GO:0097400 interleukin-17-mediated signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0097400 describes the molecular signaling cascade triggered when interleukin-17 (IL-17) binds its receptor on a target cell, culminating in regulation of downstream cellular processes such as transcription.
• The pathway canonically engages JAK/STAT, TRAF6, ERK, p38 MAPK, and NF-kB modules, and its strength is tuned by negative regulators including MCPIP1 and the aryl hydrocarbon receptor.
• IL-17 signaling drives inflammation, osteoclast differentiation, myoblast migration, and liver ischemia-reperfusion injury, making it a central node in autoimmunity and tissue injury.
• Loss of negative regulators such as IRF3 amplifies IL-17-mediated injury, demonstrating that the pathway is under active restraint in vivo.
• CRISPR knockout, point-mutation, knock-in, and overexpression models are essential to dissect which components are causally required for IL-17 signal transduction.
• EDITGENE provides end-to-end CRISPR cell model and library screening services to interrogate every node of GO:0097400.
Description
Interleukin-17 (IL-17) is a pro-inflammatory cytokine that initiates a defined intracellular signaling cascade on the surface of target cells. The Gene Ontology term GO:0097400, interleukin-17-mediated signaling pathway, captures the entire series of molecular signals that begins with IL-17 binding to its receptor and ends with regulation of a downstream cellular process, such as transcription. This term is a biological_process node and is essential for annotating how cytokines translate extracellular cues into inflammatory gene programs. Researchers studying autoimmunity, osteoimmunology, and tissue injury rely on GO:0097400 to organize experimental findings and to compare signaling architectures across cell types. The pathway is not a simple linear switch; it integrates JAK/STAT, TRAF6, MAPK, and NF-kB arms, and it is actively restrained by negative regulators such as MCPIP1 and the aryl hydrocarbon receptor. Because dysregulated IL-17 signaling underlies multiple pathologies, precise annotation and causal testing of each component are critical for therapeutic development.
interleukin-17-mediated signaling pathway At A Glance
| GO ID | GO:0097400 |
|---|---|
| GO term | interleukin-17-mediated signaling pathway |
| Ontology | biological_process |
| Synonym | IL-17-mediated signaling pathway; IL-17-mediated signalling pathway; interleukin-17-mediated signalling pathway |
| Major function | Transduces IL-17 cytokine signals from the cell surface to downstream transcriptional and cellular responses |
| Key proximal modules | JAK/STAT, TRAF6, ERK, p38 MAPK, NF-kB |
| Negative regulators | MCPIP1, aryl hydrocarbon receptor, IRF3 |
| Representative cell contexts | Osteoclast precursors, myoblasts, hepatocytes, immune cells |
What Is GO:0097400?
GO:0097400 is defined as the series of molecular signals initiated by interleukin-17 binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. In practice, this means the term covers receptor engagement, proximal adaptor recruitment, kinase cascade activation, and the resulting changes in gene expression or cell behavior.
Why Is interleukin-17-mediated signaling pathway Important in Cell Biology?
GO:0097400 is important because IL-17-mediated signaling is a primary driver of inflammatory tissue responses and is implicated in autoimmune disease, osteoclastogenesis, and ischemia-reperfusion injury. Understanding the pathway at the level of individual components allows researchers to identify causal nodes for therapeutic intervention and to interpret transcriptomic and proteomic data in a structured ontology framework.
• IL-17 signaling promotes osteoclast precursor differentiation through TRAF6/ERK/p38-dependent autophagy.
• MCPIP1 endoribonuclease activity negatively regulates IL-17-mediated signaling and inflammation, defining a built-in brake on the pathway.
• JAK/STAT involvement was demonstrated early, establishing a kinase-dependent arm of IL-17 signal transduction.
• The aryl hydrocarbon receptor acts as a novel negative regulator of IL-17-mediated signaling and inflammation in vitro.
• IRF3 deficiency leads to exacerbated IL-17-mediated liver ischemia-reperfusion injury, linking the pathway to organ damage.
• IL-17 modulates myoblast migration by inhibiting urokinase-type plasminogen activator through p38 MAPK, showing cell-type-specific outputs.
• The pathway is a target for anti-inflammatory drug discovery in autoimmunity and chronic inflammation.
• GO:0097400 provides a standardized annotation axis for comparing IL-17 responses across cell types and disease models.
• CRISPR-based causal screens can identify which pathway components are required versus redundant in a given cellular context.
• Accurate pathway annotation supports reproducible biomarker and target discovery in inflammatory disease research.
What Happens During interleukin-17-mediated signaling pathway?
Receptor engagement and proximal activation
In simple terms: IL-17 docks onto its receptor on the target cell surface, which switches on the first intracellular signals.
The pathway is initiated when interleukin-17 binds to its receptor on the surface of a target cell, as specified in the GO:0097400 definition. This binding event is the molecular trigger that converts an extracellular cytokine cue into an intracellular signal, and it is the formal starting point for all downstream annotations under this term.
JAK/STAT arm
In simple terms: A kinase called JAK and a transcription factor called STAT relay the signal from the receptor toward the nucleus.
Evidence supports involvement of the JAK/STAT pathway in the signaling mechanism of interleukin-17, indicating that kinase-dependent phosphorylation events are part of the canonical cascade. This arm contributes to the regulation of downstream cellular processes, including transcription, which is the defined endpoint of GO:0097400.
TRAF6/ERK/p38 MAPK module
In simple terms: A relay of proteins including TRAF6, ERK, and p38 transmits the signal and can also trigger autophagy.
The TRAF6/ERK/p38 pathway is involved in interleukin-17-mediated autophagy to promote osteoclast precursor cell differentiation, demonstrating that the pathway can couple to both transcriptional and autophagic outputs. Separately, IL-17 modulates myoblast cell migration by inhibiting urokinase-type plasminogen activator expression through p38 MAPK, showing that p38 is a recurring effector node in this pathway.
Negative regulation by MCPIP1 and AhR
In simple terms: Brake proteins such as MCPIP1 and the aryl hydrocarbon receptor keep the IL-17 signal from running out of control.
MCPIP1 endoribonuclease activity negatively regulates interleukin-17-mediated signaling and inflammation, establishing a post-transcriptional restraint on the pathway. The aryl hydrocarbon receptor is a novel negative regulator of interleukin-17-mediated signaling and inflammation in vitro, adding a second layer of negative control. Together these findings show that GO:0097400 is not constitutively active but is actively dampened by dedicated regulators.
IRF3-dependent modulation and tissue injury output
In simple terms: When a regulator called IRF3 is missing, IL-17 signaling becomes more damaging to tissues.
Interferon regulatory factor 3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury, demonstrating that loss of a single modulator can amplify the pathological output of this pathway. This links the molecular cascade defined by GO:0097400 directly to organ-level injury phenotypes.
Key Genes Involved in GO:0097400 interleukin-17-mediated signaling pathway
The following genes and proteins are experimentally implicated in interleukin-17-mediated signaling pathway (GO:0097400) based on the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL17A | Cytokine ligand that initiates the pathway | Core trigger of GO:0097400; target for anti-inflammatory intervention |
| IL17RA | Receptor subunit for IL-17 binding | Proximal node required for signal initiation |
| TRAF6 | Adaptor that couples receptor to downstream kinases | Required for IL-17-mediated autophagy and osteoclast differentiation |
| MAPK1/ERK2 | Kinase in the TRAF6/ERK/p38 module | Effector of IL-17-driven autophagy and differentiation |
| MAPK14/p38 | Stress kinase downstream of IL-17 | Mediates myoblast migration and autophagy outputs |
| JAK1 | Kinase in the JAK/STAT arm | Supports kinase-dependent IL-17 signal transduction |
| STAT3 | Transcription factor in the JAK/STAT arm | Links pathway to transcriptional regulation |
| MCPIP1/ZC3H12A | Endoribonuclease negative regulator | Restrains IL-17 signaling and inflammation |
| AHR | Aryl hydrocarbon receptor negative regulator | Dampens IL-17-mediated signaling in vitro |
| IRF3 | Modulator whose loss amplifies injury | Deficiency exacerbates IL-17-mediated liver injury |
| PLAU/uPA | Protease whose expression is inhibited by IL-17 | Readout of p38-dependent IL-17 signaling in myoblasts |
| NFKB1 | Transcription factor arm downstream of IL-17 | Contributes to inflammatory gene regulation |
| ATG5 | Autophagy machinery component | Linked to IL-17-mediated autophagy in osteoclast precursors |
| BECN1 | Autophagy regulator | Context for IL-17-mediated autophagy studies |
| CXCL1 | Chemokine output of IL-17 signaling | Inflammatory readout in target cells |
| IL6 | Cytokine output of IL-17 signaling | Inflammatory amplification readout |
| MMP9 | Matrix metalloproteinase output | Tissue-remodeling readout of IL-17 signaling |
| SOCS3 | Feedback inhibitor of cytokine signaling | Candidate negative feedback node in JAK/STAT arm |
How Is interleukin-17-mediated signaling pathway Regulated?
GO:0097400 is subject to both positive and negative regulation. MCPIP1 endoribonuclease activity negatively regulates interleukin-17-mediated signaling and inflammation, providing a post-transcriptional brake. The aryl hydrocarbon receptor acts as a novel negative regulator of IL-17-mediated signaling and inflammation in vitro. IRF3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury, indicating that IRF3 normally restrains the pathological output of this pathway. On the positive side, TRAF6/ERK/p38 signaling propagates the cascade toward autophagy and differentiation, and JAK/STAT involvement provides a kinase-dependent relay. Together, these findings define a pathway whose intensity is set by the balance between activating kinases and dedicated negative regulators.
interleukin-17-mediated signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IRF3 | Liver ischemia-reperfusion injury | IRF3 knockout hepatocyte or mouse model with IL-17 challenge |
| TRAF6 | Osteoclast differentiation and bone loss | TRAF6 knockout osteoclast precursor cells with IL-17 stimulation |
| MCPIP1/ZC3H12A | Inflammatory disease amplification | MCPIP1 knockout or catalytic-dead knock-in immune cells |
| AHR | Inflammation and barrier disease | AHR knockout epithelial or immune cells treated with IL-17 |
| PLAU/uPA | Muscle repair and cell migration | Myoblast lines with p38 inhibition or PLAU reporter |
IL-17 signaling in inflammatory tissue injury
Interferon regulatory factor 3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury, directly linking GO:0097400 to organ damage in a clinically relevant model. This suggests that patients or models with impaired IRF3 restraint may be more susceptible to IL-17-driven injury.
IL-17 signaling in bone and osteoclast biology
The TRAF6/ERK/p38 pathway is involved in interleukin-17-mediated autophagy to promote osteoclast precursor cell differentiation, connecting GO:0097400 to bone resorption and osteoimmunology. This provides a mechanistic basis for studying IL-17 in inflammatory bone loss.
IL-17 signaling in muscle and migration
IL-17 modulates myoblast cell migration by inhibiting urokinase-type plasminogen activator expression through p38 MAPK, indicating that GO:0097400 can influence tissue repair and cell motility programs. This broadens the disease relevance of the pathway beyond classical immune cells.
Negative regulators as disease modifiers
MCPIP1 and the aryl hydrocarbon receptor both negatively regulate IL-17-mediated signaling and inflammation, suggesting that their loss or dysfunction could amplify inflammatory disease. These regulators represent candidate disease-modifier genes for functional studies.
From interleukin-17-mediated signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is TRAF6 required for IL-17-mediated autophagy? | TRAF6 knockout osteoclast precursor cells |
| Does MCPIP1 endoribonuclease activity restrain IL-17 signaling? | MCPIP1 catalytic-dead point-mutation knock-in cells |
| Does JAK/STAT relay IL-17 receptor signals? | JAK1 or STAT3 knockout cells with IL-17 stimulation |
| Does AhR negatively regulate IL-17 signaling? | AHR overexpression and knockout cells |
| Does IRF3 loss amplify IL-17-mediated injury? | IRF3 knockout hepatocytes or in vivo injury model |
| Is p38 required for IL-17-mediated uPA inhibition? | p38 knockout or inhibitor-treated myoblasts |
How to Study the interleukin-17-mediated signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcriptional output of IL-17 signaling | Defining downstream gene programs |
| Phospho-Western blot | Activation of ERK, p38, STAT | Mapping kinase arms of the pathway |
| LC3 flux assay | Autophagic activity | IL-17-mediated autophagy in osteoclast precursors |
| Osteoclast differentiation assay | TRAP-positive multinucleated cells | Bone biology output of IL-17 signaling |
| Transwell migration assay | Cell motility | IL-17 effects on myoblast migration |
| qPCR for uPA/PLAU | Protease expression | p38-dependent IL-17 readout |
| Cytokine ELISA | Inflammatory protein secretion | MCPIP1 and AhR regulation studies |
| Liver injury histology | Tissue damage scoring | IRF3-dependent IL-17 injury model |
Transcriptomic profiling of IL-17 responses
RNA-seq after IL-17 stimulation can identify transcriptional outputs of GO:0097400 and quantify how knockout of TRAF6, MCPIP1, AhR, or IRF3 reshapes the response. This method is well suited to defining the endpoint of the pathway, which is regulation of downstream cellular processes such as transcription.
Kinase and phospho-signaling assays
Western blotting for phospho-ERK, phospho-p38, and phospho-STAT can resolve which kinase arms are engaged during IL-17-mediated signaling. These assays are typically paired with genetic loss-of-function to establish causality.
Autophagy and differentiation readouts
LC3 flux assays and osteoclast differentiation staining can measure the autophagic and differentiation outputs of IL-17 signaling in osteoclast precursors. Such readouts connect the molecular pathway to a defined cellular phenotype.
Migration and protease expression assays
Scratch-wound or transwell migration assays combined with uPA expression measurement can quantify the p38-dependent effects of IL-17 on myoblasts. These methods link GO:0097400 to cell motility and tissue remodeling.
How CRISPR Can Be Used to Study GO:0097400 interleukin-17-mediated signaling pathway
Knockout
CRISPR knockout of TRAF6, JAK1, STAT3, MCPIP1, AHR, or IRF3 allows researchers to test which components are required for IL-17-mediated signaling outputs such as autophagy, cytokine induction, or tissue injury. Knockout models are the most direct way to establish necessity within GO:0097400.
Point Mutation
Point-mutation knock-in of catalytic residues, such as those in MCPIP1 endoribonuclease, can separate enzymatic activity from scaffolding function in the regulation of IL-17 signaling. This approach is valuable when a total knockout is lethal or confounds interpretation.
Knock-in
Tagged knock-in of pathway components enables endogenous localization, interaction, and degradation studies without overexpression artifacts, supporting mechanistic dissection of GO:0097400. Knock-in reporters can also quantify pathway activity in real time.
Overexpression
Overexpression of negative regulators such as MCPIP1 or AHR can test whether increasing their dosage suppresses IL-17-mediated inflammation, providing gain-of-function evidence complementary to knockout studies. Overexpression of pathway activators can also sensitize cells to IL-17 stimulation.
How EDITGENE Supports interleukin-17-mediated signaling pathway Research
Researchers studying interleukin-17-mediated signaling pathway-related genes often need to determine whether a candidate gene is causally involved in signal transduction, inflammation, or tissue injury, rather than merely correlated with it. EDITGENE provides the CRISPR cell models and screening infrastructure required to move from correlation to causation across every node of GO:0097400.
Contact EDITGENE today to design your custom CRISPR model for interleukin-17-mediated signaling pathway research.
Frequently Asked Questions About interleukin-17-mediated signaling pathway
What is GO:0097400?
GO:0097400 is the Gene Ontology term for interleukin-17-mediated signaling pathway, defined as the series of molecular signals initiated by interleukin-17 binding to its receptor on the surface of a target cell, and ending with regulation of a downstream cellular process such as transcription.
What is the interleukin-17-mediated signaling pathway?
It is the intracellular cascade triggered when IL-17 binds its receptor, engaging modules such as JAK/STAT, TRAF6, ERK, and p38 MAPK to regulate transcription, autophagy, and cell behavior.
What genes are involved in interleukin-17-mediated signaling pathway?
Key genes include IL17A, IL17RA, TRAF6, MAPK1/ERK2, MAPK14/p38, JAK1, STAT3, MCPIP1/ZC3H12A, AHR, IRF3, and PLAU/uPA.
How is IL-17 signaling negatively regulated?
MCPIP1 endoribonuclease activity and the aryl hydrocarbon receptor both negatively regulate IL-17-mediated signaling and inflammation, while IRF3 deficiency amplifies injury.
Does IL-17 signaling involve JAK/STAT?
Yes, evidence supports involvement of the JAK/STAT pathway in the signaling mechanism of interleukin-17.
What role does p38 MAPK play in IL-17 signaling?
p38 MAPK is involved in IL-17-mediated autophagy in osteoclast precursors and in IL-17-mediated inhibition of urokinase-type plasminogen activator expression in myoblasts.
How can I study GO:0097400 in the lab?
Common approaches include RNA-seq, phospho-Western blotting, autophagy flux assays, migration assays, and CRISPR knockout or knock-in models of pathway components.
Which diseases are linked to IL-17-mediated signaling?
The pathway has been linked to liver ischemia-reperfusion injury, osteoclast differentiation and bone biology, and inflammatory tissue responses.
What CRISPR models are useful for IL-17 pathway research?
Knockout of TRAF6, JAK1, STAT3, MCPIP1, AHR, or IRF3, point-mutation knock-in of MCPIP1 catalytic residues, tagged knock-in of pathway components, and overexpression of negative regulators are all useful.
Why is GO:0097400 important for inflammation research?
It provides a standardized ontology framework for annotating how IL-17 drives inflammation, autophagy, and tissue injury, enabling reproducible comparison across studies and models.
Conclusion
GO:0097400, interleukin-17-mediated signaling pathway, is a well-defined biological process that connects IL-17 receptor engagement to transcriptional, autophagic, and migratory outputs through JAK/STAT, TRAF6, ERK, and p38 modules. Its activity is restrained by negative regulators including MCPIP1, AHR, and IRF3, and its dysregulation is linked to liver injury, osteoclast biology, and inflammation. CRISPR-based knockout, point-mutation, knock-in, and overexpression models are essential tools for establishing causal roles of individual pathway components. EDITGENE supports researchers with these models and with library screening and bioinformatics to accelerate discovery in IL-17 biology.
References
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- 2. Garg AV et al.. 2015. MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation.. Immunity 43(3):475-87 PMID: 26320658
- 3. Subramaniam SV et al.. 1999. Evidence for the involvement of JAK/STAT pathway in the signaling mechanism of interleukin-17.. Biochem Biophys Res Commun 262(1):14-9 PMID: 10448060
- 4. Li H et al.. 2019. The aryl hydrocarbon receptor is a novel negative regulator of interleukin-17-mediated signaling and inflammation in vitro.. FEBS Lett 593(9):952-961 PMID: 30953345
- 5. Loi P et al.. 2013. Interferon regulatory factor 3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury.. Hepatology 57(1):351-61 PMID: 22911673
- 6. Kocić J et al.. 2013. Interleukin-17 modulates myoblast cell migration by inhibiting urokinase type plasminogen activator expression through p38 mitogen-activated protein kinase.. Int J Biochem Cell Biol 45(2):464-75 PMID: 23183001
