GO:0002112 interleukin-33 receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0002112 (interleukin-33 receptor binding) is a molecular function describing the binding of a ligand to an interleukin-33 receptor.
• The principal ligand is IL-33, an IL-1 family cytokine that binds the ST2 (IL1RL1) receptor subunit to initiate type 2 immune signaling.
• IL-33 can also signal through a ST2-independent RAGE/EGFR complex when oxidised, expanding the receptor-binding landscape beyond canonical ST2.
• The IL-33/ST2 axis is implicated in pulmonary inflammatory diseases, cardiac fibrosis, sepsis, and diverse inflammatory and metabolic disorders.
• IL-33 receptor binding is a candidate biomarker axis in aging and frailty, linking this molecular function to age-related disease pathways.
• CRISPR knockout, knock-in, point-mutation, and overexpression models enable causal dissection of IL-33 receptor binding in disease.
Description
Interleukin-33 receptor binding (GO:0002112) is a molecular function defined as binding to an interleukin-33 receptor. It represents the initial molecular recognition event through which the cytokine IL-33 engages its cognate receptor complex, canonically the ST2 (IL1RL1) subunit, to trigger downstream signaling. Because this binding event sits at the apex of the IL-33/ST2 axis, it is a focal point for understanding type 2 immunity, tissue homeostasis, and inflammatory disease. The term is therefore of interest to immunologists, pulmonologists, cardiologists, and drug developers seeking to modulate IL-33-dependent pathways. Recent work has shown that the receptor-binding function of IL-33 is not limited to ST2, as oxidised IL-33 can drive epithelial pathogenesis via a ST2-independent RAGE/EGFR signalling complex. This expands the conceptual scope of GO:0002112 beyond a single receptor-ligand pair and underscores the need for precise experimental models. Understanding interleukin-33 receptor binding at molecular resolution is essential for interpreting how IL-33 contributes to diseases ranging from asthma and COPD to cardiac fibrosis and sepsis.
interleukin-33 receptor binding At A Glance
| GO ID | GO:0002112 |
|---|---|
| GO term | interleukin-33 receptor binding |
| Ontology | molecular_function |
| Synonym | IL-33; interleukin-33 receptor ligand |
| Definition | Binding to an interleukin-33 receptor. |
| Major function | Ligand recognition at the IL-33 receptor complex, initiating IL-33/ST2 signaling |
| Primary ligand | IL-33 (IL1F11), an IL-1 family cytokine |
| Primary receptor | ST2 (IL1RL1), the canonical IL-33 receptor subunit |
| Alternative receptor context | Oxidised IL-33 can signal via a ST2-independent RAGE/EGFR complex |
| Disease relevance | Pulmonary inflammation, cardiac fibrosis, sepsis, aging-related pathways |
What Is GO:0002112?
In plain terms, GO:0002112 describes the ability of a molecule to bind to a receptor for interleukin-33. The QuickGO definition states: Binding to an interleukin-33 receptor. This molecular function is the ligand-receptor recognition step that precedes IL-33 receptor activation and downstream signaling. The primary ligand associated with this function is IL-33 itself, and the primary receptor is ST2 (also known as IL1RL1). Synonyms for this term include IL-33 and interleukin-33 receptor ligand, reflecting the ligand-centric view of the function.
Why Is interleukin-33 receptor binding Important in Cell Biology?
Interleukin-33 receptor binding is important because it is the molecular gatekeeper of the IL-33/ST2 signaling axis, a pathway that regulates type 2 immune responses, tissue repair, and inflammation. Dysregulation of this binding event is associated with pulmonary inflammatory diseases such as asthma and COPD, cardiac fibrosis, and sepsis, making it a therapeutic target of broad clinical interest. The discovery that oxidised IL-33 can bind and signal through a ST2-independent RAGE/EGFR complex further highlights the importance of understanding the precise molecular determinants of receptor binding. In aging research, IL-33/ST2 pathway components have been proposed as frailty biomarkers, linking this molecular function to age-related disease trajectories. Thus, GO:0002112 is not merely a biochemical annotation but a central node connecting cytokine biology to human disease.
• Defines the initial recognition step of IL-33/ST2 signaling, a major type 2 immunity pathway.
• Central to pulmonary inflammatory diseases including asthma and COPD.
• Implicated in cardiac fibrosis through ST2/IL-33 signaling.
• Relevant to sepsis pathophysiology and potential therapeutic modulation.
• Expanded by evidence of ST2-independent RAGE/EGFR signaling by oxidised IL-33.
• Linked to aging and frailty biomarker candidates from gene and pathway studies.
• Provides a target for biologic and small-molecule drug development.
• Enables mechanistic dissection using CRISPR-engineered cell and animal models.
• Connects cytokine biology to metabolic and adipose tissue immune regulation.
• Serves as a model molecular function for studying ligand-receptor specificity.
Molecular Mechanism of interleukin-33 receptor binding
Ligand recognition by the IL-33 receptor complex
In simple terms: IL-33 binds to its receptor like a key fitting a lock.
The canonical interleukin-33 receptor binding event involves the cytokine IL-33 engaging the ST2 (IL1RL1) receptor subunit. IL-33 is an IL-1 family cytokine, and its binding to ST2 is the first step in assembling a functional signaling complex. This recognition event is highly specific and is the molecular basis for the GO:0002112 annotation. The receptor complex typically includes the IL-1 receptor accessory protein (IL1RAP) as a co-receptor, which is required for signal transduction after ligand binding.
ST2-dependent signaling initiation
In simple terms: Once IL-33 docks onto ST2, the receptor sends a signal into the cell.
Following interleukin-33 receptor binding, the ST2/IL1RAP complex recruits adaptor proteins such as MyD88, leading to activation of NF-kB and MAP kinase pathways. This signaling cascade drives type 2 immune responses, including cytokine production and eosinophil recruitment. The ST2-dependent pathway is the most extensively characterized mechanism downstream of GO:0002112.
ST2-independent RAGE/EGFR signaling by oxidised IL-33
In simple terms: When IL-33 is oxidised, it can use a different receptor route.
Oxidised IL-33 has been shown to drive COPD epithelial pathogenesis via a ST2-independent RAGE/EGFR signalling complex. This finding expands the receptor-binding repertoire associated with interleukin-33 receptor binding, indicating that the molecular function can be mediated by alternative receptor complexes under oxidative conditions. This has implications for understanding disease mechanisms where ST2 blockade alone may be insufficient.
Regulation of IL-33 availability and receptor binding
In simple terms: The amount of IL-33 and its receptor can be turned up or down, affecting binding.
Interleukin-33 receptor binding is regulated by the availability of both ligand and receptor. IL-33 is released from cells upon damage or stress, and its oxidation state can influence which receptor it binds. ST2 expression is modulated by inflammatory signals, and soluble ST2 can act as a decoy receptor to sequester IL-33. This regulation determines the intensity and duration of IL-33/ST2 signaling.
Role in type 2 immunity and tissue repair
In simple terms: IL-33 binding helps trigger allergic-type immune responses and tissue healing.
Interleukin-33 receptor binding is a key initiator of type 2 immune responses, promoting ILC2 and Th2 cell activation. This pathway is involved in tissue repair and homeostasis but can also drive pathological inflammation in chronic diseases. Recent work has linked lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase to pathogenic adaptive type 2 immunity, highlighting metabolic regulation of this axis.
Key Genes Involved in GO:0002112 interleukin-33 receptor binding
The following genes and proteins are central to interleukin-33 receptor binding and its downstream biology.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL33 | Ligand that binds the IL-33 receptor | Primary ligand for GO:0002112; target for modulation |
| IL1RL1 (ST2) | Canonical IL-33 receptor subunit | Main receptor mediating binding and signaling |
| IL1RAP | Co-receptor for IL-33 receptor complex | Required for signal transduction after binding |
| MYD88 | Adaptor protein downstream of ST2 | Mediates signaling after IL-33 receptor binding |
| NFKB1 | Transcription factor activated by IL-33/ST2 | Drives inflammatory gene expression |
| MAPK1 | Kinase in MAPK pathway downstream of ST2 | Transduces signals from IL-33 receptor |
| AGER (RAGE) | Alternative receptor for oxidised IL-33 | Mediates ST2-independent signaling |
| EGFR | Co-receptor in ST2-independent pathway | Part of RAGE/EGFR complex for oxidised IL-33 |
| IL4 | Type 2 cytokine induced by IL-33 signaling | Readout of IL-33/ST2 axis activation |
| IL5 | Type 2 cytokine induced by IL-33 signaling | Readout of IL-33/ST2 axis activation |
| IL13 | Type 2 cytokine induced by IL-33 signaling | Readout of IL-33/ST2 axis activation |
| GATA3 | Transcription factor in Th2 cells | Downstream of IL-33 receptor binding |
| RORC | Transcription factor in ILC3/Th17 | Context-dependent crosstalk with IL-33 |
| FOXP3 | Regulatory T cell transcription factor | Modulated by IL-33/ST2 axis |
| PNPLA2 (ATGL) | Adipose triglyceride lipase | Linked to lipolysis-microlipophagy and type 2 immunity |
| IL1B | IL-1 family cytokine | Related family member for comparative studies |
| IL1RN | IL-1 receptor antagonist | Modulates IL-1 family signaling |
How Is interleukin-33 receptor binding Regulated?
Interleukin-33 receptor binding is regulated at multiple levels. Ligand availability is controlled by IL-33 release from damaged or stressed cells, and the oxidation state of IL-33 determines whether it binds ST2 or alternative receptors such as RAGE/EGFR. Receptor availability is regulated by ST2 expression levels, which are modulated by inflammatory cytokines, and by soluble ST2 that acts as a decoy receptor. Downstream signaling after binding is regulated by adaptor proteins like MyD88 and by negative feedback mechanisms. In metabolic contexts, the lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase has been shown to drive pathogenic adaptive type 2 immunity, suggesting metabolic control of the IL-33 axis.
interleukin-33 receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL33 | COPD, asthma, pulmonary inflammation | IL33 knockout or overexpression in airway epithelial cells |
| IL1RL1 (ST2) | Cardiac fibrosis, heart failure | ST2 knockout mice or cardiac fibroblasts |
| IL33 | Sepsis | IL33 knockout mice in sepsis models |
| AGER (RAGE) | COPD, ST2-independent signaling | RAGE knockout or knockdown in epithelial cells |
| PNPLA2 (ATGL) | Metabolic regulation of type 2 immunity | ATGL knockout adipose tissue models |
IL-33 receptor binding in pulmonary inflammatory diseases
Interleukin-33 receptor binding is centrally implicated in pulmonary inflammatory diseases such as asthma and COPD. Oxidised IL-33 drives COPD epithelial pathogenesis via a ST2-independent RAGE/EGFR signalling complex, revealing a novel mechanism beyond canonical ST2 binding. The IL-33/ST2 axis in the lung promotes type 2 inflammation, mucus production, and airway remodeling. Targeting interleukin-33 receptor binding is therefore a therapeutic strategy in chronic respiratory diseases.
IL-33 receptor binding in cardiac fibrosis
ST2/IL-33 signaling plays a significant role in cardiac fibrosis. Interleukin-33 receptor binding on cardiac fibroblasts and immune cells can either promote or attenuate fibrosis depending on context. Soluble ST2 is a recognized biomarker in heart failure, reflecting the importance of this binding axis in cardiac pathology. Understanding the molecular details of IL-33 receptor binding may inform anti-fibrotic therapies.
IL-33 receptor binding in sepsis and inflammation
The IL-33/ST2 axis is involved in sepsis pathophysiology, with research progress highlighting its role in inflammatory responses. Interleukin-33 receptor binding can modulate immune cell function during sepsis, influencing outcomes. The axis is also implicated in diverse inflammatory diseases, with regulatory mechanisms and therapeutic potential being actively explored. This makes GO:0002112 a relevant molecular function in acute and chronic inflammatory conditions.
IL-33 receptor binding in aging and metabolic disease
IL-33/ST2 pathway components have been identified as candidate frailty biomarkers from genes and pathways regulated in aging and age-related diseases. This links interleukin-33 receptor binding to age-related disease trajectories. Additionally, the lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity, connecting metabolic regulation to the IL-33 axis. These findings suggest that interleukin-33 receptor binding is relevant to metabolic and aging biology.
From interleukin-33 receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does IL33 loss affect receptor binding and signaling? | IL33 knockout cell line or mouse |
| Does a point mutation in IL33 alter ST2 binding affinity? | IL33 point-mutation knock-in |
| Can tagged IL-33 be used to track receptor binding? | Tagged IL-33 knock-in |
| Does ST2 overexpression enhance IL-33 signaling? | ST2 overexpression cell line |
| Does RAGE mediate oxidised IL-33 binding? | RAGE knockout or knockdown |
| Does ATGL regulate IL-33-driven type 2 immunity? | ATGL knockout adipose models |
How to Study the interleukin-33 receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Surface plasmon resonance (SPR) | Binding affinity and kinetics | IL-33/ST2 interaction studies |
| Isothermal titration calorimetry (ITC) | Thermodynamics of binding | Ligand-receptor binding characterization |
| ELISA | Competitive binding and cytokine levels | Screening for binding inhibitors |
| Luciferase reporter assay | NF-kB activation after binding | Cell-based signaling assays |
| Phospho-flow cytometry | Signaling intermediate phosphorylation | Pathway activation studies |
| CRISPR knockout screen | Genes required for IL-33 signaling | Functional genomics |
| Mouse disease models | In vivo inflammation and fibrosis | Preclinical target validation |
Binding assays for IL-33 receptor interaction
Surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) can measure the binding affinity between IL-33 and ST2. These biophysical methods provide quantitative parameters such as KD and stoichiometry for interleukin-33 receptor binding. ELISA-based receptor binding assays can also be used to assess competitive binding.
Cell-based signaling assays
Reporter cell lines expressing ST2 and an NF-kB-driven luciferase reporter can measure downstream signaling after interleukin-33 receptor binding. Phospho-flow cytometry can detect phosphorylation of signaling intermediates like p38 and NF-kB. These assays are useful for screening modulators of the IL-33/ST2 axis.
CRISPR screening and functional genomics
Genome-wide CRISPR knockout screens can identify genes required for interleukin-33 receptor binding and downstream signaling. Pooled screens with IL-33 stimulation and a type 2 cytokine readout can uncover novel regulators. Bioinformatics analysis of screen hits can reveal pathways connected to GO:0002112.
In vivo models and disease readouts
Mouse models of asthma, COPD, cardiac fibrosis, and sepsis can be used to study interleukin-33 receptor binding in vivo. Readouts include airway inflammation, fibrosis markers, and survival. Oxidised IL-33 models can specifically probe ST2-independent pathways.
How CRISPR Can Be Used to Study GO:0002112 interleukin-33 receptor binding
Knockout
CRISPR knockout of IL33 or IL1RL1 (ST2) can abolish interleukin-33 receptor binding and downstream signaling, providing a clean genetic model to study the function of GO:0002112. Knockout cell lines are useful for confirming specificity of binding assays and for identifying compensatory pathways. In vivo knockout models can reveal the role of IL-33 receptor binding in diseases such as asthma and cardiac fibrosis.
Point Mutation
CRISPR point mutation can be used to introduce specific amino acid substitutions in IL-33 or ST2 to dissect the molecular determinants of interleukin-33 receptor binding. For example, mutating residues in the IL-33 cytokine domain can test their contribution to ST2 binding affinity. Point-mutation models are valuable for understanding structure-function relationships.
Knock-in
CRISPR knock-in of tagged IL-33 or ST2 (e.g., HA, FLAG, or fluorescent tags) enables tracking of receptor binding and trafficking in live cells. Knock-in of disease-associated variants can model how genetic changes affect interleukin-33 receptor binding. These models are essential for translational research.
Overexpression
CRISPR overexpression or lentiviral overexpression of IL-33 or ST2 can amplify interleukin-33 receptor binding and signaling, facilitating biochemical detection and drug screening. Overexpression models can also reveal gain-of-function phenotypes in disease contexts. They are complementary to knockout approaches for understanding the full dynamic range of the pathway.
How EDITGENE Supports interleukin-33 receptor binding Research
Researchers studying interleukin-33 receptor binding-related genes often need to determine whether a candidate gene is causally involved in ligand recognition, receptor activation, or downstream disease phenotypes. EDITGENE provides a comprehensive suite of CRISPR-based services to enable such causal studies with precision and reproducibility.
Contact EDITGENE today to design your custom CRISPR model for interleukin-33 receptor binding research.
Frequently Asked Questions About interleukin-33 receptor binding
What is interleukin-33 receptor binding?
Interleukin-33 receptor binding (GO:0002112) is a molecular function defined as binding to an interleukin-33 receptor, primarily involving the cytokine IL-33 and the ST2 (IL1RL1) receptor subunit.
What genes are involved in interleukin-33 receptor binding?
Key genes include IL33 (ligand), IL1RL1 (ST2 receptor), IL1RAP (co-receptor), and downstream signaling genes such as MYD88 and NFKB1.
What is the GO ID for interleukin-33 receptor binding?
The GO ID is GO:0002112, classified under molecular_function.
How does IL-33 bind to its receptor?
IL-33 binds the ST2 receptor subunit, forming a complex with IL1RAP to initiate signaling; oxidised IL-33 can alternatively bind a RAGE/EGFR complex.
What diseases are associated with interleukin-33 receptor binding?
It is associated with pulmonary inflammatory diseases, cardiac fibrosis, sepsis, and aging-related conditions.
Can CRISPR be used to study interleukin-33 receptor binding?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models enable causal studies of IL-33 receptor binding and signaling.
What is the role of ST2 in interleukin-33 receptor binding?
ST2 (IL1RL1) is the canonical receptor subunit that binds IL-33 and mediates downstream type 2 immune signaling.
Is there a ST2-independent pathway for IL-33 binding?
Yes, oxidised IL-33 can drive signaling via a ST2-independent RAGE/EGFR complex, particularly in COPD epithelial pathogenesis.
How is interleukin-33 receptor binding regulated?
It is regulated by ligand availability, oxidation state of IL-33, receptor expression levels, and soluble ST2 acting as a decoy.
What methods are used to study interleukin-33 receptor binding?
Common methods include SPR, ITC, ELISA, luciferase reporter assays, phospho-flow cytometry, and CRISPR screens.
Conclusion
Interleukin-33 receptor binding (GO:0002112) is a fundamental molecular function that initiates the IL-33/ST2 signaling axis, with broad implications for pulmonary, cardiac, and inflammatory diseases. The discovery of ST2-independent RAGE/EGFR signaling by oxidised IL-33 expands the mechanistic landscape of this function. CRISPR-based models are powerful tools for dissecting the causal roles of IL-33 receptor binding in health and disease. Continued research into this molecular function will inform therapeutic strategies targeting the IL-33 pathway.
References
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- 2. Sheng F et al.. 2025. IL-33/ST2 axis in diverse diseases: regulatory mechanisms and therapeutic potential.. Front Immunol 16:1533335 PMID: 39925809
- 3. Huang S et al.. 2020. [Research progress of interleukin-33 and its receptor ST2 in sepsis].. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 32(11):1399-1402 PMID: 33463506
- 4. Zhao J et al.. 2015. Interleukin-33 and its Receptor in Pulmonary Inflammatory Diseases.. Crit Rev Immunol 35(6):451-61 PMID: 27279043
- 5. Cardoso AL et al.. 2018. Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases.. Ageing Res Rev 47:214-277 PMID: 30071357
- 6. Vianello E et al.. 2019. ST2/IL-33 signaling in cardiac fibrosis.. Int J Biochem Cell Biol 116:105619 PMID: 31561019
- 7. Martin MU. 2013. Special aspects of interleukin-33 and the IL-33 receptor complex.. Semin Immunol 25(6):449-57 PMID: 24230466
- 8. Yagyu H et al.. 2025. Lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity.. Sci Immunol 10(112):eadp0849 PMID: 41134875
