GO:0045519 interleukin-23 receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0045519 (interleukin-23 receptor binding) is a molecular_function term defined as binding to an interleukin-23 receptor.
• The interleukin-23 (IL-23) cytokine is a heterodimer of p19 and p40 subunits, and receptor engagement requires the IL-23R and IL-12Rbeta1 chains.
• IL-23 receptor binding initiates JAK-STAT signaling that stabilizes RORgammat and sustains pathogenic Th17 cell states.
• Therapeutic blockade of IL-23 receptor binding with the oral peptide icotrokinra reduces plaque psoriasis severity in phase 3 trials.
• Structural studies show that IL-12 and IL-23 share receptor subunits, revealing a gateway that shapes T cell versus NK cell responses.
• Aptamers and peptides that inhibit IL-23/IL-23R interaction provide chemical tools to probe this binding event.
Description
Interleukin-23 receptor binding (GO:0045519) is a molecular_function term that describes the binding of a ligand to an interleukin-23 receptor. This event is the first committed step in IL-23 signal transduction and is central to the differentiation and maintenance of pathogenic Th17 cells. Because IL-23 receptor binding controls inflammatory gene programs, it is a validated therapeutic node in autoimmune and inflammatory diseases such as psoriasis. Researchers study this term to understand cytokine-receptor recognition, to design blocking biologics or oral peptides, and to build CRISPR cell models that test causality of receptor-ligand interactions. The term is therefore both a mechanistic concept and a practical target for drug discovery and functional genomics.
interleukin-23 receptor binding At A Glance
| GO ID | GO:0045519 |
|---|---|
| GO term | interleukin-23 receptor binding |
| Ontology | molecular_function |
| Synonym | IL-23, interleukin-23 receptor ligand |
| Definition | Binding to an interleukin-23 receptor |
| Major function | Ligand recognition at the IL-23 receptor complex that initiates IL-23 signaling |
| Representative ligand | IL-23 cytokine (p19/p40 heterodimer) |
| Representative receptor | IL-23R paired with IL-12Rbeta1 |
| Disease relevance | Psoriasis and other IL-23-driven inflammatory disorders |
What Is GO:0045519?
GO:0045519 describes the molecular function of selectively interacting with an interleukin-23 receptor. In practice, this means a ligand, such as the IL-23 cytokine or a synthetic binder, physically associates with the IL-23 receptor complex. The QuickGO definition is binding to an interleukin-23 receptor, and the synonym IL-23 receptor ligand captures the ligand-side perspective of this function. This binding event is distinct from downstream signaling; it is the recognition step that precedes JAK-STAT activation and Th17 stabilization.
Why Is interleukin-23 receptor binding Important in Cell Biology?
Interleukin-23 receptor binding is important because it gates a cytokine pathway that controls Th17 cell pathogenicity and mucosal inflammation. Blocking this binding event with an oral peptide such as icotrokinra selectively inhibits IL-23 receptor signaling and improves plaque psoriasis in phase 3 trials. Structural analysis of shared IL-12 and IL-23 receptor subunits explains how this binding event can be shaped to favor T cell versus NK cell actions. In addition, aptamers that inhibit IL-23/IL-23R interaction demonstrate that this binding interface is druggable with non-antibody modalities. Together, these findings make GO:0045519 a high-value term for immunology, pharmacology, and CRISPR functional studies.
• Defines the first step of IL-23 signal transduction and Th17 maintenance.
• Provides a validated drug target for plaque psoriasis and related diseases.
• Enables selective blockade of IL-23 receptor signaling by oral peptides.
• Explains receptor sharing between IL-12 and IL-23 and its impact on T versus NK cells.
• Supports development of aptamer and peptide inhibitors of IL-23/IL-23R interaction.
• Links cytokine binding to downstream JAK-STAT and RORgammat stabilization.
• Offers a mechanistic readout for CRISPR knockout or knock-in of receptor components.
• Guides translational pharmacokinetic studies of IL-23 receptor blockers.
• Connects to keratinocyte inflammation and HMGB1 release in psoriatic skin.
• Provides a model for studying GP130/IL23R-p38 crosstalk in adipose biology.
Molecular Mechanism of interleukin-23 receptor binding
Ligand recognition by the IL-23 receptor complex
In simple terms: The IL-23 cytokine docks onto a two-part receptor on the cell surface.
IL-23 is a heterodimeric cytokine that must engage a receptor complex containing IL-23R and IL-12Rbeta1 to initiate signaling. The binding event described by GO:0045519 is the selective recognition of this receptor complex by IL-23 or by synthetic binders such as icotrokinra. Structural work shows that IL-12 and IL-23 share receptor subunits, which creates a gateway for shaping actions on T versus NK cells. This recognition step is therefore the molecular decision point for IL-23 responsiveness.
Initiation of JAK-STAT signaling
In simple terms: Once IL-23 binds, enzymes inside the cell start a signaling chain.
Receptor engagement by IL-23 activates JAK-STAT signaling, which propagates the inflammatory program. Icotrokinra selectively blocks the interleukin-23 receptor and inhibits signaling, confirming that binding is required for downstream activation. This signaling cascade sustains the expression of Th17-associated transcription factors and cytokines. The binding event is thus mechanistically coupled to transcriptional outcomes.
Stabilization of RORgammat and Th17 pathogenicity
In simple terms: IL-23 signaling keeps the Th17 cell in a pro-inflammatory state.
IL-23 promotes a pro-inflammatory Th17 cell state by stabilizing RORgammat and suppressing glucocorticoid receptor activity. This stabilization depends on continuous IL-23 receptor binding and signaling. The result is a self-reinforcing inflammatory loop that is relevant to autoimmune pathology. Blocking the binding event therefore destabilizes the pathogenic Th17 program.
Receptor sharing and cell-type selectivity
In simple terms: Different immune cells can respond differently because receptors are shared.
IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells. This means the same binding interface can produce distinct cellular outcomes depending on which receptor chains are expressed. Understanding this selectivity is important for designing therapeutics that target IL-23 receptor binding without unwanted NK cell effects. Structural insights into the shared interface guide such design.
Chemical inhibition of the binding interface
In simple terms: Small molecules and aptamers can physically block IL-23 from touching its receptor.
An artificial aptamer that inhibits interleukin-23/interleukin-23 receptor interaction was discovered via SELEX, demonstrating that the binding interface is targetable by nucleic acid ligands. The oral peptide icotrokinra selectively blocks the interleukin-23 receptor and inhibits signaling, providing a clinical-stage example of binding inhibition. These agents validate GO:0045519 as a druggable function. They also provide tool compounds for mechanistic studies.
Key Genes Involved in GO:0045519 interleukin-23 receptor binding
The following genes and proteins are central to interleukin-23 receptor binding and its downstream biology.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL23A | Encodes the p19 subunit of the IL-23 heterodimer | Ligand-side component required for receptor binding |
| IL12B | Encodes the p40 subunit shared by IL-12 and IL-23 | Shared subunit that enables receptor engagement |
| IL23R | Encodes the IL-23 receptor chain | Primary receptor for GO:0045519 binding event |
| IL12RB1 | Encodes the IL-12 receptor beta 1 chain | Co-receptor required for IL-23 signaling |
| JAK2 | Janus kinase that propagates IL-23 receptor signaling | Downstream effector of receptor engagement |
| TYK2 | Janus kinase involved in IL-23 receptor signaling | Signaling node downstream of binding |
| STAT3 | Transcription factor activated by IL-23 signaling | Mediates transcriptional output of binding |
| RORC | Encodes RORgammat, stabilized by IL-23 signaling | Th17 pathogenicity factor |
| NR3C1 | Encodes the glucocorticoid receptor suppressed by IL-23 | Links IL-23 signaling to glucocorticoid resistance |
| HMGB1 | Released by keratinocytes during psoriatic inflammation | Connects IL-23-driven skin inflammation to autophagy |
| ORM2 | Orm2 mediates adipose browning via GP130/IL23R-p38 | Non-immune role of IL23R signaling |
| GP130 | Partners with IL23R in the p38 cascade | Context-dependent IL23R signaling |
| MAPK14 | Encodes p38 MAP kinase in the GP130/IL23R cascade | Downstream kinase in IL23R signaling |
| IL17A | Th17 effector cytokine induced downstream of IL-23 | Readout of IL-23 receptor binding activity |
| IL17F | Th17 effector cytokine induced downstream of IL-23 | Readout of IL-23 receptor binding activity |
| SOCS3 | Negative regulator of cytokine signaling | Potential feedback regulator of IL-23 signaling |
| PTPN2 | Phosphatase that modulates cytokine signaling | Candidate regulator of IL-23 receptor signaling |
How Is interleukin-23 receptor binding Regulated?
Interleukin-23 receptor binding and its downstream signaling are regulated at multiple levels. IL-23 signaling stabilizes RORgammat while suppressing glucocorticoid receptor activity, creating a feed-forward inflammatory loop. Negative regulators such as SOCS proteins and phosphatases can dampen JAK-STAT signaling downstream of receptor engagement. In adipose tissue, Orm2 promotes browning via a GP130/IL23R-p38 cascade, showing that IL23R signaling can be rewired by context-specific partners. Therapeutic regulation of this binding event is achieved by selective blockers such as icotrokinra, which inhibits IL-23 receptor signaling. Aptamer-based inhibitors further demonstrate that the binding interface can be regulated extracellularly.
interleukin-23 receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL23R | Plaque psoriasis and IL-23-driven inflammation | IL23R knockout keratinocyte or T cell line |
| IL23A | Th17-mediated autoimmunity | IL23A knockout with IL-17 readout |
| RORC | Th17 pathogenicity and glucocorticoid resistance | RORC point-mutation reporter line |
| HMGB1 | Psoriatic skin inflammation and autophagy | HMGB1 knockout keratinocyte model |
| ORM2 | Adipose browning via GP130/IL23R-p38 | ORM2 overexpression adipocyte model |
Plaque psoriasis
IL-23 receptor binding is a validated therapeutic target in plaque psoriasis. The oral peptide icotrokinra selectively blocks the interleukin-23 receptor and inhibits signaling, and it improved outcomes in adults and adolescents with plaque psoriasis. In phase 3 trials, once-daily oral icotrokinra was compared with placebo and deucravacitinib in moderate-to-severe plaque psoriasis, supporting the clinical relevance of blocking this binding event. Keratinocyte autophagy and HMGB1 release also contribute to psoriatic skin inflammation, linking IL-23-driven pathways to broader inflammatory mechanisms.
Th17-mediated autoimmunity
IL-23 promotes a pro-inflammatory Th17 cell state by stabilizing RORgammat and suppressing glucocorticoid receptor activity. Because this state depends on IL-23 receptor binding, the term GO:0045519 is mechanistically linked to Th17-mediated autoimmune pathology. Therapeutic blockade of the receptor-ligand interaction therefore has potential beyond psoriasis. Structural understanding of receptor sharing helps predict cell-type-specific effects.
Metabolic and adipose biology
Intermittent fasting-induced Orm2 promotes adipose browning via the GP130/IL23R-p38 cascade, revealing a non-canonical role for IL23R signaling. This finding expands the biological contexts in which interleukin-23 receptor binding and IL23R-dependent signaling may matter. It also suggests that IL23R can partner with GP130 outside classical immune cells. Such context dependence is important when interpreting CRISPR models of IL23R function.
From interleukin-23 receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of IL23R abolish IL-23-induced signaling? | IL23R knockout cell line |
| Does a specific receptor residue control ligand selectivity? | IL23R point-mutation knock-in |
| Can a tagged receptor track binding dynamics? | IL23R tagged knock-in |
| Does overexpression of IL-23 subunits drive Th17 programs? | IL23A/IL12B overexpression model |
| Can aptamers block IL-23/IL-23R interaction in cells? | Aptamer-treated reporter cell line |
| Does Orm2 modulate IL23R-p38 signaling in adipocytes? | ORM2 overexpression adipocyte model |
How to Study the interleukin-23 receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Surface plasmon resonance | Binding affinity and kinetics | Characterizing IL-23/IL-23R interaction |
| Phospho-STAT3 immunoblot | JAK-STAT pathway activation | Testing receptor engagement |
| Luciferase reporter assay | Transcriptional activity downstream of binding | Screening IL-23 receptor blockers |
| RNA-seq | Global transcriptional changes | Profiling Th17 programs |
| Cryo-EM | Three-dimensional receptor-ligand structure | Mapping shared receptor interfaces |
| SELEX | Aptamer selection against IL-23/IL-23R | Discovering binding inhibitors |
| Cytokine profiling | Secreted IL-17 family cytokines | Measuring functional outcomes |
| Pharmacokinetic assay | Drug exposure and receptor occupancy | Translational studies of icotrokinra |
Binding assays and surface plasmon resonance
Direct measurement of interleukin-23 receptor binding can be performed using purified receptor ectodomains and ligand, or with cell-based binding assays. Surface plasmon resonance and related biophysical methods quantify affinity and kinetics of the interaction. These assays are used to characterize blockers such as icotrokinra and aptamers. They provide the quantitative foundation for GO:0045519 annotation.
Signaling readouts by immunoblot and reporter assays
Downstream JAK-STAT activation can be measured by phospho-STAT3 immunoblot or luciferase reporter assays. These readouts confirm that receptor binding leads to functional signaling. They are commonly used to test whether a candidate blocker inhibits IL-23 receptor signaling. Combining binding and signaling data strengthens mechanistic conclusions.
Transcriptomics and cytokine profiling
RNA-seq and cytokine profiling measure the transcriptional consequences of IL-23 receptor binding, including IL-17 family cytokines. These methods reveal how binding shapes Th17 cell states and inflammatory programs. They are also used to compare responses across cell types that differ in receptor chain expression. Such data help interpret CRISPR perturbations of the pathway.
Structural biology and modeling
Cryo-EM and crystallography have revealed the structural basis for IL-12 and IL-23 receptor sharing. These structures identify the interface that mediates interleukin-23 receptor binding. They guide the design of selective blockers and aptamers. Structural models also help predict the impact of point mutations in receptor chains.
How CRISPR Can Be Used to Study GO:0045519 interleukin-23 receptor binding
Knockout
CRISPR knockout of IL23R or its co-receptor IL12RB1 abolishes interleukin-23 receptor binding and downstream signaling, providing a clean loss-of-function model. Such models are used to confirm that a candidate ligand acts through the canonical receptor complex. Knockout of IL23A or IL12B removes the ligand side of the interaction. These experiments directly test the requirement for GO:0045519 in cellular responses.
Point Mutation
Point mutations in the IL-23 receptor interface can dissect which residues mediate ligand selectivity and receptor sharing. CRISPR point-mutation knock-in allows testing of structural predictions in a native genomic context. Such models are valuable for understanding why IL-12 and IL-23 produce distinct T versus NK cell outcomes. They also help identify resistance mutations to blocking agents.
Knock-in
Tagged knock-in of IL23R or IL12RB1 enables tracking of receptor localization, trafficking, and binding dynamics in live cells. Knock-in of reporter cassettes downstream of IL-23-responsive promoters provides a sensitive readout of receptor engagement. These models link the binding event to transcriptional output. They are useful for high-content imaging and flow cytometry.
Overexpression
Overexpression of IL23A and IL12B drives constitutive IL-23 production and amplifies receptor binding, creating a gain-of-function inflammatory model. Overexpression of IL23R can sensitize cells to low ligand concentrations. In adipose biology, ORM2 overexpression activates the GP130/IL23R-p38 cascade, illustrating context-specific gain-of-function. These models complement knockout studies for bidirectional pathway analysis.
How EDITGENE Supports interleukin-23 receptor binding Research
Researchers studying interleukin-23 receptor binding-related genes often need to determine whether a candidate gene is causally involved in ligand recognition, signaling, or disease pathology. Rigorous causal inference requires isogenic cell models in which the gene of interest is knocked out, point-mutated, tagged, or overexpressed. EDITGENE provides these models together with screening and bioinformatics support to accelerate IL-23 pathway research.
Contact EDITGENE today to design your custom CRISPR model for interleukin-23 receptor binding research.
Frequently Asked Questions About interleukin-23 receptor binding
What is interleukin-23 receptor binding?
It is the molecular function defined by GO:0045519, describing binding to an interleukin-23 receptor.
What genes are involved in interleukin-23 receptor binding?
Key genes include IL23A, IL12B, IL23R, and IL12RB1, which encode the ligand subunits and receptor chains.
What is the GO ID for interleukin-23 receptor binding?
The GO ID is GO:0045519, a molecular_function term.
How does IL-23 receptor binding lead to Th17 inflammation?
Binding activates JAK-STAT signaling that stabilizes RORgammat and sustains a pro-inflammatory Th17 state.
Which drugs block interleukin-23 receptor binding?
The oral peptide icotrokinra selectively blocks the interleukin-23 receptor and inhibits signaling.
Is interleukin-23 receptor binding a drug target for psoriasis?
Yes, phase 3 trials of oral icotrokinra in plaque psoriasis support targeting this binding event.
What is the structure of the IL-23 receptor complex?
IL-23 engages a complex containing IL-23R and IL-12Rbeta1, and receptor sharing with IL-12 shapes T versus NK cell responses.
Can aptamers inhibit IL-23/IL-23R interaction?
Yes, an artificial aptamer discovered via SELEX inhibits interleukin-23/interleukin-23 receptor interaction.
How do CRISPR knockouts help study IL-23 receptor binding?
Knockout of IL23R or IL12RB1 abolishes binding and signaling, providing a clean loss-of-function test.
Does IL23R signaling have non-immune roles?
Yes, Orm2 promotes adipose browning via the GP130/IL23R-p38 cascade, showing context-dependent IL23R signaling.
Conclusion
GO:0045519 interleukin-23 receptor binding is a molecular_function term that captures the ligand recognition step at the IL-23 receptor complex. This event initiates JAK-STAT signaling, stabilizes RORgammat, and sustains pathogenic Th17 states relevant to psoriasis and autoimmunity. Structural studies of receptor sharing and clinical-stage blockers such as icotrokinra confirm that this binding interface is both mechanistically informative and therapeutically actionable. CRISPR knockout, point-mutation, knock-in, and overexpression models provide the causal toolkit needed to dissect this function in disease-relevant cells.
References
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