GO:0070748 interleukin-35 receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0070748 (interleukin-35 receptor binding) is a molecular function defined as binding to an interleukin-35 receptor [QuickGO].
• IL-35 is a heterodimeric cytokine composed of the p35 (IL12A) and EBI3 (IL27B) subunits, and its receptor binding initiates JAK/STAT signaling.
• IL-35 receptor binding triggers JAK1/STAT1 signaling, which can shift osteoclast precursor activation from TRADD-TRAF2 to TRADD-FADD, promoting apoptosis.
• IL-35 suppresses endothelial activation by inhibiting mitochondrial reactive oxygen species-mediated H3K14 acetylation.
• IL-35 sensitizes monocytes from asthma patients to glucocorticoid therapy via p38 MAPK regulation.
• IL-35 inhibits adipogenesis through PPARγ-Wnt/β-catenin signaling by targeting Axin2.
Description
Interleukin-35 (IL-35) is an anti-inflammatory heterodimeric cytokine belonging to the IL-12 family, composed of the p35 subunit (encoded by IL12A) and the EBI3 subunit (encoded by IL27B). The Gene Ontology molecular function term GO:0070748, interleukin-35 receptor binding, describes the binding of IL-35 to its receptor complex, a critical initial step in IL-35-mediated signaling [QuickGO]. This binding event is essential for transmitting extracellular IL-35 signals into cells, leading to activation of JAK/STAT pathways and modulation of immune responses. Researchers study interleukin-35 receptor binding to understand how IL-35 exerts its immunoregulatory functions in autoimmune diseases, inflammatory conditions, and cancer. The binding of IL-35 to its receptor triggers downstream signaling cascades that can suppress T cell proliferation, inhibit osteoclastogenesis, and modulate endothelial cell activation. Dysregulation of IL-35 receptor binding has been implicated in various pathological states, including autoimmune dermatoses, Sjögren's syndrome, and asthma. Understanding the molecular details of interleukin-35 receptor binding provides insights into potential therapeutic strategies targeting this pathway. For example, IL-35's ability to sensitize monocytes to glucocorticoid therapy in asthma highlights the clinical relevance of this interaction. Furthermore, IL-35's role in inhibiting adipogenesis via PPARγ-Wnt/β-catenin signaling suggests broader metabolic implications. This article synthesizes current knowledge on GO:0070748, covering its definition, mechanism, key genes, research methods, and disease associations.
interleukin-35 receptor binding At A Glance
| GO ID | GO:0070748 |
|---|---|
| GO term | interleukin-35 receptor binding |
| Ontology | molecular_function |
| Synonym | IL-35, interleukin-35 receptor ligand |
| Definition | Binding to an interleukin-35 receptor. |
| Major function | Mediates the initial interaction between IL-35 and its receptor, triggering downstream signaling. |
| Related cytokine | Interleukin-35 (IL-35), a heterodimer of p35 (IL12A) and EBI3 (IL27B). |
| Signaling pathway | JAK/STAT, particularly JAK1/STAT1. |
| Disease relevance | Autoimmune diseases, inflammatory conditions, asthma, and metabolic disorders. |
What Is GO:0070748?
Interleukin-35 receptor binding (GO:0070748) is a molecular function defined by the Gene Ontology as the binding to an interleukin-35 receptor [QuickGO]. In other words, it is the specific interaction between the cytokine IL-35 and its cell surface receptor complex, which initiates intracellular signaling. This term encompasses the physical binding event but does not include the downstream signaling cascade itself. IL-35 is a heterodimeric cytokine, and its binding to the receptor is a prerequisite for activating JAK/STAT pathways and exerting immunomodulatory effects.
Why Is interleukin-35 receptor binding Important in Cell Biology?
Interleukin-35 receptor binding is a critical molecular event that governs the immunoregulatory functions of IL-35. By binding to its receptor, IL-35 initiates signaling cascades that suppress inflammatory responses, modulate immune cell differentiation, and maintain immune homeostasis. This binding event is essential for IL-35's ability to inhibit osteoclastogenesis, suppress endothelial activation, and sensitize monocytes to glucocorticoids. Dysregulation of this interaction contributes to the pathogenesis of autoimmune diseases such as autoimmune dermatoses and Sjögren's syndrome, as well as inflammatory conditions like asthma. Therefore, understanding the molecular mechanisms of interleukin-35 receptor binding is crucial for developing targeted therapies that modulate IL-35 signaling in disease contexts.
• IL-35 receptor binding initiates JAK1/STAT1 signaling, which is critical for its anti-inflammatory effects.
• It mediates IL-35-induced inhibition of TNF-α-induced osteoclastogenesis and promotes apoptosis in osteoclast precursors.
• IL-35 receptor binding suppresses endothelial cell activation by inhibiting mitochondrial ROS-mediated H3K14 acetylation.
• It sensitizes monocytes from asthma patients to glucocorticoid therapy via p38 MAPK regulation.
• IL-35 receptor binding inhibits adipogenesis through PPARγ-Wnt/β-catenin signaling by targeting Axin2.
• Dysregulation of IL-35 receptor binding is implicated in autoimmune dermatoses.
• It plays a role in the genetics of Sjögren's syndrome.
• IL-35 receptor binding is a potential therapeutic target for inflammatory autoimmune diseases.
• Understanding this binding event aids in the development of IL-35-based therapies.
• It is a key molecular function for studying cytokine-receptor interactions in immunology.
Molecular Mechanism of interleukin-35 receptor binding
IL-35 Structure and Receptor Complex
In simple terms: IL-35 is a two-part cytokine that binds to a receptor on the cell surface.
IL-35 is a heterodimeric cytokine composed of the p35 subunit (IL12A) and the EBI3 subunit (IL27B). The receptor for IL-35 is a heterodimer composed of IL-12Rβ2 and gp130 (IL6ST) subunits, or IL-12Rβ2 and IL-27Rα, depending on the cell type. The binding of IL-35 to its receptor is mediated by specific interactions between the cytokine subunits and the receptor chains. This binding event is the first step in IL-35 signaling and is required for the activation of downstream pathways.
JAK/STAT Activation
In simple terms: Once IL-35 binds, it turns on a signaling pathway inside the cell.
Upon IL-35 binding to its receptor, receptor-associated JAK kinases, particularly JAK1, are activated. JAK1 then phosphorylates STAT1, leading to STAT1 dimerization and translocation to the nucleus, where it regulates gene expression. This JAK1/STAT1 pathway is central to IL-35's biological effects, including the inhibition of osteoclastogenesis and promotion of apoptosis in osteoclast precursors.
Modulation of Apoptosis Signaling
In simple terms: IL-35 binding can change how cells decide to live or die.
IL-35 receptor binding shifts the activation of TNF receptor-associated death domain (TRADD) from TRAF2 to Fas-associated death domain (FADD) in a JAK1/STAT1-dependent manner. This switch promotes apoptosis in osteoclast precursors, thereby inhibiting osteoclastogenesis. This mechanism highlights how IL-35 receptor binding can directly influence cell fate decisions.
Regulation of Mitochondrial ROS and Epigenetic Modifications
In simple terms: IL-35 binding can reduce harmful molecules and change gene expression.
IL-35 receptor binding suppresses endothelial cell activation by inhibiting mitochondrial reactive oxygen species (ROS)-mediated site-specific acetylation of histone H3 lysine 14 (H3K14). This epigenetic modification is associated with inflammatory gene expression, and its inhibition by IL-35 contributes to the anti-inflammatory effects of IL-35 in endothelial cells.
Regulation of p38 MAPK Signaling
In simple terms: IL-35 binding can affect stress-response pathways in immune cells.
In monocytes from asthma patients, IL-35 receptor binding sensitizes cells to glucocorticoid therapy by regulating p38 MAPK signaling. This suggests that IL-35 can modulate intracellular signaling pathways to enhance the responsiveness of immune cells to anti-inflammatory treatments.
Inhibition of Adipogenesis via PPARγ-Wnt/β-catenin
In simple terms: IL-35 binding can block fat cell formation.
IL-35 receptor binding inhibits adipogenesis through the PPARγ-Wnt/β-catenin signaling pathway by targeting Axin2. This indicates that IL-35 has metabolic functions beyond immunoregulation, and its receptor binding can influence adipocyte differentiation.
Key Genes Involved in GO:0070748 interleukin-35 receptor binding
The following genes and proteins are involved in interleukin-35 receptor binding and its downstream signaling.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL12A | Encodes the p35 subunit of IL-35 | Essential for IL-35 heterodimer formation and receptor binding. |
| EBI3 | Encodes the EBI3 subunit of IL-35 | Required for IL-35 secretion and function. |
| IL12RB2 | Encodes a subunit of the IL-35 receptor | Mediates IL-35 binding and signaling. |
| IL6ST | Encodes gp130, a receptor subunit | Forms part of the IL-35 receptor complex. |
| JAK1 | Kinase activated upon IL-35 binding | Phosphorylates STAT1 to propagate signaling. |
| STAT1 | Transcription factor activated by JAK1 | Mediates IL-35-induced gene expression. |
| TRADD | Adaptor protein in TNF signaling | IL-35 binding shifts TRADD binding from TRAF2 to FADD. |
| TRAF2 | Adaptor protein in survival signaling | Displaced by FADD upon IL-35 treatment. |
| FADD | Adaptor protein in apoptosis signaling | Recruited to TRADD upon IL-35 treatment, promoting apoptosis. |
| AXIN2 | Target of IL-35 signaling | Mediates IL-35 inhibition of adipogenesis via Wnt/β-catenin. |
| PPARG | Master regulator of adipogenesis | Inhibited by IL-35 via PPARγ-Wnt/β-catenin pathway. |
| CTNNB1 | β-catenin, key Wnt signaling component | Involved in IL-35-mediated inhibition of adipogenesis. |
| MAPK14 | p38 MAPK, stress kinase | Regulated by IL-35 in asthma monocytes. |
| H3K14ac | Histone modification | Inhibited by IL-35 via mitochondrial ROS suppression. |
| IL12B | Encodes IL-12 p40 subunit | Related to IL-12 receptor binding, but not IL-35. |
| IL12RB1 | IL-12 receptor subunit | Binds IL-12 p40 homodimer, not IL-35. |
| IL27RA | IL-27 receptor alpha subunit | May form part of IL-35 receptor in some cells. |
How Is interleukin-35 receptor binding Regulated?
Interleukin-35 receptor binding and its downstream signaling are regulated at multiple levels. The expression of IL-35 subunits (IL12A and EBI3) is controlled by various transcription factors and cytokines, influencing the availability of IL-35 for receptor binding. Receptor expression levels, including IL12RB2 and IL6ST, can also modulate the sensitivity of cells to IL-35. Additionally, intracellular signaling molecules such as JAK1 and STAT1 are subject to negative feedback regulation, which can dampen IL-35 signaling. In asthma monocytes, p38 MAPK signaling modulates the response to IL-35 and glucocorticoid therapy. Furthermore, IL-35 receptor binding can be influenced by the cellular redox state, as mitochondrial ROS levels affect downstream epigenetic modifications.
interleukin-35 receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL12A | Autoimmune dermatoses | Knockout mouse models or cell lines |
| EBI3 | Sjögren's syndrome | Knock-in or overexpression models |
| IL12RB2 | Asthma | Point mutation or knockout models |
| AXIN2 | Metabolic disorders | Overexpression or knockout models |
| JAK1 | Inflammatory diseases | Knockout or point mutation models |
Autoimmune Dermatoses
IL-35 and its receptor binding play a role in autoimmune dermatoses, where dysregulated IL-35 signaling contributes to chronic inflammation and tissue damage. Understanding IL-35 receptor binding in these conditions may lead to novel therapeutic approaches targeting the IL-35 pathway.
Sjögren's Syndrome
Genetic studies have implicated IL-35-related pathways in Sjögren's syndrome, an autoimmune disease characterized by dry eyes and mouth. IL-35 receptor binding may influence the inflammatory processes in salivary and lacrimal glands.
Asthma
In asthma, IL-35 receptor binding sensitizes monocytes to glucocorticoid therapy by regulating p38 MAPK. This suggests that modulating IL-35 signaling could improve treatment responses in asthma patients.
Metabolic Disorders
IL-35 receptor binding inhibits adipogenesis via the PPARγ-Wnt/β-catenin pathway by targeting Axin2. This links IL-35 signaling to metabolic regulation and suggests potential roles in obesity and related disorders.
From interleukin-35 receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does IL-35 receptor binding inhibit osteoclastogenesis? | Knockout of IL12A or EBI3 in osteoclast precursors |
| How does IL-35 binding affect endothelial activation? | Overexpression of IL-35 subunits in endothelial cells |
| Can IL-35 sensitize asthma monocytes to glucocorticoids? | Point mutation in IL12RB2 or JAK1 in monocytes |
| Does IL-35 inhibit adipogenesis via Axin2? | Knock-in of Axin2 reporter in adipocytes |
| What is the role of IL-35 in autoimmune dermatoses? | Knockout mouse models of IL12A or EBI3 |
| How does IL-35 signaling affect Sjögren's syndrome? | Overexpression of IL-35 in salivary gland cells |
How to Study the interleukin-35 receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Surface plasmon resonance (SPR) | Binding affinity and kinetics | IL-35-receptor interaction studies |
| Immunoblotting | Phospho-STAT1 levels | JAK/STAT activation |
| Flow cytometry | Apoptosis (Annexin V) | Osteoclast precursor apoptosis |
| MitoSOX staining | Mitochondrial ROS | Endothelial cell activation |
| ELISA | Cytokine levels | IL-35 quantification |
| qRT-PCR | Gene expression | IL-35 target genes |
| Western blot | Protein expression | PPARγ, β-catenin |
| Luciferase reporter assay | Transcriptional activity | STAT1 or Wnt/β-catenin reporters |
Receptor Binding Assays
Direct binding of IL-35 to its receptor can be measured using surface plasmon resonance (SPR) or enzyme-linked immunosorbent assays (ELISA). These methods quantify the affinity and kinetics of IL-35-receptor interactions, providing insights into the molecular basis of GO:0070748.
Phospho-STAT1 Immunoblotting
Activation of JAK/STAT signaling upon IL-35 receptor binding can be assessed by immunoblotting for phosphorylated STAT1. This method detects the downstream signaling events triggered by IL-35 binding and is useful for studying pathway inhibitors or genetic modifications.
Flow Cytometry for Apoptosis
IL-35-induced apoptosis in osteoclast precursors can be measured by flow cytometry using Annexin V staining. This technique allows quantification of apoptotic cells following IL-35 treatment and can be combined with genetic knockouts to dissect the role of specific genes.
Mitochondrial ROS Detection
Mitochondrial reactive oxygen species (ROS) levels can be measured using fluorescent probes such as MitoSOX. This method helps evaluate the effect of IL-35 receptor binding on mitochondrial ROS and downstream epigenetic modifications.
How CRISPR Can Be Used to Study GO:0070748 interleukin-35 receptor binding
Knockout
CRISPR knockout of IL12A or EBI3 can abolish IL-35 production and receptor binding, enabling studies on the loss of IL-35 signaling in autoimmune and inflammatory models. Knockout of IL12RB2 or IL6ST can disrupt the receptor complex and prevent IL-35 binding, helping to delineate receptor-specific effects.
Point Mutation
Point mutations in JAK1 or STAT1 can be introduced to study the specific phosphorylation events required for IL-35 receptor binding-induced signaling. For example, mutation of the JAK1 kinase domain can block STAT1 activation without affecting receptor binding.
Knock-in
Knock-in of tagged IL-35 subunits (e.g., HA-tagged IL12A) allows for tracking of IL-35 secretion and receptor binding in live cells. Similarly, knock-in of fluorescent reporters for STAT1 can visualize signaling dynamics upon IL-35 binding.
Overexpression
Overexpression of IL-35 subunits or its receptor components can enhance IL-35 receptor binding and downstream signaling, useful for gain-of-function studies in endothelial cells or adipocytes.
How EDITGENE Supports interleukin-35 receptor binding Research
Researchers studying interleukin-35 receptor binding-related genes often need to determine whether a candidate gene is causally involved in IL-35 signaling or is merely correlated with its effects. EDITGENE provides a comprehensive suite of CRISPR-based services to enable precise genetic modifications, from knockout to knock-in, facilitating functional studies of GO:0070748 and its associated pathways.
Contact EDITGENE today to design your custom CRISPR model for interleukin-35 receptor binding research.
Frequently Asked Questions About interleukin-35 receptor binding
What is interleukin-35 receptor binding?
Interleukin-35 receptor binding (GO:0070748) is the molecular function of binding to an interleukin-35 receptor, initiating downstream signaling [QuickGO].
What genes are involved in interleukin-35 receptor binding?
Key genes include IL12A, EBI3, IL12RB2, IL6ST, JAK1, and STAT1.
How does IL-35 receptor binding affect immune cells?
It activates JAK/STAT signaling, modulates apoptosis, and suppresses inflammatory responses.
What diseases are associated with interleukin-35 receptor binding?
Autoimmune dermatoses, Sjögren's syndrome, asthma, and metabolic disorders.
What is the role of IL-35 in osteoclastogenesis?
IL-35 receptor binding inhibits TNF-α-induced osteoclastogenesis and promotes apoptosis via JAK1/STAT1.
How does IL-35 affect endothelial cells?
IL-35 suppresses endothelial activation by inhibiting mitochondrial ROS-mediated H3K14 acetylation.
Can IL-35 sensitize asthma monocytes to glucocorticoids?
Yes, IL-35 sensitizes monocytes from asthma patients to glucocorticoid therapy by regulating p38 MAPK.
Does IL-35 inhibit adipogenesis?
IL-35 inhibits adipogenesis via PPARγ-Wnt/β-catenin signaling by targeting Axin2.
What methods are used to study interleukin-35 receptor binding?
SPR, immunoblotting, flow cytometry, and mitochondrial ROS detection.
How can CRISPR be used to study interleukin-35 receptor binding?
CRISPR knockout, point mutation, knock-in, and overexpression models enable functional studies of IL-35 signaling.
Conclusion
Interleukin-35 receptor binding (GO:0070748) is a pivotal molecular function that initiates the immunoregulatory and metabolic effects of IL-35. Through JAK/STAT signaling and modulation of apoptosis, mitochondrial ROS, and adipogenesis, IL-35 receptor binding influences diverse biological processes and disease states. Continued research using CRISPR-based models and advanced molecular techniques will further elucidate the mechanisms and therapeutic potential of targeting this interaction.
References
- 1. Xie Y et al.. 2022. Interleukin-35 in autoimmune dermatoses: Current concepts.. Open Med (Wars) 17(1):589-600 PMID: 35434379
- 2. Peng M et al.. 2018. Interleukin-35 Inhibits TNF-α-Induced Osteoclastogenesis and Promotes Apoptosis via Shifting the Activation From TNF Receptor-Associated Death Domain (TRADD)-TRAF2 to TRADD-Fas-Associated Death Domain by JAK1/STAT1.. Front Immunol 9:1417 PMID: 30061878
- 3. Teos LY et al.. 2017. Genetics of Sjögren's syndrome.. Clin Immunol 182:41-47 PMID: 28476436
- 4. Wang X et al.. 1999. Characterization of mouse interleukin-12 p40 homodimer binding to the interleukin-12 receptor subunits.. Eur J Immunol 29(6):2007-13 PMID: 10382764
- 5. Li X et al.. 2018. IL-35 (Interleukin-35) Suppresses Endothelial Cell Activation by Inhibiting Mitochondrial Reactive Oxygen Species-Mediated Site-Specific Acetylation of H3K14 (Histone 3 Lysine 14).. Arterioscler Thromb Vasc Biol 38(3):599-609 PMID: 29371247
- 6. Su LC et al.. 2018. Emerging role of IL-35 in inflammatory autoimmune diseases.. Autoimmun Rev 17(7):665-673 PMID: 29729445
- 7. Qian L et al.. 2020. Interleukin-35 sensitizes monocytes from patients with asthma to glucocorticoid therapy by regulating p38 MAPK.. Exp Ther Med 19(5):3247-3258 PMID: 32266020
- 8. Li Y et al.. 2023. IL-35 inhibits adipogenesis via PPARγ-Wnt/β-catenin signaling pathway by targeting Axin2.. Int Immunopharmacol 122:110615 PMID: 37429144
