GO:0038173 interleukin-17A-mediated signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0038173 describes the molecular signaling cascade triggered when interleukin-17A (IL-17A) binds its receptor on target cells, culminating in regulation of downstream cellular processes such as transcription.
• IL-17A is a key cytokine in asthma, where sex hormones influence its production and contribute to disease severity.
• In human keratinocytes, IL-17A synergizes with TNF-α to induce IL-36γ, a process critically regulated by IκBζ.
• The pathway is a major therapeutic target in autoimmune and inflammatory diseases, including psoriasis and asthma.
• CRISPR-based models (knockout, knock-in, overexpression) enable precise dissection of IL-17A signaling components and their disease relevance.
• Understanding GO:0038173 supports development of targeted biologics and small molecules that modulate IL-17A-driven inflammation.
Description
Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that orchestrates immune responses by binding to its receptor complex on the surface of target cells, initiating a signaling cascade defined by the Gene Ontology term GO:0038173, interleukin-17A-mediated signaling pathway. This pathway is essential for host defense against extracellular pathogens but also drives chronic inflammation in diseases such as asthma, psoriasis, and rheumatoid arthritis. The signaling cascade involves recruitment of adaptor proteins, activation of transcription factors, and induction of downstream genes that amplify inflammatory responses. Researchers study GO:0038173 to understand how IL-17A contributes to disease pathogenesis and to identify novel therapeutic targets. The pathway is particularly relevant in epithelial cells and keratinocytes, where IL-17A synergizes with other cytokines like TNF-α to induce inflammatory mediators. Given its central role in autoimmunity and inflammation, precise experimental models are needed to dissect the molecular players and regulatory mechanisms of this pathway.
interleukin-17A-mediated signaling pathway At A Glance
| GO ID | GO:0038173 |
|---|---|
| GO term | interleukin-17A-mediated signaling pathway |
| Ontology | biological_process |
| Synonym | IL-17A-mediated signaling pathway; IL17A signaling pathway; interleukin-17A-mediated signalling pathway; interleukin-17A signaling pathway |
| Major function | Transduces IL-17A signals from the cell surface to the nucleus, regulating inflammatory gene expression |
| Cellular context | Acts in various cell types including epithelial cells, keratinocytes, and fibroblasts |
| Key downstream effect | Induction of pro-inflammatory cytokines and chemokines, such as IL-36γ in keratinocytes |
| Disease relevance | Asthma, psoriasis, autoimmune inflammation |
What Is GO:0038173?
The interleukin-17A-mediated signaling pathway (GO:0038173) is the series of molecular events that begins when IL-17A binds to its receptor on the surface of a target cell and ends with the regulation of a downstream cellular process, such as transcription. This definition, based on the QuickGO annotation, encompasses receptor engagement, intracellular signal transduction, and transcriptional changes that mediate IL-17A's biological effects.
Why Is interleukin-17A-mediated signaling pathway Important in Cell Biology?
The interleukin-17A-mediated signaling pathway is a central driver of inflammatory responses and is critically involved in the pathogenesis of asthma, psoriasis, and other autoimmune diseases. Understanding this pathway at the molecular level is essential for developing targeted therapies that can modulate IL-17A activity without compromising host defense. Moreover, the interplay between IL-17A and other cytokines, such as TNF-α, highlights the complexity of inflammatory networks and the need for precise experimental models to dissect these interactions.
• IL-17A signaling is a major contributor to airway inflammation in asthma, with sex hormones influencing its production.
• In keratinocytes, IL-17A synergizes with TNF-α to induce IL-36γ, a cytokine involved in psoriatic inflammation.
• The pathway is a validated drug target; biologics against IL-17A or its receptor are used clinically for psoriasis.
• IκBζ acts as a key regulator of IL-17A-mediated induction of IL-36γ, representing a potential therapeutic node.
• Dysregulated IL-17A signaling is implicated in autoimmune diseases, including rheumatoid arthritis and multiple sclerosis.
• Studying GO:0038173 helps identify biomarkers and novel targets for inflammatory diseases.
• CRISPR screens can uncover genes that modulate IL-17A signaling, accelerating drug discovery.
• The pathway's cross-talk with TNF-α signaling underscores the importance of combination therapies.
• Understanding sex-specific differences in IL-17A signaling may lead to personalized treatments for asthma.
• Experimental models of IL-17A signaling are essential for preclinical testing of anti-inflammatory compounds.
What Happens During interleukin-17A-mediated signaling pathway?
IL-17A Binding to Its Receptor
In simple terms: IL-17A docks onto its receptor on the cell surface, like a key fitting a lock.
The pathway begins when IL-17A binds to the IL-17 receptor complex (IL-17RA/IL-17RC) on the surface of target cells. This binding triggers conformational changes that allow the receptor to recruit intracellular adaptor proteins, initiating downstream signaling.
Recruitment of Adaptor Proteins and Activation of Transcription Factors
In simple terms: The receptor sends a message inside the cell by activating proteins that turn on genes.
Upon ligand binding, the IL-17 receptor recruits adaptor proteins such as Act1, which activates TRAF6 and downstream kinases (e.g., TAK1, IKK). This leads to activation of transcription factors including NF-κB and C/EBPβ, which translocate to the nucleus.
Transcriptional Regulation of Inflammatory Genes
In simple terms: Activated transcription factors switch on genes that cause inflammation.
In the nucleus, NF-κB and other factors bind to promoter regions of target genes, inducing expression of pro-inflammatory cytokines and chemokines. For example, in human keratinocytes, IL-17A together with TNF-α induces IL-36γ, a process dependent on IκBζ.
Synergy with TNF-α and Other Cytokines
In simple terms: IL-17A often works together with other signals to amplify inflammation.
IL-17A signaling frequently synergizes with TNF-α to enhance inflammatory gene expression. This synergy involves cooperative activation of transcription factors and is critical in diseases like psoriasis.
Negative Feedback and Regulation
In simple terms: The cell has brakes to prevent runaway inflammation.
The pathway is tightly regulated by negative feedback mechanisms, including induction of SOCS proteins and deubiquitinases, which dampen IL-17A signaling to prevent excessive inflammation.
Key Genes Involved in GO:0038173 interleukin-17A-mediated signaling pathway
The following genes and proteins are key components or regulators of the interleukin-17A-mediated signaling pathway, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL17A | Ligand that initiates the pathway | Target for anti-inflammatory biologics |
| IL17RA | Receptor subunit for IL-17A | Mediates signal transduction; knockout models available |
| IL17RC | Receptor subunit for IL-17A | Essential for ligand binding and signaling |
| ACT1 (TRAF3IP2) | Adaptor protein recruited to IL-17 receptor | Knockout reduces IL-17A signaling |
| TRAF6 | E3 ubiquitin ligase downstream of Act1 | Activates NF-κB and MAPK pathways |
| NFKB1 | Transcription factor activated by IL-17A | Drives inflammatory gene expression |
| NFKB2 | Transcription factor activated by IL-17A | Regulates target genes |
| RELB | NF-κB subunit involved in IL-17A signaling | Modulates gene transcription |
| CEBPB | Transcription factor cooperating with NF-κB | Enhances IL-17A-induced gene expression |
| TNF | Cytokine that synergizes with IL-17A | Co-stimulates inflammatory responses |
| IL36G | Downstream target gene induced by IL-17A/TNF-α | Biomarker of psoriatic inflammation |
| NFKBIZ (IκBζ) | Key regulator of IL-17A-mediated IL-36γ induction | Potential therapeutic target |
| SOCS1 | Negative regulator of cytokine signaling | Feedback inhibition of IL-17A pathway |
| SOCS3 | Negative regulator of cytokine signaling | Attenuates IL-17A signaling |
| MAP3K7 (TAK1) | Kinase activating NF-κB and MAPK | Central node in IL-17A signaling |
| IKBKB (IKKβ) | Kinase required for NF-κB activation | Essential for IL-17A-induced transcription |
| TRAF3IP2 | Adaptor protein (Act1) in IL-17 receptor complex | Knockout abolishes IL-17A signaling |
How Is interleukin-17A-mediated signaling pathway Regulated?
The interleukin-17A-mediated signaling pathway is regulated at multiple levels. Negative feedback loops involving SOCS proteins and deubiquitinases attenuate the signal to prevent excessive inflammation. Additionally, sex hormones such as estrogen can modulate IL-17A production and signaling, contributing to sex differences in asthma prevalence and severity. In keratinocytes, IκBζ (NFKBIZ) acts as a key regulator of IL-17A/TNF-α-induced IL-36γ expression, highlighting cell-type-specific control mechanisms.
interleukin-17A-mediated signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL17A | Asthma, psoriasis | Knockout mouse or human cell line KO |
| IL17RA | Psoriasis, autoimmune inflammation | Conditional knockout in keratinocytes |
| NFKBIZ | Psoriasis (IL-36γ induction) | Knockout in human keratinocytes |
| TNF | Inflammatory synergy in psoriasis | Double knockout with IL17A |
| IL36G | Psoriasis biomarker | Reporter knock-in for high-throughput screening |
Asthma and Allergic Airway Inflammation
IL-17A-mediated signaling contributes to neutrophilic asthma, a severe subtype often resistant to corticosteroids. Sex hormones influence IL-17A production, with higher levels observed in females, potentially explaining sex disparities in asthma. Targeting this pathway may offer therapeutic benefits for severe asthma.
Psoriasis and Skin Inflammation
In psoriatic keratinocytes, IL-17A synergizes with TNF-α to induce IL-36γ, a cytokine that amplifies skin inflammation. IκBζ is a critical regulator of this process, and its inhibition reduces IL-36γ production, suggesting a therapeutic strategy for psoriasis.
Autoimmune Diseases
Dysregulated IL-17A signaling is implicated in rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. The pathway promotes recruitment of neutrophils and activation of stromal cells, perpetuating tissue damage.
From interleukin-17A-mediated signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does IL17A knockout reduce airway inflammation? | IL17A knockout mouse or human bronchial epithelial cells |
| What is the role of IκBζ in IL-17A-induced IL-36γ? | NFKBIZ knockout in human keratinocytes |
| Can a point mutation in IL17RA abolish signaling? | CRISPR knock-in of point mutation in IL17RA |
| How does IL-17A synergize with TNF-α? | Double knockout of IL17A and TNF in keratinocytes |
| What genes are essential for IL-17A signaling? | Genome-wide CRISPR knockout screen in reporter cells |
| Can overexpression of SOCS3 dampen IL-17A signaling? | Overexpression of SOCS3 in target cells |
How to Study the interleukin-17A-mediated signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify IL-17A target genes |
| Phosphoproteomics | Kinase activation and signaling dynamics | Map IL-17A signaling network |
| Luciferase reporter assay | Transcriptional activity of IL-17A-responsive promoters | High-throughput drug screening |
| Immunofluorescence | Nuclear translocation of NF-κB | Validate pathway activation |
| CRISPR knockout screen | Genes essential for IL-17A signaling | Discover novel regulators |
| CRISPR activation screen | Genes that enhance IL-17A signaling | Identify positive regulators |
| ELISA | Cytokine secretion (e.g., IL-36γ) | Quantify pathway output |
| Flow cytometry | Surface marker expression and immune cell activation | Analyze IL-17A effects on immune cells |
Transcriptomic Analysis (RNA-seq)
RNA sequencing can identify global transcriptional changes induced by IL-17A, revealing downstream target genes and pathways. This method is useful for comparing wild-type and knockout cells to pinpoint IL-17A-specific gene signatures.
Proteomic and Phosphoproteomic Profiling
Mass spectrometry-based proteomics can quantify protein expression and phosphorylation changes following IL-17A stimulation, uncovering activated signaling nodes such as NF-κB and MAPK.
Reporter Assays and Imaging
Luciferase reporter assays driven by IL-17A-responsive promoters (e.g., IL-36γ promoter) enable high-throughput screening of modulators. Fluorescence microscopy can visualize nuclear translocation of NF-κB.
CRISPR Screening
Genome-wide CRISPR knockout or activation screens can identify genes that regulate IL-17A signaling. For example, a screen for regulators of IL-36γ induction in keratinocytes could uncover novel therapeutic targets.
How CRISPR Can Be Used to Study GO:0038173 interleukin-17A-mediated signaling pathway
Knockout
CRISPR knockout of key genes such as IL17A, IL17RA, or NFKBIZ can abolish or reduce IL-17A signaling, providing causal evidence for their roles. For example, NFKBIZ knockout in human keratinocytes diminishes IL-17A/TNF-α-induced IL-36γ expression.
Point Mutation
Introducing point mutations in receptor or signaling genes (e.g., IL17RA) can dissect specific domains required for signal transduction. This approach helps identify critical residues for ligand binding or adaptor recruitment.
Knock-in
Knock-in of reporter genes (e.g., luciferase or fluorescent proteins) under the control of IL-17A-responsive promoters allows real-time monitoring of pathway activity. Tagged knock-in of signaling proteins enables tracking of their localization and interactions.
Overexpression
Overexpression of negative regulators (e.g., SOCS3) or constitutively active signaling components can modulate the pathway. This is useful for gain-of-function studies and for validating therapeutic targets.
How EDITGENE Supports interleukin-17A-mediated signaling pathway Research
Researchers studying interleukin-17A-mediated signaling pathway-related genes often need to determine whether a candidate gene is causally involved in the pathway or merely correlated with its activation. EDITGENE provides a comprehensive suite of CRISPR-based services to enable precise genetic manipulation and functional validation.
Contact EDITGENE today to design your custom CRISPR model for interleukin-17A-mediated signaling pathway research.
Frequently Asked Questions About interleukin-17A-mediated signaling pathway
What is the interleukin-17A-mediated signaling pathway?
It is the series of molecular signals initiated by IL-17A binding to its receptor, leading to regulation of downstream cellular processes such as transcription (GO:0038173).
What genes are involved in interleukin-17A-mediated signaling pathway?
Key genes include IL17A, IL17RA, IL17RC, ACT1 (TRAF3IP2), TRAF6, NFKB1, RELB, CEBPB, and NFKBIZ.
How does IL-17A signaling contribute to asthma?
IL-17A signaling drives neutrophilic inflammation in asthma, and sex hormones can influence its production, contributing to disease severity.
What is the role of IκBζ in IL-17A signaling?
IκBζ (encoded by NFKBIZ) is a key regulator of IL-17A and TNF-α-mediated induction of IL-36γ in human keratinocytes.
What diseases are associated with IL-17A signaling?
Asthma, psoriasis, rheumatoid arthritis, and other autoimmune diseases are linked to dysregulated IL-17A signaling.
How can CRISPR be used to study IL-17A signaling?
CRISPR knockout, knock-in, point mutation, and overexpression models allow precise dissection of gene function in the pathway.
What are the downstream targets of IL-17A signaling?
Downstream targets include pro-inflammatory cytokines and chemokines such as IL-36γ, as well as NF-κB-responsive genes.
What cell types respond to IL-17A?
Epithelial cells, keratinocytes, fibroblasts, and immune cells express IL-17 receptor and respond to IL-17A.
How is IL-17A signaling regulated?
It is regulated by negative feedback loops involving SOCS proteins and deubiquitinases, and by sex hormones.
What experimental models are used to study IL-17A signaling?
Models include knockout mice, CRISPR-edited cell lines, reporter assays, and genome-wide screens.
Conclusion
The interleukin-17A-mediated signaling pathway (GO:0038173) is a critical driver of inflammation and a key therapeutic target in asthma, psoriasis, and autoimmune diseases. Understanding its molecular components and regulatory mechanisms is essential for developing new treatments. CRISPR-based models provide powerful tools to dissect this pathway and identify novel drug targets.
References
- 1. Yung JA et al.. 2018. Hormones, sex, and asthma.. Ann Allergy Asthma Immunol 120(5):488-494 PMID: 29410216
- 2. Ovesen SK et al.. 2021. IkBζ is a Key Regulator of Tumour Necrosis Factor-a and Interleukin-17A-mediated Induction of Interleukin-36g in Human Keratinocytes.. Acta Derm Venereol 101(2):adv00386 PMID: 33491092
