GO:0070429 negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0070429 describes any process that stops, prevents, or reduces the frequency, rate, or extent of NOD1 signaling, a key innate immune pathway that senses bacterial peptidoglycan fragments.
• NOD1 signaling is negatively regulated at multiple levels, including ubiquitination and degradation of pathway components, microRNA-mediated suppression, and crosstalk with other inflammatory pathways.
• Dysregulation of NOD1 negative regulation contributes to inflammatory diseases, including gastric injury, small intestinal damage, and asthma.
• Key negative regulators include PPARγ-regulated miR-125a, which directly targets NOD1 to inhibit angiogenesis, and ubiquitin-editing enzymes that modulate NOD1 protein stability.
• Loss of NOD1 and NOD2 alters T cell survival and activation-induced cell death, highlighting the importance of negative regulation in adaptive immunity.
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) are essential to dissect the causal roles of negative regulators in NOD1 signaling.
Description
The nucleotide-binding oligomerization domain containing 1 (NOD1) signaling pathway is a critical component of innate immunity that detects bacterial peptidoglycan fragments, particularly meso-diaminopimelic acid, leading to NF-κB activation and pro-inflammatory cytokine production. To prevent excessive inflammation and tissue damage, this pathway is tightly controlled by negative regulatory mechanisms collectively classified under GO:0070429, negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway. This GO term encompasses any process that stops, prevents, or reduces the frequency, rate, or extent of NOD1 signaling. Understanding these negative regulatory mechanisms is essential for researchers studying inflammatory diseases, host-pathogen interactions, and immune homeostasis. Recent studies have identified diverse negative regulators, including ubiquitin-modifying enzymes, microRNAs, and nuclear receptors, that fine-tune NOD1 activity. Dysregulation of these negative regulators can lead to chronic inflammation, autoimmune conditions, and impaired pathogen clearance, making GO:0070429 a focal point for therapeutic intervention.
negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway At A Glance
| GO ID | GO:0070429 |
|---|---|
| GO term | negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway |
| Ontology | biological_process |
| Synonym | negative regulation of NOD1 signaling pathway; negative regulation of nucleotide-binding oligomerization domain containing 1 signalling pathway |
| Major function | Suppression or attenuation of NOD1-mediated innate immune signaling to prevent excessive inflammation |
| Key negative regulators | Ubiquitin-editing enzymes, PPARγ-regulated miR-125a, and other modulators |
| Associated diseases | Gastric injury, small intestinal damage, asthma, and inflammatory disorders |
| Research methods | CRISPR knockout, point mutation, knock-in, overexpression, RNA-seq, proteomics, and imaging |
What Is GO:0070429?
GO:0070429 is a biological process term defined as any process that stops, prevents, or reduces the frequency, rate, or extent of the nucleotide-binding oligomerization domain containing 1 (NOD1) signaling pathway. In simpler terms, it covers all molecular and cellular events that put the brakes on NOD1-mediated immune signaling, ensuring that inflammatory responses are appropriately controlled and terminated.
Why Is negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway Important in Cell Biology?
Negative regulation of NOD1 signaling is vital for maintaining immune homeostasis and preventing inflammatory pathology. Without proper control, NOD1 activation can lead to chronic inflammation, tissue damage, and autoimmune responses. Understanding GO:0070429 provides insights into how the body balances effective pathogen defense with tolerance to commensal microbiota, and it offers therapeutic targets for inflammatory diseases such as asthma, gastric injury, and inflammatory bowel disease.
• Prevents excessive inflammation by terminating NOD1-mediated NF-κB activation.
• Protects against tissue damage in the gastrointestinal tract, as shown in models of gastric injury and NSAID-induced small intestinal damage.
• Modulates angiogenesis through PPARγ-regulated miR-125a targeting of NOD1.
• Influences T cell survival and activation-induced cell death, linking innate and adaptive immunity.
• Dysregulation is implicated in asthma pathogenesis via PI3K-induced NLRP3 inflammasome activation.
• Provides potential therapeutic targets for inflammatory diseases and cancer.
• Helps maintain tolerance to commensal microbiota.
• Serves as a model for understanding crosstalk between NOD1 and other inflammasome pathways.
• Critical for designing CRISPR-based therapies that modulate immune signaling.
• Enables precise dissection of gene function through knockout and knock-in models.
What Happens During negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway?
Initiation of NOD1 signaling and the need for negative regulation
In simple terms: When NOD1 detects bacterial fragments, it starts an inflammatory alarm; negative regulation ensures the alarm is turned off.
NOD1 recognizes bacterial peptidoglycan fragments, leading to its oligomerization and recruitment of the adaptor protein RIP2, which activates NF-κB and MAPK pathways. This response must be tightly controlled to avoid collateral tissue damage. Negative regulation begins as soon as NOD1 is activated, involving mechanisms that either degrade NOD1 or block its downstream signaling.
Ubiquitin-mediated degradation of NOD1
In simple terms: Tagging NOD1 with ubiquitin marks it for destruction, stopping the signal.
Ubiquitination plays a central role in negative regulation of NOD1 signaling. Specific E3 ubiquitin ligases attach ubiquitin chains to NOD1 or its signaling partners, targeting them for proteasomal degradation. This process reduces the availability of NOD1 for further signaling and is essential for preventing sustained inflammation.
MicroRNA-mediated suppression of NOD1 expression
In simple terms: Small RNA molecules can block the production of NOD1 protein, reducing the pathway's activity.
MicroRNAs such as miR-125a, which is regulated by PPARγ, directly target NOD1 mRNA to suppress its expression. This negative regulation inhibits NOD1-mediated angiogenesis and inflammatory responses, demonstrating a layer of post-transcriptional control.
Crosstalk with other inflammatory pathways
In simple terms: Other inflammation pathways can interfere with NOD1 signaling to keep it in check.
Negative regulation of NOD1 signaling also occurs through crosstalk with other pathways. For example, NLRP3 inflammasome activation can be modulated by glucose and hypoxia, indirectly affecting NOD1-mediated responses. Additionally, triiodothyronine alleviates alcoholic liver injury through negative regulation of NLRP3, suggesting broader interconnected regulatory networks.
Role of negative regulators in immune cell survival
In simple terms: Proper control of NOD1 signaling affects whether immune cells live or die.
Lack of both NOD1 and NOD2 primes T cells for activation-induced cell death, indicating that negative regulation of NOD1 is critical for T cell survival and immune homeostasis. This highlights the importance of balanced NOD1 signaling in adaptive immunity.
Key Genes Involved in GO:0070429 negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway
The following genes and proteins are central to the negative regulation of NOD1 signaling, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| NOD1 | Intracellular sensor of bacterial peptidoglycan; target of negative regulation | Core pathway component; knockout models reveal its role in inflammation |
| RIP2 | Adaptor kinase downstream of NOD1; ubiquitinated for degradation | Key node for negative regulation by ubiquitin editing |
| PPARγ | Nuclear receptor that regulates miR-125a expression | Controls negative regulation of NOD1-mediated angiogenesis |
| miR-125a | MicroRNA targeting NOD1 mRNA | Direct negative regulator; potential therapeutic target |
| NLRP3 | Inflammasome component with crosstalk to NOD1 | Modulated by glucose and hypoxia; linked to gastric injury |
| GLCCI1 | Inhibitor of PI3K-induced NLRP3 inflammasome activation | Role in asthma; potential crosstalk with NOD1 |
| NOD2 | Related sensor with overlapping functions | Co-deletion with NOD1 affects T cell survival |
| Ubiquitin | Post-translational modifier tagging NOD1/RIP2 | Central to negative regulation via proteasomal degradation |
| T3 (Triiodothyronine) | Hormone that negatively regulates NLRP3 | Indirect modulator of inflammatory pathways |
| Caspase-1 | Effector of inflammasome; modulated by NOD1 crosstalk | Linked to IL-1β processing in inflammation |
| NF-κB | Transcription factor activated by NOD1 | Readout of NOD1 pathway activity |
| MAPK | Signaling cascade activated by NOD1 | Contributes to inflammatory gene expression |
| IL-1β | Pro-inflammatory cytokine downstream of NOD1/NLRP3 | Marker of pathway activation |
| IL-18 | Cytokine processed by inflammasome | Indicator of inflammatory responses |
| PI3K | Kinase involved in NLRP3 activation; inhibited by GLCCI1 | Crosstalk with NOD1 in asthma |
| ATG16L1 | Autophagy-related protein; potential negative regulator | Implicated in inflammatory bowel disease |
| XBP1 | Transcription factor in ER stress; modulates inflammation | Potential crosstalk with NOD1 |
| TNF-α | Pro-inflammatory cytokine | Readout of NOD1 pathway activation |
How Is negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway Regulated?
Negative regulation of NOD1 signaling is itself regulated at multiple levels. PPARγ controls the expression of miR-125a, which in turn suppresses NOD1. Ubiquitin-editing enzymes are regulated by cellular stress and immune signals, affecting NOD1 stability. Additionally, metabolic factors such as glucose and hypoxia modulate NLRP3 inflammasome activation, which can indirectly influence NOD1 signaling. Hormonal signals like triiodothyronine also impact inflammatory pathways, suggesting endocrine regulation of NOD1 negative feedback.
negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| NOD1 | Gastric injury, small intestinal damage | NOD1 knockout mice treated with NSAIDs |
| NLRP3 | Asthma, gastric injury | NLRP3 knockout or overexpression in airway epithelial cells |
| GLCCI1 | Asthma | GLCCI1 knockout or overexpression in lung cells |
| PPARγ | Angiogenesis, inflammation | PPARγ knockout or agonist treatment in endothelial cells |
| NOD2 | T cell survival | NOD1/NOD2 double knockout T cells |
Gastric injury and gastrointestinal inflammation
Dysregulation of NOD1 negative regulation contributes to stress-induced gastric injury and NSAID-induced small intestinal damage. Microbiota plays a key role in these processes, and NLRP3 inflammasome activation is involved. Impaired negative regulation can lead to excessive inflammation and tissue damage.
Asthma and airway inflammation
In asthma, GLCCI1 inhibits PI3K-induced NLRP3 inflammasome activation, suggesting that negative regulation of related pathways is protective. NOD1 signaling crosstalk may exacerbate airway inflammation when negative regulation fails.
Alcoholic liver disease
Triiodothyronine alleviates alcoholic liver injury through negative regulation of the NLRP3 signaling pathway, indicating that hormonal modulation of inflammatory pathways can be therapeutic. NOD1 negative regulation may similarly impact liver inflammation.
T cell-mediated immune disorders
Lack of both NOD1 and NOD2 primes T cells for activation-induced cell death, highlighting the importance of negative regulation in preventing inappropriate T cell apoptosis and maintaining immune tolerance.
From negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a candidate negative regulator increase NOD1 signaling? | CRISPR knockout of the regulator in macrophages or epithelial cells |
| Does a specific point mutation in NOD1 affect its ubiquitination? | Point mutation knock-in of NOD1 at ubiquitination sites |
| Does overexpression of miR-125a suppress NOD1-mediated angiogenesis? | Overexpression of miR-125a in endothelial cells |
| Does tagging NOD1 with a fluorescent protein alter its localization? | Knock-in of tagged NOD1 |
| Does PPARγ regulate miR-125a promoter activity? | Knock-in of reporter gene under miR-125a promoter |
| Does GLCCI1 inhibit PI3K-induced NLRP3 activation? | Overexpression or knockout of GLCCI1 in asthma models |
How to Study the negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screen | Loss-of-function effects on NOD1 signaling | Identify novel negative regulators |
| RNA-seq | Transcriptional changes | Map feedback loops and microRNA targets |
| Proteomics | Protein abundance and ubiquitination | Detect NOD1 degradation and modifications |
| NF-κB luciferase reporter | NF-κB activity | Quantify NOD1 pathway activation |
| Western blot | Protein levels of NOD1, RIP2, etc. | Validate knockout or overexpression |
| qPCR | mRNA levels of NOD1 and cytokines | Measure negative regulation at transcript level |
| Immunofluorescence | Subcellular localization | Visualize NOD1 trafficking |
| ELISA | Cytokine secretion (IL-1β, TNF-α) | Functional readout of pathway activity |
CRISPR-based genetic screens
Genome-wide CRISPR knockout or activation screens can identify novel negative regulators of NOD1 signaling. Cells are stimulated with NOD1 ligands, and readouts such as NF-κB reporter activity or cytokine production are measured to pinpoint regulators.
RNA sequencing and transcriptomics
RNA-seq after NOD1 activation and negative regulator perturbation reveals transcriptional changes, including feedback loops and microRNA targets. This helps map the regulatory network of GO:0070429.
Proteomics and ubiquitin analysis
Mass spectrometry-based proteomics can identify ubiquitination sites on NOD1 and its partners, and quantify protein stability changes upon negative regulator knockout.
Imaging and reporter assays
Fluorescent tagging of NOD1 or NF-κB reporters allows live-cell imaging of pathway dynamics and the impact of negative regulators on signaling kinetics.
How CRISPR Can Be Used to Study GO:0070429 negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway
Knockout
CRISPR knockout of candidate negative regulators (e.g., PPARγ, GLCCI1) in cell lines or primary cells can reveal their role in suppressing NOD1 signaling. Loss of function typically leads to enhanced NF-κB activation and cytokine production upon NOD1 stimulation.
Point Mutation
Introducing point mutations in NOD1 at ubiquitination sites or in regulatory domains can prevent negative regulation, causing constitutive signaling. This helps map precise residues required for negative regulation.
Knock-in
Knock-in of tagged NOD1 (e.g., GFP or HA) allows tracking of protein localization and stability. Knock-in of reporter genes under negative regulator promoters enables real-time monitoring of their expression.
Overexpression
Overexpression of negative regulators such as miR-125a or GLCCI1 can suppress NOD1 signaling and reduce inflammation. This approach validates sufficiency of a regulator in inhibiting the pathway.
How EDITGENE Supports negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway Research
Researchers studying negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway-related genes often need to determine whether a candidate gene is causally involved in suppressing NOD1 signaling or is merely correlated with it. EDITGENE provides the precise CRISPR tools and services to establish causality, from knockout to knock-in models, enabling rigorous dissection of this critical immune regulatory pathway.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway research.
Frequently Asked Questions About negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway
What is GO:0070429?
GO:0070429 is a Gene Ontology term for any process that stops, prevents, or reduces the frequency, rate, or extent of the NOD1 signaling pathway, a key innate immune response to bacterial fragments.
What genes are involved in negative regulation of NOD1 signaling?
Key genes include NOD1 itself, RIP2, PPARγ, miR-125a, GLCCI1, and ubiquitin-editing enzymes that target pathway components for degradation.
How is NOD1 signaling negatively regulated?
Negative regulation occurs through ubiquitin-mediated degradation of NOD1/RIP2, microRNA suppression of NOD1 expression, and crosstalk with other inflammatory pathways.
What diseases are linked to defective negative regulation of NOD1?
Defective negative regulation is associated with gastric injury, NSAID-induced small intestinal damage, asthma, and alcoholic liver disease.
What is the role of miR-125a in NOD1 signaling?
miR-125a, regulated by PPARγ, directly targets NOD1 mRNA to suppress its expression and inhibit NOD1-mediated angiogenesis.
How does ubiquitination control NOD1 signaling?
Ubiquitin chains attached to NOD1 or RIP2 mark them for proteasomal degradation, thereby terminating the signaling cascade.
Can CRISPR be used to study negative regulation of NOD1?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are powerful tools to dissect the function of negative regulators in NOD1 signaling.
What is the connection between NOD1 and NLRP3?
NOD1 and NLRP3 are both innate immune sensors; crosstalk exists, and factors like glucose and hypoxia can modulate NLRP3, indirectly affecting NOD1 responses.
Why is negative regulation of NOD1 important for T cells?
Lack of NOD1 and NOD2 primes T cells for activation-induced cell death, showing that negative regulation is crucial for T cell survival and immune homeostasis.
What experimental models are used to study GO:0070429?
Common models include CRISPR knockout mice or cell lines, overexpression of microRNAs, and reporter assays to measure NF-κB activity.
Conclusion
GO:0070429, negative regulation of NOD1 signaling, is a critical biological process that safeguards against excessive inflammation and tissue damage. Through mechanisms such as ubiquitination, microRNA suppression, and pathway crosstalk, cells finely tune NOD1 activity to balance effective immunity with tolerance. Dysregulation of this process is implicated in gastrointestinal, respiratory, and hepatic diseases, making it a promising therapeutic target. CRISPR-based models and advanced omics technologies are indispensable for unraveling the complex regulatory networks and for developing targeted interventions.
References
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- 2. Kasimsetty SG et al.. 2017. Lack of Both Nucleotide-Binding Oligomerization Domain-Containing Proteins 1 and 2 Primes T Cells for Activation-Induced Cell Death.. J Immunol 199(3):1196-1205 PMID: 28652394
- 3. Ver Heul AM et al.. 2013. Ubiquitin regulates caspase recruitment domain-mediated signaling by nucleotide-binding oligomerization domain-containing proteins NOD1 and NOD2.. J Biol Chem 288(10):6890-902 PMID: 23300079
- 4. Otani K et al.. 2017. Microbiota Plays a Key Role in Non-Steroidal Anti-Inflammatory Drug-Induced Small Intestinal Damage.. Digestion 95(1):22-28 PMID: 28052268
- 5. Kang H et al.. 2017. Negative regulation of NOD1 mediated angiogenesis by PPARγ-regulated miR-125a.. Biochem Biophys Res Commun 482(1):28-34 PMID: 27836539
- 6. Watanabe S et al.. 2020. Glucose regulates hypoxia-induced NLRP3 inflammasome activation in macrophages.. J Cell Physiol 235(10):7554-7566 PMID: 32115713
- 7. Dong X et al.. 2018. Triiodothyronine alleviates alcoholic liver disease injury through the negative regulation of the NLRP3 signaling pathway.. Exp Ther Med 16(3):1866-1872 PMID: 30186412
- 8. Zhang Y et al.. 2024. Role of GLCCI1 in inhibiting PI3K-induced NLRP3 inflammasome activation in asthma.. Chin Med J Pulm Crit Care Med 2(4):279-288 PMID: 39834584
