GO:0140896 cGAS/STING signaling pathway: Innate Immune DNA Sensing, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0140896 (cGAS/STING signaling pathway) is the biological process in which cytosolic cGAS binds double-stranded DNA or RNA from another organism and produces the second messenger cGAMP, which activates STING to trigger innate immune responses.
• The pathway is a central node in antimicrobial defense, antitumor immunity, autoinflammation, and tissue injury, and is therefore a high-value target for mechanistic and therapeutic research.
• Core signaling proceeds through cGAS activation, cGAMP synthesis, STING activation at the ER-Golgi interface, TBK1/IRF3 phosphorylation, and NF-kB-dependent gene expression.
• The pathway is tightly regulated by ubiquitination-directed degradation of cytosolic DNA, mitochondrial quality control, and metabolic cues such as aspartate availability.
• Dysregulated cGAS/STING signaling contributes to liver fibrosis, sepsis-associated encephalopathy, diabetes-related atrial fibrillation, influenza spillover, and multiple urogenital cancers.
• CRISPR knockout, point-mutation, knock-in, and overexpression cell models are essential tools for dissecting causal gene contributions within this pathway.
Description
The cGAS/STING signaling pathway (GO:0140896) is a cytosolic innate immune sensing cascade that detects double-stranded DNA or RNA from another organism and converts that detection event into a transcriptional immune response. The sensor cyclic GMP-AMP synthase (cGAS) binds foreign nucleic acid and synthesizes the second messenger cyclic GMP-AMP (cGAMP), which activates the endoplasmic reticulum adaptor STING to initiate downstream signaling. This process is a biological_process ontology term that captures the entire sequence of molecular signals from ligand binding to innate immune activation. Researchers study GO:0140896 because it sits at the intersection of host defense, cancer immunology, autoinflammation, and metabolic disease. The pathway is now recognized as a major determinant of antitumor immunity and a driver of tissue pathology when chronically activated. In parallel, its role in viral spillover barriers and in sepsis-associated neuroinflammation has expanded the clinical relevance of this GO term. Understanding the precise molecular steps, regulatory checkpoints, and disease contexts of cGAS/STING signaling is therefore essential for both basic immunology and translational medicine.
cGAS/STING signaling pathway At A Glance
| GO ID | GO:0140896 |
|---|---|
| GO term | cGAS/STING signaling pathway |
| Ontology | biological_process |
| Synonym | None listed in QuickGO |
| Major function | Innate immune sensing of cytosolic double-stranded DNA or RNA from another organism via cGAS, cGAMP production, and STING activation |
| Key sensor | Cyclic GMP-AMP synthase (cGAS) |
| Key adaptor | STING |
| Second messenger | cGAMP |
| Downstream effectors | TBK1, IRF3, NF-kB |
What Is GO:0140896?
GO:0140896, cGAS/STING signaling pathway, is defined as the series of molecular signals initiated by the binding of a double-stranded DNA or RNA from another organism to cytosolic cyclic GMP-AMP (cGAMP) synthase (cGAS) that activates innate immune responses through production of the second messenger cGAMP, which activates the adaptor STING. In other words, it is the complete signaling route from cytosolic foreign nucleic acid recognition by cGAS to STING-dependent innate immune gene expression.
Why Is cGAS/STING signaling pathway Important in Cell Biology?
The cGAS/STING signaling pathway is important because it is a primary innate immune mechanism for detecting foreign nucleic acids and for coupling that detection to interferon and NF-kB-dependent immune programs. Its dysregulation is implicated in infectious disease, cancer, autoinflammation, metabolic liver disease, cardiac arrhythmia, and neuroinflammation, making it a central research axis in immunology and medicine.
• Provides cytosolic surveillance of double-stranded DNA or RNA from another organism and initiates innate immune responses.
• Drives antitumor immunity and is a focus of cancer immunotherapy research.
• Contributes to metabolic dysfunction-associated steatotic liver disease and liver fibrosis.
• Builds an influenza spillover barrier through STING-NF-kB signaling.
• Is linked to diabetes-related atrial fibrillation via mitochondrial quality control and cardiomyocyte-macrophage crosstalk.
• Mediates microglia pyroptosis in sepsis-associated encephalopathy.
• Is regulated by ubiquitination-directed cytosolic DNA degradation after DNA damage.
• Is modulated by metabolic status, including aspartate deficiency.
• Represents a therapeutic target across urogenital oncology.
• Requires precise experimental models to separate causal genes from correlative changes.
What Happens During cGAS/STING signaling pathway?
Recognition of cytosolic double-stranded DNA or RNA from another organism
In simple terms: The pathway starts when cGAS finds foreign DNA or RNA floating in the cell cytosol.
The cGAS/STING signaling pathway is initiated by the binding of double-stranded DNA or RNA from another organism to cytosolic cGAS. This recognition event is the defining trigger of GO:0140896 and distinguishes it from other innate immune sensing routes.
cGAMP synthesis and STING activation
In simple terms: After binding DNA or RNA, cGAS makes a small messenger molecule called cGAMP that switches on STING.
Activated cGAS produces the second messenger cGAMP, which then activates the adaptor STING. STING activation is the central relay step that converts cytosolic nucleic acid detection into downstream signaling.
TBK1-IRF3 and NF-kB downstream signaling
In simple terms: STING turns on kinases and transcription factors that switch on immune genes.
STING activation leads to downstream innate immune responses, including TBK1-IRF3 and NF-kB signaling. STING-NF-kB signaling specifically has been shown to build an influenza spillover barrier.
Regulation by cytosolic DNA degradation and ubiquitination
In simple terms: The cell can shut down the pathway by destroying the DNA that started it.
Ubiquitination-directed cytosolic DNA degradation governs cGAS-STING-mediated immune responses to DNA damage. This regulatory layer prevents excessive or prolonged pathway activation.
Metabolic and mitochondrial control of pathway intensity
In simple terms: The cell's metabolic state and mitochondrial health tune how strongly the pathway fires.
Impairment of mitochondrial quality control exacerbates diabetes-related atrial fibrillation through cGAS-STING signaling and cardiomyocyte-macrophage crosstalk. Aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity, showing that metabolic cues directly modulate this pathway.
Key Genes Involved in GO:0140896 cGAS/STING signaling pathway
The following genes and proteins are core components or regulators of GO:0140896 and are commonly studied in mechanistic and translational research.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CGAS | Cytosolic sensor that binds double-stranded DNA or RNA from another organism and synthesizes cGAMP | Central initiator of GO:0140896; target for knockout and point-mutation studies |
| STING1 | Adaptor activated by cGAMP that relays signaling to downstream effectors | Key node for STING-NF-kB signaling and influenza spillover barrier research |
| TBK1 | Kinase downstream of STING that contributes to IRF3 activation | Effector kinase for pathway activation assays |
| IRF3 | Transcription factor activated downstream of STING-TBK1 signaling | Readout of interferon-related innate immune activation |
| NFKB1 | Transcription factor contributing to STING-dependent inflammatory gene expression | Relevant to STING-NF-kB signaling and spillover barrier studies |
| TRIM family E3 ligases | Mediate ubiquitination-directed cytosolic DNA degradation | Regulators of cGAS-STING-mediated immune response to DNA damage |
| Mitochondrial quality control genes | Maintain mitochondrial homeostasis that restrains cGAS-STING signaling | Implicated in diabetes-related atrial fibrillation models |
| Aspartate metabolism genes | Modulate cGAS-STING signaling intensity | Relevant to antitumor immunity and metabolic intervention studies |
| cGAS-STING pathway genes in urogenital oncology | Regulate response and resistance in urogenital cancers | Targets for resistance and response studies |
| Microglia pyroptosis genes | Mediate sepsis-associated encephalopathy downstream of cGAS-STING | Relevant to neuroinflammation models |
| Liver fibrosis pathway genes | Contribute to MASLD and liver fibrosis through cGAS-STING | Targets for metabolic liver disease research |
| Influenza restriction genes | Participate in STING-NF-kB-dependent spillover barrier | Relevant to antiviral barrier studies |
| DNA damage response genes | Link DNA damage to cGAS-STING activation | Used to study immune response to genomic stress |
| Cardiomyocyte-macrophage crosstalk genes | Mediate cGAS-STING effects in atrial fibrillation | Relevant to cardiac inflammation models |
| Tumor immunity genes | Modulate antitumor immunity via cGAS-STING | Targets for immuno-oncology studies |
| Sepsis-associated neuroinflammation genes | Drive microglia pyroptosis through cGAS-STING | Relevant to sepsis-associated encephalopathy models |
How Is cGAS/STING signaling pathway Regulated?
The cGAS/STING signaling pathway is regulated at multiple levels. Ubiquitination-directed cytosolic DNA degradation controls the availability of the triggering ligand and thereby governs cGAS-STING-mediated immune responses to DNA damage. Mitochondrial quality control influences pathway intensity, as its impairment exacerbates diabetes-related atrial fibrillation through cGAS-STING signaling and cardiomyocyte-macrophage crosstalk. Metabolic status also regulates the pathway, since aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity. In addition, STING-NF-kB signaling is a regulated output arm that builds an influenza spillover barrier. Together, these mechanisms ensure that GO:0140896 is tightly controlled in time and magnitude.
cGAS/STING signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CGAS | Antitumor immunity and DNA sensing | Knockout and point-mutation cell models |
| STING1 | Influenza spillover barrier and innate immune signaling | Knock-in and tagged knock-in models |
| cGAS-STING pathway genes | MASLD and liver fibrosis | Overexpression and knockout hepatocyte models |
| Mitochondrial quality control genes | Diabetes-related atrial fibrillation | Knockout cardiomyocyte-macrophage co-culture models |
| Microglia pyroptosis genes | Sepsis-associated encephalopathy | Pharmacological inhibition and knockout microglia models |
cGAS/STING signaling in metabolic liver disease and fibrosis
The cGAS-STING signaling pathway is implicated in metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis. Research in this area focuses on how chronic pathway activation contributes to hepatic inflammation and fibrotic remodeling.
cGAS/STING signaling in cancer and antitumor immunity
cGAS-STING signaling is a key determinant of antitumor immunity, and aspartate deficiency amplifies this pathway to enhance immune responses. In urogenital oncology, the pathway is studied in terms of regulation, resistance, and routes to response. These findings position GO:0140896 as a therapeutic axis in immuno-oncology.
cGAS/STING signaling in infection and neuroinflammation
STING-NF-kB signaling builds an influenza spillover barrier, linking the pathway to antiviral defense. In sepsis-associated encephalopathy, pharmacological inhibition of the cGAS-STING pathway suppresses microglia pyroptosis, indicating a pathogenic role for pathway overactivation.
cGAS/STING signaling in cardiac and metabolic complications
Impairment of mitochondrial quality control exacerbates diabetes-related atrial fibrillation by cGAS-STING signaling and cardiomyocyte-macrophage crosstalk. This connects GO:0140896 to cardiac arrhythmia mechanisms in the setting of diabetes.
From cGAS/STING signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is CGAS required for cytosolic DNA sensing? | CGAS knockout cell line |
| Does a specific STING1 variant alter downstream NF-kB signaling? | STING1 point-mutation knock-in |
| How does tagged STING behave at the ER-Golgi interface? | Tagged knock-in of STING1 |
| Does overexpression of a candidate regulator amplify cGAS-STING signaling? | Overexpression cell model |
| Which E3 ligases control cytosolic DNA degradation? | Knockout of TRIM family E3 ligases |
| Does metabolic perturbation alter pathway output? | Aspartate-deficient or mitochondrial quality control knockout models |
How to Study the cGAS/STING signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global transcriptional changes downstream of cGAS-STING | Innate immune gene expression profiling |
| Ubiquitination assay | Ubiquitination-directed cytosolic DNA degradation | Identifying regulators of cGAS-STING signaling |
| Metabolic profiling | Aspartate and related metabolic status | Studying metabolic amplification of antitumor immunity |
| Mitochondrial function assay | Mitochondrial quality control | Diabetes-related atrial fibrillation models |
| Pharmacological inhibition | Pathway activity suppression | Sepsis-associated encephalopathy studies |
| Cytokine profiling | NF-kB-dependent output | Influenza spillover barrier research |
| Immunofluorescence imaging | STING localization and activation | ER-Golgi trafficking studies |
| Proteomics | Protein interactions and modifications | Pathway regulator discovery |
Transcriptional and cytokine readouts of pathway activation
Because cGAS/STING signaling converges on TBK1-IRF3 and NF-kB-dependent gene expression, RNA-seq and targeted gene expression assays are used to measure innate immune activation. These readouts help distinguish pathway-specific effects in disease models such as influenza spillover barrier studies.
Protein interaction and ubiquitination assays
Ubiquitination-directed cytosolic DNA degradation is a key regulatory mechanism, so ubiquitination assays and proteomic approaches are used to identify regulators of cGAS-STING-mediated immune responses. Such methods can reveal E3 ligases and degradation machinery that control pathway intensity.
Metabolic and mitochondrial functional assays
Mitochondrial quality control and aspartate metabolism modulate cGAS-STING signaling, so metabolic profiling and mitochondrial function assays are used to study pathway regulation. These approaches are particularly relevant in diabetes-related atrial fibrillation and antitumor immunity models.
Pharmacological inhibition and neuroinflammation models
Pharmacological inhibition of the cGAS-STING pathway suppresses microglia pyroptosis in sepsis-associated encephalopathy, making inhibitor studies and neuroinflammation models valuable for validating pathway contributions. Such experiments link GO:0140896 to neuroinflammatory disease mechanisms.
How CRISPR Can Be Used to Study GO:0140896 cGAS/STING signaling pathway
Knockout
CRISPR knockout of CGAS or STING1 is used to test whether the cGAS/STING signaling pathway is required for a given innate immune response. Knockout of regulatory genes such as E3 ligases can reveal their role in ubiquitination-directed cytosolic DNA degradation. In disease models, knockout approaches help establish causality for pathway contributions to liver fibrosis or neuroinflammation.
Point Mutation
Point-mutation models are used to dissect specific residues required for cGAS activation, cGAMP synthesis, or STING downstream signaling. Such models can separate DNA-binding functions from catalytic functions within GO:0140896. They are also useful for studying STING-NF-kB signaling specificity.
Knock-in
Knock-in of tagged STING1 or CGAS allows tracking of protein localization and interaction dynamics during pathway activation. Knock-in models can also introduce disease-associated variants to test their impact on innate immune signaling. These models are valuable for linking genotype to pathway output in urogenital oncology research.
Overexpression
Overexpression of candidate regulators is used to test whether increased protein levels amplify cGAS-STING signaling. This approach is particularly relevant for metabolic regulators such as aspartate metabolism genes that modulate antitumor immunity. Overexpression models also help identify rate-limiting components of the pathway.
How EDITGENE Supports cGAS/STING signaling pathway Research
Researchers studying cGAS/STING signaling pathway-related genes often need to determine whether a candidate gene is causally involved in innate immune sensing, downstream NF-kB activation, or disease-associated pathway dysregulation. Establishing causality requires precise genetic models that can isolate the contribution of individual genes within GO:0140896.
Contact EDITGENE today to design your custom CRISPR model for cGAS/STING signaling pathway research.
Frequently Asked Questions About cGAS/STING signaling pathway
What is the cGAS/STING signaling pathway?
It is the biological process GO:0140896 in which cytosolic cGAS binds double-stranded DNA or RNA from another organism, produces cGAMP, and activates STING to trigger innate immune responses.
What genes are involved in cGAS/STING signaling pathway?
Core genes include CGAS, STING1, TBK1, IRF3, and NFKB1, along with regulators such as E3 ligases involved in cytosolic DNA degradation.
What does GO:0140896 mean?
GO:0140896 is the Gene Ontology identifier for the cGAS/STING signaling pathway, a biological_process term describing innate immune sensing of foreign cytosolic nucleic acids.
How is cGAS/STING signaling regulated?
It is regulated by ubiquitination-directed cytosolic DNA degradation, mitochondrial quality control, and metabolic cues such as aspartate availability.
What diseases are linked to cGAS/STING signaling?
It is linked to MASLD and liver fibrosis, urogenital cancers, influenza spillover, diabetes-related atrial fibrillation, and sepsis-associated encephalopathy.
Why is cGAS/STING signaling important for antitumor immunity?
Aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity, and the pathway is a focus of cancer immunotherapy research.
How do researchers study cGAS/STING signaling?
They use RNA-seq, ubiquitination assays, metabolic profiling, mitochondrial function assays, pharmacological inhibition, and CRISPR models.
What CRISPR models are used for cGAS/STING research?
Knockout, point-mutation, knock-in, tagged knock-in, and overexpression cell models are used to dissect pathway gene function.
Is cGAS/STING signaling involved in neuroinflammation?
Yes, pharmacological inhibition of the cGAS-STING pathway suppresses microglia pyroptosis in sepsis-associated encephalopathy.
What is the role of STING-NF-kB signaling?
STING-NF-kB signaling builds an influenza spillover barrier and contributes to downstream innate immune gene expression.
Conclusion
GO:0140896, the cGAS/STING signaling pathway, is a central innate immune sensing cascade that converts cytosolic detection of foreign double-stranded DNA or RNA into cGAMP production, STING activation, and downstream TBK1-IRF3 and NF-kB responses. Its regulation by ubiquitination-directed DNA degradation, mitochondrial quality control, and metabolic status determines whether the pathway protects the host or drives pathology. Disease links span liver fibrosis, urogenital cancers, influenza spillover, diabetes-related atrial fibrillation, and sepsis-associated encephalopathy. Precise CRISPR models are essential for establishing causal gene contributions within this pathway.
References
- 1. Hooftman A et al.. 2026. The cGAS-STING pathway: Mechanism and medical implications.. Cell 189(13):3849-3870 PMID: 42349382
- 2. Xiao Y et al.. 2026. cGAS-STING signaling pathway in MASLD and liver fibrosis.. J Mol Med (Berl) 104(1):29 PMID: 41540282
- 3. Ye R et al.. 2026. STING-NF-κB signaling builds an influenza spillover barrier.. Science 391(6788):eads4405 PMID: 41747053
- 4. Li L et al.. 2026. Ubiquitination-directed cytosolic DNA degradation governs cGAS-STING-mediated immune response to DNA damage.. Cancer Cell 44(2):306-320.e7 PMID: 41512867
- 5. Meng S et al.. 2026. Impairment of mitochondrial quality control exacerbates diabetes-related atrial fibrillation by cGAS-STING signaling pathway and cardiomyocyte-macrophage crosstalk.. Theranostics 16(4):1701-1719 PMID: 41356195
- 6. Liao Y et al.. 2026. Aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity.. J Clin Invest 136(11) PMID: 42222880
- 7. Gong C et al.. 2026. cGAS-STING signaling pathway in urogenital oncology: Regulation, resistance, and routes to response.. Crit Rev Oncol Hematol 221:105222 PMID: 41713564
- 8. Zeng QQ et al.. 2025. Pharmacological inhibition of the cGAS-STING pathway suppresses microglia pyroptosis in sepsis-associated encephalopathy.. J Neuroinflammation 22(1):176 PMID: 40634978
