolysaccharide
  evidence_type: IDA
  original_reference_id: PMID:12023369
  review:
    summary: BHF-UCL IDA annotation. Parham et al. (2002) studied IL23R expression
      and response in cells stimulated with LPS and other stimuli. IL23R expression
      may be upregulated by LPS in certain immune cell types.
    action: KEEP_AS_NON_CORE
    reason: Response to LPS is a stimulus-response annotation that reflects IL23R
      expression regulation rather than IL23R's core signaling function. LPS can induce
      IL-23 production and modulate IL23R expression, but this represents the inflammatory
      context rather than the receptor's primary activity.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: The ability of cells to respond to IL-23 or IL-12 correlates
        with expression of IL-23R or IL-12Rbeta2, respectively.
- term:
    id: GO:0032729
    label: positive regulation of type II interferon production
  evidence_type: IDA
  original_reference_id: PMID:11114383
  review:
    summary: BHF-UCL IDA annotation. Oppmann et al. (2000) showed IL-23 promotes IFN-gamma
      production in activated T cells.
    action: ACCEPT
    reason: IFN-gamma promotion is a well-established downstream effect of IL-23 signaling
      through IL23R, demonstrated in the original IL-23 discovery paper.
    supported_by:
    - reference_id: PMID:11114383
      supporting_text: Similar to IL-12, human IL-23 stimulates IFN-gamma production
        and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cells.
- term:
    id: GO:0034341
    label: response to type II interferon
  evidence_type: IDA
  original_reference_id: PMID:12023369
  review:
    summary: BHF-UCL IDA annotation. Parham et al. (2002) showed that IFN-gamma can
      modulate IL23R expression and the ability of cells to respond to IL-23.
    action: KEEP_AS_NON_CORE
    reason: Response to IFN-gamma reflects transcriptional regulation of IL23R expression
      rather than a core function of IL23R itself. IFN-gamma upregulates IL23R in
      some contexts, but this is a regulatory input not a core activity.
    supported_by:
    - reference_id: PMID:12023369
      supporting_text: The ability of cells to respond to IL-23 or IL-12 correlates
        with expression of IL-23R or IL-12Rbeta2, respectively.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-447130
  review:
    summary: Reactome TAS annotation from the IL-23 binding reaction in the Reactome
      pathway model. IL23R is located at the plasma membrane.
    action: ACCEPT
    reason: Correct. Duplicate plasma membrane annotation from a different Reactome
      pathway step.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6790022
  review:
    summary: Reactome TAS annotation from the STAT3-upregulated plasma membrane proteins
      pathway. IL23R is at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL23R is a plasma membrane protein. This Reactome step captures
      IL23R in the context of STAT3-regulated expression.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on inter-ontology
    links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11114383
  title: Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological
    activities similar as well as distinct from IL-12
  findings:
  - statement: IL-23 uniquely stimulates memory T cell proliferation and promotes
      IFN-gamma production in activated T cells.
    supporting_text: IL-23 induces strong proliferation of mouse memory (CD4(+)CD45Rb(low))
      T cells, a unique activity of IL-23 as IL-12 has no effect on this cell population.
      Similar to IL-12, human IL-23 stimulates IFN-gamma production and proliferation
      in PHA blast T cells, as well as in CD45RO (memory) T cells.
- id: PMID:12023369
  title: A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1
    and a novel cytokine receptor subunit, IL-23R.
  findings:
  - statement: Identified IL23R as the IL-23-specific receptor subunit. IL23R pairs
      with IL12RB1 to form the functional IL-23 receptor. IL23R constitutively associates
      with JAK2 and, upon IL-23 binding, recruits STAT3. IL-23 activates JAK2, TYK2,
      STAT1, STAT3, STAT4, and STAT5 but with weaker STAT4 activation than IL-12.
      IL23R is expressed on NK cells, T cells, monocytes, and dendritic cells.
    supporting_text: IL-23R pairs with IL-12Rbeta1 to confer IL-23 responsiveness
      on cells expressing both subunits. Human IL-23, but not IL-12, exhibits detectable
      affinity for human IL-23R.
- id: PMID:12421946
  title: Regulation of virus-induced IL-12 and IL-23 expression in human macrophages
  findings:
  - statement: Sendai virus induces IL-23 production in macrophages, promoting IFN-gamma
      production in NK cells for antiviral defense.
    supporting_text: Sendai virus stimulates the expression of p19 and p40 mRNAs in
      macrophages. Furthermore, it enhances p35 mRNA expression and the production
      of IL-12. Influenza A virus, in contrast, fails to stimulate IL-12 or IL-23
      expression in macrophages. IL-12 and IL-23 contribute to the IFN-gamma-inducing
      activity that cell culture supernatant from Sendai virus-infected macrophages
      show in NK-92 cells.
- id: PMID:15114670
  title: Commensal Gram-negative bacteria prime human dendritic cells for enhanced
    IL-23 and IL-27 expression and enhanced Th1 development
  findings:
  - statement: Gram-negative bacteria prime dendritic cells for enhanced IL-23 production,
      driving Th1 development.
    supporting_text: all Gram-negative bacteria (GnB) primed moDC for enhanced Th1
      cell development, which was dependent on IL-12 and an additional unidentified
      cofactor. Strikingly, GnB-matured moDC expressed elevated levels of p19 and
      p28 mRNA, the critical subunits of IL-23 and IL-27, respectively, suggesting
      that the IL-12 family members may jointly be responsible for their Th1-driving
      capacity.
- id: PMID:16482511
  title: Divergent effects of IL-12 and IL-23 on the production of IL-17 by human
    T cells.
  findings:
  - statement: IL-23 enhances IL-17 secretion by human T cells while IL-12 specifically
      inhibits IL-17 production, establishing divergent roles in Th17 biology.
    supporting_text: IL-23 enhanced IL-17 secretion, as did IL-2, IL-15, IL-18 and
      IL-21. In contrast, IL-12 mediated specific inhibition of IL-17 production.
      These data support the role of IL-23 in inflammation through stimulating IL-17
      production by T lymphocytes, and importantly indicate a novel regulatory function
      for IL-12 by specifically suppressing IL-17 secretion.
- id: PMID:16751425
  title: IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation
    of IL-23 by antisense oligos increases dendritic cell IL-10 production
  findings:
  - statement: IL-23 suppression in dendritic cells increases IL-10 and decreases
      TNF-alpha production.
    supporting_text: Inhibition of IL-23 and IL-12 was associated with increased IL-10
      and decreased TNF-alpha production. Furthermore, transfected DCs were poor allostimulators
      in the MLR.
- id: PMID:17068223
  title: A genome-wide association study identifies IL23R as an inflammatory bowel
    disease gene.
  findings:
  - statement: IL23R R381Q variant (rs11209026) is strongly protective against Crohn's
      disease and ulcerative colitis.
    supporting_text: An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln)
      confers strong protection against Crohn's disease, and additional noncoding
      IL23R variants are independently associated. Replication studies confirmed IL23R
      associations in independent cohorts of patients with Crohn's disease or ulcerative
      colitis.
- id: PMID:17888176
  title: IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23
    antibody attenuates collagen-induced arthritis in rats
  findings:
  - statement: IL-23 promotes osteoclastogenesis via IL-17 induction and elevates
      IL-17/IFN-gamma ratio in activated T cells.
    supporting_text: This study demonstrates that IL-23 stimulates the differentiation
      of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore,
      in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody
      attenuates collagen-induced arthritis in rats by preventing both inflammation
      and bone destruction.
- id: PMID:19088061
  title: IL-23 modulates CD56+/CD3- NK cell and CD56+/CD3+ NK-like T cell function
    differentially from IL-12
  findings:
  - statement: IL-23 and IL-18 synergistically promote IFN-gamma production in NKT
      cells but not NK cells, supporting early immune activation.
    supporting_text: Our findings show that IL-23 and IL-18 synergistically elicit
      IFN-gamma production in NK-like T cells but not in NK cells. In contrast, IL-12
      together with IL-18-induced secretion of IFN-gamma in both populations.
- id: PMID:20027291
  title: Salmonella induced IL-23 and IL-1beta allow for IL-12 production by monocytes
    and Mphi1 through induction of IFN-gamma in CD56 NK/NK-like T cells
  findings:
  - statement: Salmonella-induced IL-23 drives IFN-gamma and GM-CSF production through
      CD56+ cells, enabling monocyte IL-12 production.
    supporting_text: The findings implicate a positive feedback loop in which IL-23
      can enhance its release via induction of IFN-gamma and GM-CSF. The IL-23 induced
      cytokines allow for the subsequent production of IL-12 and amplify the IFN-gamma
      production in the type-1 cytokine pathway.
- id: PMID:23382219
  title: Structural basis for endosomal trafficking of diverse transmembrane cargos
    by PX-FERM proteins.
  findings:
  - statement: PX-FERM proteins bind transmembrane cargos including cytokine receptors
      for endosomal sorting.
    supporting_text: the PX-FERM proteins share a promiscuous ability to bind a wide
      array of putative cargo molecules, including receptor tyrosine kinases, and
      propose a model for their coordinated molecular interactions with membrane,
      cargo, and regulatory proteins.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings:
  - statement: High-throughput Y2H screen identifying ~14,000 binary protein-protein
      interactions including IL23R-C1D.
    supporting_text: Here, we describe a systematic map of ?14,000 high-quality human
      binary protein-protein interactions. At equal quality, this map is ?30% larger
      than what is available from small-scale studies published in the literature
      in the last few decades.
- id: PMID:29287995
  title: Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate
    IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1.
  findings:
  - statement: Crystal structure of IL-23 bound to IL23R reveals binding exclusively
      through the N-terminal Ig domain, which restructures p19 to enable IL12RB1 recruitment.
    supporting_text: revealed that IL-23R bound to IL-23 exclusively via its N-terminal
      immunoglobulin domain. The structural and functional hotspot of this interaction
      partially restructured the helical IL-23p19 subunit of IL-23 and restrained
      its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rβ1 with
      high affinity.
- id: Reactome:R-HSA-447130
  title: Interleukin-23 binds interleukin-23 receptor
  findings: []
- id: Reactome:R-HSA-6790022
  title: Expression of STAT3-upregulated plasma membrane proteins
  findings: []
- id: Reactome:R-HSA-8950269
  title: STAT3, STAT4 are phosphorylated by p-JAK2, p-TYK2 in IL23:IL23 receptor
  findings: []
- id: Reactome:R-HSA-8952749
  title: STAT4 binds p-Y-IL23R in IL23:IL23 receptor
  findings: []
- id: Reactome:R-HSA-8952823
  title: p-Y693-STAT4, p-Y705-STAT3 dissociate from IL23:IL23 receptor
  findings: []
- id: file:human/IL23R/IL23R-deep-research-falcon.md
  title: Deep research report on IL23R
  findings: []
core_functions:
- description: IL23R is the IL-23-specific subunit of the heterodimeric IL-23 receptor.
    It binds IL-23 p19 through its N-terminal Ig domain and pairs with IL12RB1 (which
    binds IL-12 p40) to form the signaling-competent receptor complex. Upon IL-23
    binding, IL23R constitutively associates with JAK2 and recruits STAT3, activating
    the JAK2/TYK2-STAT3 cascade that drives Th17 gene expression programs.
  molecular_function:
    id: GO:0042020
    label: interleukin-23 receptor activity
  directly_involved_in:
  - id: GO:0038155
    label: interleukin-23-mediated signaling pathway
  - id: GO:2000318
    label: positive regulation of T-helper 17 type immune response
  in_complex:
    id: GO:0072536
    label: interleukin-23 receptor complex
  supported_by:
  - reference_id: PMID:12023369
    supporting_text: IL-23R associates constitutively with Jak2 and in a ligand-dependent
      manner with stat3.
  - reference_id: PMID:29287995
    supporting_text: IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin
      domain.

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

Citations

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