GO:0045523 interleukin-27 receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0045523 (interleukin-27 receptor binding) is a molecular function describing the binding of IL-27 to its receptor complex, a key step in initiating JAK-STAT signaling [2,7].
• IL-27 is a heterodimeric cytokine composed of p28 and EBI3 subunits that binds a receptor composed of IL-27Rα (WSX-1) and gp130 [2,7].
• The interaction triggers phosphorylation of JAK1, JAK2, TYK2, and STAT1/STAT3, driving diverse immune responses [2,3,5].
• IL-27 receptor binding is implicated in infectious diseases, autoimmunity, and cancer, with context-dependent pro- and anti-inflammatory effects [4,5,8].
• Structural studies have revealed the quaternary assembly of the IL-27 signaling complex, providing a basis for therapeutic targeting [2,7].
• CRISPR-based models (knockout, knock-in, point mutation) are essential to dissect the functional consequences of IL-27 receptor binding in health and disease.
Description
Interleukin-27 (IL-27) is a pleiotropic cytokine belonging to the IL-12 family, and its binding to the IL-27 receptor complex is the first committed step in a signaling cascade that regulates innate and adaptive immunity [2,5]. The Gene Ontology term GO:0045523, interleukin-27 receptor binding, captures this molecular function, which is essential for understanding how IL-27 exerts its diverse biological effects [2,7]. Dysregulation of IL-27 signaling has been linked to a wide range of pathological conditions, including tuberculosis, sepsis, fibrosis, and cancer [3,4,8]. Therefore, studying the molecular details of IL-27 receptor binding is critical for both basic immunology and translational research.
interleukin-27 receptor binding At A Glance
| GO ID | GO:0045523 |
|---|---|
| GO term | interleukin-27 receptor binding |
| Ontology | molecular_function |
| Synonym | IL-27, interleukin-27 receptor ligand |
| Major function | Binding of IL-27 cytokine to its receptor complex, initiating JAK-STAT signaling |
| Cytokine subunits | p28 (IL27) and EBI3 (IL27B) |
| Receptor subunits | IL-27Rα (WSX-1) and gp130 (IL6ST) |
| Downstream signaling | JAK1, JAK2, TYK2, STAT1, STAT3 |
| Cellular context | T cells, B cells, macrophages, dendritic cells, and non-immune cells |
What Is GO:0045523?
GO:0045523 is defined as the binding of an interleukin-27 molecule to an interleukin-27 receptor. This molecular function encompasses the physical interaction between the IL-27 cytokine (a heterodimer of p28 and EBI3) and its cognate receptor complex, which consists of IL-27Rα (also known as WSX-1) and gp130. This binding event is a prerequisite for receptor activation and subsequent intracellular signaling [2,7].
Why Is interleukin-27 receptor binding Important in Cell Biology?
IL-27 receptor binding is a critical checkpoint in immune regulation, influencing the balance between protective immunity and immunopathology. It modulates T cell differentiation, B cell responses, and macrophage function, and its dysregulation contributes to infectious diseases, autoimmune disorders, and cancer [2,4,5,8]. Understanding the molecular basis of this interaction is essential for developing targeted therapies that can either enhance or inhibit IL-27 signaling depending on the disease context.
• Controls T helper cell differentiation and cytokine production [2,5].
• Regulates B cell function and antibody responses.
• Modulates macrophage polarization and inflammatory mediator release.
• Plays a dual role in tuberculosis, with both protective and pathological effects.
• Involved in neonatal sepsis transcriptome signatures.
• Linked to pulmonary fibrosis through platelet-macrophage circuits.
• Potential target for cancer immunotherapy [2,5].
• Structural insights enable rational design of IL-27 mimetics or antagonists [2,7].
• Essential for understanding cytokine-receptor specificity within the IL-12 family.
• Provides a model for studying JAK-STAT activation mechanisms [2,3].
Molecular Mechanism of interleukin-27 receptor binding
IL-27 Cytokine Structure and Receptor Recognition
In simple terms: IL-27 is a two-part cytokine that must assemble correctly to bind its receptor.
IL-27 is a heterodimeric cytokine composed of the p28 subunit (encoded by IL27) and the EBI3 subunit (encoded by IL27B). The p28 subunit shares structural homology with IL-12 p35, while EBI3 resembles IL-12 p40. The heterodimerization is essential for secretion and receptor binding. Structural studies have revealed that the p28 subunit primarily engages the IL-27Rα chain, while EBI3 contributes to the overall stability and may interact with gp130 [2,7].
Receptor Complex Assembly and Stoichiometry
In simple terms: The receptor is made of two different proteins that come together when IL-27 binds.
The functional IL-27 receptor is a heterodimer consisting of IL-27Rα (also known as WSX-1 or IL27RA) and gp130 (IL6ST). IL-27Rα is unique to IL-27, whereas gp130 is shared with other cytokines such as IL-6. Binding of IL-27 to IL-27Rα induces recruitment of gp130, forming a quaternary signaling complex. Recent cryo-EM structures have elucidated the architecture of this complex, showing a 2:2:2 stoichiometry of IL-27, IL-27Rα, and gp130 [2,7].
JAK-STAT Activation and Signal Transduction
In simple terms: Once IL-27 binds, it turns on enzymes that send signals to the cell nucleus.
The IL-27 receptor complex lacks intrinsic enzymatic activity and relies on associated Janus kinases (JAKs). IL-27Rα is constitutively associated with JAK1, JAK2, and TYK2, while gp130 recruits JAK1, JAK2, and TYK2. Ligand-induced receptor dimerization brings JAKs into proximity, leading to their activation and phosphorylation of tyrosine residues on the receptor cytoplasmic domains. These phosphotyrosines serve as docking sites for STAT1 and STAT3, which are then phosphorylated, dimerize, and translocate to the nucleus to regulate gene expression [2,3,5].
Regulation of IL-27 Receptor Binding
In simple terms: The strength and duration of IL-27 binding can be controlled by various factors.
IL-27 receptor binding is regulated at multiple levels. Expression of IL-27Rα and gp130 is modulated by cellular activation and cytokine milieu. Soluble forms of IL-27Rα can act as decoy receptors. Additionally, IL-27 signaling is negatively regulated by SOCS proteins and phosphatases. The binding affinity and kinetics can be influenced by post-translational modifications of the cytokine or receptor [2,4,5].
Structural Basis of Antagonism and Therapeutic Targeting
In simple terms: Understanding how IL-27 binds its receptor helps design drugs that block or mimic it.
Structural studies have identified key interfacial residues critical for IL-27 binding to IL-27Rα and gp130. This knowledge has facilitated the development of IL-27 antagonists, such as antibodies or mutated cytokines, that can disrupt the interaction. Conversely, engineered IL-27 variants with enhanced affinity are being explored for immunotherapy. These efforts highlight the translational potential of targeting GO:0045523 [2,7].
Key Genes Involved in GO:0045523 interleukin-27 receptor binding
The following genes encode the core components and regulators of interleukin-27 receptor binding and its downstream signaling.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL27 | Encodes p28 subunit of IL-27 | Knockout models show impaired Th1 responses; target for autoimmune disease |
| EBI3 | Encodes EBI3 subunit of IL-27 | Knockout mice exhibit defects in T cell differentiation; linked to inflammatory bowel disease |
| IL27RA | Encodes IL-27Rα (WSX-1) receptor chain | Essential for IL-27 binding; polymorphisms associated with susceptibility to infections |
| IL6ST | Encodes gp130 receptor chain | Shared receptor subunit; mutations cause hyper-IgE syndrome and immune dysregulation |
| JAK1 | Janus kinase 1; phosphorylates STATs | Mutations linked to immune deficiencies and cancers; drug target |
| JAK2 | Janus kinase 2; phosphorylates STATs | Driver mutations in myeloproliferative neoplasms; target of ruxolitinib |
| TYK2 | Tyrosine kinase 2; phosphorylates STATs | Deficiency causes immunodeficiency; target for psoriasis therapy |
| STAT1 | Signal transducer and activator of transcription 1 | Gain-of-function mutations cause chronic mucocutaneous candidiasis |
| STAT3 | Signal transducer and activator of transcription 3 | Critical for IL-27-mediated immunosuppression; mutations in hyper-IgE syndrome |
| SOCS1 | Suppressor of cytokine signaling 1 | Negative regulator of IL-27 signaling; knockout mice die neonatally |
| SOCS3 | Suppressor of cytokine signaling 3 | Inhibits JAK-STAT pathway; regulates IL-27 responses |
| BATF3 | Basic leucine zipper ATF-like transcription factor 3 | Regulates IL-27 production in B cells; involved in regulatory B cell function |
| IL10 | Interleukin-10 | Induced by IL-27; mediates immunosuppressive effects |
| IFNG | Interferon gamma | Induced by IL-27 in T cells; promotes Th1 responses |
| TBX21 | T-box transcription factor 21 (T-bet) | Induced by IL-27; drives Th1 differentiation |
| GATA3 | GATA binding protein 3 | Suppressed by IL-27; inhibits Th2 differentiation |
| RORC | RAR-related orphan receptor C | Inhibited by IL-27; suppresses Th17 development |
| FOXP3 | Forkhead box P3 | Modulated by IL-27; influences regulatory T cell generation |
How Is interleukin-27 receptor binding Regulated?
IL-27 receptor binding and signaling are tightly regulated. Expression of the IL-27 receptor subunits IL-27Rα and gp130 is controlled by transcription factors such as NF-κB and STATs. Soluble IL-27Rα can act as a decoy receptor, and SOCS proteins provide negative feedback. Additionally, post-translational modifications of IL-27, such as glycosylation, can affect binding affinity. The balance between activating and inhibitory signals determines the cellular outcome [2,4,5].
interleukin-27 receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL27 | Tuberculosis susceptibility | IL27 knockout mice infected with M. tuberculosis |
| IL27RA | Neonatal sepsis | IL27RA knockout mice subjected to sepsis models |
| IL6ST | Hyper-IgE syndrome | Patient-derived iPSCs with IL6ST mutations |
| STAT3 | Hyper-IgE syndrome | STAT3 knockout cell lines and mouse models |
| BATF3 | Regulatory B cell function | BATF3 knockout mice and B cell-specific knockouts |
Infectious Diseases
IL-27 receptor binding plays a complex role in infections. In tuberculosis, IL-27 can both promote protective Th1 responses and exacerbate immunopathology. In neonatal sepsis, IL-27-dependent transcriptome signatures are associated with disease severity. IL-27 also modulates bacterial infections by influencing macrophage and neutrophil functions.
Autoimmunity and Inflammation
IL-27 signaling is implicated in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Depending on the context, IL-27 can suppress or promote inflammation by regulating T cell subsets and cytokine production [2,5].
Fibrosis
Externalized histones fuel pulmonary fibrosis via a platelet-macrophage circuit involving TGFβ1 and IL-27. IL-27 receptor binding on macrophages may contribute to fibrotic remodeling.
Cancer
IL-27 has anti-tumor and pro-tumor effects. It can enhance cytotoxic T cell activity and NK cell function, but also induce immunosuppressive molecules like PD-L1. Targeting IL-27 receptor binding is being explored for cancer immunotherapy [2,5].
From interleukin-27 receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does IL27RA knockout abolish IL-27 binding? | IL27RA knockout cell line (e.g., HEK293T) via CRISPR |
| What is the effect of a point mutation in IL27 on receptor binding affinity? | Knock-in mice expressing mutant IL27 |
| Can a tagged IL-27Rα be used to track receptor localization? | Knock-in of fluorescent tag (e.g., GFP) into IL27RA locus |
| Does overexpression of IL-27 enhance anti-tumor immunity? | IL-27 overexpression in tumor cell lines or mouse models |
| What is the role of gp130 in IL-27 signaling? | IL6ST conditional knockout mice |
| How does IL-27 affect B cell function? | BATF3 knockout mice and adoptive transfer models |
How to Study the interleukin-27 receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Surface plasmon resonance | Binding affinity and kinetics | Characterization of IL-27 mutants |
| Cryo-EM | 3D structure of receptor complex | Structural basis of IL-27 binding |
| Phospho-STAT Western blot | STAT1/STAT3 activation | Validation of IL-27 signaling |
| RNA-seq | Global gene expression changes | Identification of IL-27 target genes |
| Flow cytometry | Cell surface receptor expression | Quantification of IL-27Rα and gp130 |
| Immunoprecipitation | Protein-protein interactions | Detection of IL-27-receptor complexes |
| Luciferase reporter assay | STAT transcriptional activity | High-throughput screening of IL-27 pathway modulators |
Surface Plasmon Resonance (SPR)
SPR measures real-time binding kinetics between IL-27 and its receptor. It provides quantitative data on association and dissociation rates, affinity constants, and the effect of mutations. This method is ideal for studying the molecular details of GO:0045523.
Cryo-Electron Microscopy (Cryo-EM)
Cryo-EM has been used to solve the structure of the IL-27 quaternary receptor signaling complex, revealing the architecture of the ligand-receptor interaction. This technique provides high-resolution insights into the binding interface and conformational changes.
Phospho-STAT Western Blotting
This method detects phosphorylation of STAT1 and STAT3 following IL-27 stimulation. It is a standard readout for IL-27 receptor activation and can be used to assess the impact of genetic modifications [3,5].
Transcriptomics (RNA-seq)
RNA-seq can identify gene expression changes downstream of IL-27 receptor binding. It has been used to define IL-27-dependent transcriptome signatures in neonatal sepsis and other contexts.
How CRISPR Can Be Used to Study GO:0045523 interleukin-27 receptor binding
Knockout
CRISPR knockout of IL27, EBI3, IL27RA, or IL6ST can abolish IL-27 receptor binding and downstream signaling. These models are essential to study the loss-of-function effects in immune cells and disease models.
Point Mutation
Introducing point mutations in the IL-27 binding interface or receptor ectodomain can fine-tune binding affinity. This approach helps identify critical residues and mimic human polymorphisms associated with disease.
Knock-in
Knock-in of epitope tags (e.g., FLAG, HA) or fluorescent proteins into endogenous IL27 or IL27RA loci allows tracking of protein expression and localization. This is valuable for studying receptor trafficking and complex assembly.
Overexpression
Overexpression of IL-27 or its receptor subunits in cell lines or mouse models can enhance signaling and is used to study gain-of-function effects, such as enhanced anti-tumor immunity or autoimmunity.
How EDITGENE Supports interleukin-27 receptor binding Research
Researchers studying interleukin-27 receptor binding-related genes often need to determine whether a candidate gene is causally involved in immune regulation, disease susceptibility, or therapeutic response. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this discovery process.
Contact EDITGENE today to design your custom CRISPR model for interleukin-27 receptor binding research.
Frequently Asked Questions About interleukin-27 receptor binding
What is interleukin-27 receptor binding?
Interleukin-27 receptor binding (GO:0045523) is the molecular function by which the cytokine IL-27 binds to its specific receptor complex, initiating intracellular signaling [2,7].
What genes are involved in interleukin-27 receptor binding?
Key genes include IL27 (p28 subunit), EBI3 (EBI3 subunit), IL27RA (IL-27Rα), and IL6ST (gp130), as well as downstream JAK and STAT genes [2,5].
What is the GO ID for interleukin-27 receptor binding?
The Gene Ontology ID is GO:0045523.
Which receptor subunits form the IL-27 receptor?
The IL-27 receptor is a heterodimer of IL-27Rα (WSX-1) and gp130 (IL6ST) [2,7].
What signaling pathways are activated by IL-27 receptor binding?
IL-27 binding activates the JAK-STAT pathway, primarily JAK1, JAK2, TYK2, and STAT1/STAT3 [2,3,5].
How is IL-27 receptor binding studied experimentally?
Common methods include surface plasmon resonance, cryo-EM, phospho-STAT Western blotting, and RNA-seq [2,3,7].
What diseases are associated with IL-27 receptor binding?
It is implicated in infectious diseases (e.g., tuberculosis, sepsis), autoimmune disorders, fibrosis, and cancer [3,4,5,8].
Can CRISPR be used to study IL-27 receptor binding?
Yes, CRISPR knockout, knock-in, and point mutation models are powerful tools to dissect the functional roles of IL-27 and its receptor.
What is the role of IL-27 in tuberculosis?
IL-27 has both protective and pathological roles in tuberculosis, influencing Th1 responses and immunopathology.
How does IL-27 affect B cells?
IL-27 modulates B cell function, including regulatory B cell activity, partly through BATF3-dependent mechanisms.
Conclusion
Interleukin-27 receptor binding (GO:0045523) is a fundamental molecular event that governs diverse immune responses and disease outcomes. Structural and functional studies have elucidated the molecular details of this interaction, providing a foundation for therapeutic targeting. CRISPR-based models are indispensable for dissecting the causal roles of IL-27 and its receptor in health and disease. EDITGENE offers comprehensive services to support these research efforts.
References
- 2. Składanowska K et al.. 2022. Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27.. Cell Rep 41(3):111490 PMID: 36261006
- 3. Povroznik JM et al.. 2023. Interleukin-27-dependent transcriptome signatures during neonatal sepsis.. Front Immunol 14:1124140 PMID: 36891292
- 4. Ritter K et al.. 2021. Interleukin-27 in Tuberculosis: A Sheep in Wolf's Clothing?. Front Immunol 12:810602 PMID: 35116036
- 5. Morita Y et al.. 2021. Interleukin-27 and Its Diverse Effects on Bacterial Infections.. Front Immunol 12:678515 PMID: 34079555
- 6. Yan H et al.. 2025. Ligand-receptor interactions induce and mediate regulatory functions of BATF3(+) B cells.. Sci Adv 11(41):eadx9917 PMID: 41061049
- 7. Caveney NA et al.. 2022. Structure of the IL-27 quaternary receptor signaling complex.. Elife 11 PMID: 35579417
- 8. Riehl DR et al.. 2023. Externalized histones fuel pulmonary fibrosis via a platelet-macrophage circuit of TGFβ1 and IL-27.. Proc Natl Acad Sci U S A 120(40):e2215421120 PMID: 37756334
