GO:2000639 negative regulation of SREBP signaling pathway: Lipid Homeostasis, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:2000639 describes any process that stops, prevents, or reduces the frequency, rate, or extent of the SREBP signaling pathway, a central regulator of cholesterol and fatty acid synthesis.
• Negative regulation of SREBP signaling is critical for maintaining lipid homeostasis and preventing lipotoxicity, and its dysregulation is linked to cancer, metabolic disorders, and viral infections.
• Key negative regulators include microRNAs such as miR-29, kinases like CDK8, and metabolic sensors such as AMPK and glutamine availability.
• The SREBP pathway is controlled by a feedback loop involving SCAP, INSIG, and the mTORC1-PI3K/AKT axis, which integrates nutrient and growth factor signals.
• Experimental models for studying GO:2000639 include CRISPR knockout of negative regulators, point mutations in phosphorylation sites, and overexpression of microRNAs or dominant-negative constructs.
• Understanding negative regulation of SREBP signaling offers therapeutic opportunities for targeting cholesterol metabolism in cancer and antiviral defense.
Description
The SREBP (sterol regulatory element-binding protein) signaling pathway is a master regulator of lipid biosynthesis, controlling the expression of genes involved in cholesterol, fatty acid, and triglyceride synthesis. The Gene Ontology term GO:2000639, negative regulation of SREBP signaling pathway, encompasses any process that stops, prevents, or reduces the frequency, rate, or extent of this pathway. This negative regulation is essential for preventing excessive lipid accumulation, which can lead to cellular toxicity and metabolic diseases. Researchers study this process to understand how cells balance lipid synthesis with environmental cues such as nutrient availability and growth factor signaling. Dysregulation of SREBP negative regulation has been implicated in various pathologies, including cancer, where enhanced SREBP activity supports tumor growth, and viral infections, where modulating the pathway can affect viral replication. For example, negative regulation of SREBP-1/FAS signaling activates the RIG-1/TBK1-mediated IFN-I pathway to inhibit BVDV replication. Additionally, glutamine sensing licenses cholesterol synthesis by regulating SREBP, highlighting the interplay between metabolism and lipid homeostasis. Given its broad impact on cellular physiology, understanding the mechanisms and key players in negative regulation of SREBP signaling is crucial for developing targeted therapies. This article provides a comprehensive overview of GO:2000639, including its definition, biological significance, key genes, research methods, and CRISPR-based models for studying this process.
negative regulation of SREBP signaling pathway At A Glance
| GO ID | GO:2000639 |
|---|---|
| GO term | negative regulation of SREBP signaling pathway |
| Ontology | biological_process |
| Synonym | negative regulation of SREBP-mediated signaling pathway, negative regulation of SREBP-mediated signalling pathway |
| Major function | Inhibition of the SREBP signaling pathway, which controls lipid biosynthesis |
| Related pathways | mTOR signaling, PI3K/AKT signaling, AMPK signaling, insulin signaling |
| Key regulators | miR-29, CDK8, AMPK, glutamine, SCAP, INSIG |
| Disease relevance | Cancer, metabolic disorders, viral infections |
What Is GO:2000639?
GO:2000639, negative regulation of SREBP signaling pathway, is defined as any process that stops, prevents, or reduces the frequency, rate, or extent of the SREBP signaling pathway. This regulation can occur at multiple levels, including inhibition of SREBP cleavage, promotion of SREBP degradation, or interference with SREBP transcriptional activity. It is a biological process that ensures lipid homeostasis and prevents excessive lipogenesis.
Why Is negative regulation of SREBP signaling pathway Important in Cell Biology?
Negative regulation of SREBP signaling is vital for maintaining lipid homeostasis and preventing the detrimental effects of excessive cholesterol and fatty acid synthesis. This process integrates nutrient and hormonal signals to fine-tune lipid production, and its dysregulation contributes to a range of diseases, including cancer, where tumor cells often hijack SREBP activity to support rapid growth. Understanding how this negative regulation occurs can reveal therapeutic targets for metabolic disorders and cancers.
• Prevents lipotoxicity by limiting excessive lipid synthesis.
• Integrates nutrient signals such as glutamine availability to control cholesterol synthesis.
• Modulates immune responses, as shown by SREBP-1/FAS negative regulation activating IFN-I pathway against BVDV.
• Influences cancer progression by regulating lipid metabolism in tumors like glioblastoma and esophageal squamous cell carcinoma.
• Involved in feedback loops with growth factor signaling, such as EGFR and PI3K/AKT/mTOR pathways.
• Provides targets for therapeutic intervention in metabolic diseases and viral infections.
• Essential for normal cellular function and survival under varying metabolic conditions.
• Regulated by microRNAs and kinases, offering diverse molecular entry points for research.
What Happens During negative regulation of SREBP signaling pathway?
Inhibition of SREBP Cleavage and Activation
In simple terms: This step stops the SREBP protein from being cut and activated, so it cannot turn on lipid-making genes.
SREBP is a membrane-bound transcription factor that requires proteolytic cleavage to become active. Negative regulation can occur by preventing this cleavage, for example through the action of microRNAs such as miR-29, which targets SCAP and SREBP-1, thereby reducing the feedback loop that modulates EGFR signaling-driven glioblastoma growth. Additionally, glutamine sensing can license cholesterol synthesis by regulating SREBP activation, indicating that metabolic cues can inhibit SREBP processing.
Promotion of SREBP Degradation
In simple terms: This step involves breaking down the SREBP protein so it cannot function.
Negative regulation of SREBP signaling can be achieved by enhancing the degradation of SREBP. For instance, cyclin-dependent kinase 8 (CDK8) phosphorylates SREBP-1, leading to its degradation and reduced lipogenesis. This phosphorylation-dependent degradation is a key mechanism for controlling SREBP levels in response to cellular signals.
Interference with SREBP Transcriptional Activity
In simple terms: This step blocks SREBP from binding to DNA and activating its target genes.
Even if SREBP is cleaved and enters the nucleus, its transcriptional activity can be inhibited. For example, negative regulation of SREBP-1/FAS signaling molecules activates the RIG-1/TBK1-mediated IFN-I pathway to inhibit BVDV replication, suggesting that interfering with SREBP transcriptional output can have antiviral effects. This may involve competition for binding sites or cofactor sequestration.
Integration of Nutrient and Hormonal Signals
In simple terms: This step uses signals from nutrients and hormones to decide whether to shut down lipid production.
Negative regulation of SREBP signaling is tightly linked to nutrient availability and hormonal cues. AMPK activation, for example, can inhibit SREBP and reduce lipid levels, as shown in dietary choline studies in shrimp. Similarly, the PI3K/AKT/mTOR axis, which is often oncogenic, can modulate SREBP activity, and its inhibition can lead to negative regulation of SREBP signaling. Glutamine sensing also plays a role in licensing cholesterol synthesis, indicating that amino acid availability can influence SREBP negative regulation.
Feedback Loops and Cross-Talk with Other Pathways
In simple terms: This step involves communication with other cellular pathways to fine-tune lipid production.
Negative regulation of SREBP signaling is embedded in feedback loops. For instance, miR-29 modulates a feedback loop regulation of SCAP/SREBP-1 by EGFR signaling, which affects glioblastoma growth. Additionally, ZKSCAN5 transcriptional regulation of APOC1 modulates ferroptosis via the PI3K/AKT/SREBP2/SLC1A5 axis, showing cross-talk between SREBP and ferroptosis pathways. LPCAT1 reprogramming cholesterol metabolism also promotes esophageal squamous cell carcinoma progression, highlighting the interplay between lipid metabolism and cancer.
Key Genes Involved in GO:2000639 negative regulation of SREBP signaling pathway
The following genes and proteins are key players in the negative regulation of SREBP signaling pathway, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SREBP1 | Transcription factor controlling lipogenic genes; target of negative regulation | Knockout reduces lipogenesis; overexpression increases lipid accumulation |
| SREBP2 | Transcription factor controlling cholesterol synthesis genes; target of negative regulation | Modulated by ZKSCAN5/APOC1 axis in ferroptosis |
| SCAP | Escort protein for SREBP; regulated by miR-29 | Feedback loop with EGFR signaling in glioblastoma |
| INSIG | Retains SREBP in ER; negative regulator of SREBP processing | Not directly cited in provided references, but part of canonical pathway |
| miR-29 | MicroRNA targeting SCAP and SREBP-1; negative regulator | Modulates EGFR signaling-driven glioblastoma growth |
| CDK8 | Kinase phosphorylating SREBP-1; promotes degradation | Regulates lipogenesis; potential target in metabolic diseases |
| AMPK | Energy sensor; inhibits SREBP and lipid synthesis | Activated by dietary choline to decrease lipid levels |
| PI3K/AKT/mTOR | Growth factor signaling axis; can activate SREBP | Oncogenic roles; inhibition may negatively regulate SREBP |
| FAS | Fatty acid synthase; downstream of SREBP | Negative regulation of SREBP-1/FAS activates IFN-I pathway |
| APOC1 | Apolipoprotein; regulated by ZKSCAN5; modulates ferroptosis via SREBP2 | Potential target in cancer and lipid metabolism |
| ZKSCAN5 | Transcription factor regulating APOC1 | Modulates ferroptosis via PI3K/AKT/SREBP2/SLC1A5 axis |
| LPCAT1 | Enzyme involved in phospholipid remodeling; reprograms cholesterol metabolism | Promotes esophageal squamous cell carcinoma progression |
| SLC1A5 | Glutamine transporter; part of SREBP2 axis in ferroptosis | Modulated by ZKSCAN5/APOC1 |
| RIG-1 | Pattern recognition receptor; activated by negative regulation of SREBP-1/FAS | Inhibits BVDV replication via IFN-I pathway |
| TBK1 | Kinase in IFN-I pathway; activated downstream of RIG-1 | Mediates antiviral response upon SREBP negative regulation |
| Glutamine | Metabolite sensing; licenses cholesterol synthesis | Regulates SREBP activation |
| EGFR | Growth factor receptor; cross-talk with SREBP via miR-29 | Drives glioblastoma growth through SREBP feedback loop |
How Is negative regulation of SREBP signaling pathway Regulated?
The negative regulation of SREBP signaling is itself regulated by various upstream signals. The PI3K/AKT/mTOR axis, a major oncogenic pathway, can modulate SREBP activity, and its inhibition may lead to negative regulation of SREBP signaling. AMPK, an energy sensor, inhibits SREBP and lipid synthesis when activated, as seen with dietary choline. Glutamine availability acts as a licensing signal for cholesterol synthesis, influencing SREBP activation. Additionally, microRNAs such as miR-29 provide a layer of post-transcriptional regulation by targeting SCAP and SREBP-1. These regulatory inputs ensure that SREBP activity is tightly coupled to cellular metabolic status.
negative regulation of SREBP signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SREBP1 | Glioblastoma, lipogenesis | Knockout or overexpression in glioblastoma cell lines |
| SREBP2 | Ferroptosis, cholesterol metabolism | Point mutation or knockout in cancer cells |
| LPCAT1 | Esophageal squamous cell carcinoma | Knockdown or overexpression in ESCC cell lines |
| CDK8 | Metabolic disorders, cancer | Kinase-dead knock-in or knockout |
| AMPK | Metabolic syndrome, lipid levels | Activator treatment or knockout in hepatocytes |
Cancer
Dysregulation of SREBP negative regulation is common in cancer. In glioblastoma, miR-29 modulates a feedback loop regulation of SCAP/SREBP-1 by EGFR signaling, promoting tumor growth. In esophageal squamous cell carcinoma, LPCAT1 reprogramming cholesterol metabolism enhances progression. The PI3K/AKT/mTOR axis, frequently activated in cancers, can stimulate SREBP and lipid synthesis to support rapid proliferation. Targeting negative regulators of SREBP signaling may therefore offer therapeutic benefits.
Metabolic Disorders
Impaired negative regulation of SREBP signaling can lead to excessive lipid accumulation, contributing to metabolic disorders such as fatty liver disease and obesity. AMPK activation, which negatively regulates SREBP, reduces lipid levels and is a target for metabolic syndrome. Glutamine sensing also links amino acid metabolism to cholesterol synthesis, and its dysregulation may contribute to metabolic pathologies.
Viral Infections
Negative regulation of SREBP-1/FAS signaling activates the RIG-1/TBK1-mediated IFN-I pathway, which inhibits BVDV replication. This suggests that modulating SREBP negative regulation could be a strategy to boost antiviral innate immunity. Further research may uncover similar mechanisms for other viruses.
Ferroptosis and Oxidative Stress
ZKSCAN5 transcriptional regulation of APOC1 modulates ferroptosis via the PI3K/AKT/SREBP2/SLC1A5 axis, linking SREBP negative regulation to cell death pathways. This connection highlights the broader impact of SREBP signaling on cellular stress responses and potential implications for diseases involving ferroptosis, such as neurodegeneration and cancer.
From negative regulation of SREBP signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does knockout of a negative regulator increase SREBP activity? | CRISPR knockout of candidate gene in HepG2 or HEK293T cells |
| Does a specific phosphorylation site on SREBP control its stability? | Point mutation (e.g., phospho-deficient) knock-in via CRISPR |
| Does overexpression of miR-29 reduce SREBP target genes? | Overexpression of miR-29 mimic in glioblastoma cells |
| Can a tagged SREBP be used to track its degradation? | Knock-in of fluorescent or epitope tag at endogenous SREBP locus |
| Does AMPK activation negatively regulate SREBP in vivo? | Liver-specific AMPK knockout or knock-in mice |
| Does negative regulation of SREBP affect viral replication? | CRISPR knockout of SREBP-1/FAS in BVDV-infected cells |
How to Study the negative regulation of SREBP signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Gene expression changes | Identify SREBP target genes upon negative regulation |
| Phosphoproteomics | Phosphorylation of SREBP and related proteins | Detect CDK8-mediated SREBP phosphorylation |
| Lipidomics | Lipid species abundance | Quantify cholesterol and fatty acids after AMPK activation |
| Luciferase reporter assay | SREBP transcriptional activity | Screen for negative regulators |
| Western blot | SREBP protein levels and cleavage | Assess degradation or processing inhibition |
| Immunofluorescence | Subcellular localization of SREBP | Track nuclear translocation |
| CRISPR screen | Identify genes that negatively regulate SREBP | Genome-wide knockout library |
| qPCR | mRNA levels of SREBP targets | Validate RNA-seq findings |
Transcriptomic Analysis (RNA-seq)
RNA sequencing can measure the expression of SREBP target genes and identify changes upon negative regulation. For example, knockdown of miR-29 or overexpression of CDK8 would alter lipogenic gene expression. This method provides a global view of pathway activity.
Proteomic and Phosphoproteomic Profiling
Mass spectrometry-based proteomics can quantify SREBP protein levels and phosphorylation status. CDK8-mediated phosphorylation of SREBP-1 leads to its degradation, which can be detected by phosphoproteomics. This approach identifies post-translational modifications critical for negative regulation.
Lipidomics
Lipidomic profiling measures the abundance of cholesterol, fatty acids, and phospholipids. Negative regulation of SREBP signaling would result in reduced lipid species, as seen with AMPK activation or glutamine deprivation. This method directly assesses the functional outcome of pathway inhibition.
Reporter Assays and Imaging
SREBP-responsive luciferase reporters can monitor transcriptional activity. Imaging of fluorescently tagged SREBP can track its nuclear translocation and degradation. These techniques are useful for high-throughput screening of negative regulators.
How CRISPR Can Be Used to Study GO:2000639 negative regulation of SREBP signaling pathway
Knockout
CRISPR knockout of negative regulators such as CDK8 or miR-29 host genes can be used to assess their role in SREBP signaling. For example, knocking out CDK8 would stabilize SREBP-1 and increase lipogenesis. Knockout of SREBP-1/FAS can activate IFN-I pathway, demonstrating antiviral effects.
Point Mutation
Point mutations can be introduced to study phosphorylation sites on SREBP that control its stability. For instance, mutating the CDK8 phosphorylation site on SREBP-1 would prevent its degradation, leading to constitutive activation. This approach helps dissect the precise molecular mechanisms of negative regulation.
Knock-in
Knock-in of tags (e.g., GFP, HA) at the endogenous SREBP locus allows real-time tracking of protein dynamics and localization. This can reveal how negative regulators affect SREBP processing and degradation. Knock-in of mutant alleles, such as constitutively active SREBP, can model disease states.
Overexpression
Overexpression of negative regulators like miR-29 or dominant-negative AMPK can suppress SREBP signaling. This is useful to study the consequences of enhanced negative regulation on lipid metabolism and cell growth. Overexpression models can also validate therapeutic targets.
How EDITGENE Supports negative regulation of SREBP signaling pathway Research
Researchers studying negative regulation of SREBP signaling pathway-related genes often need to determine whether a candidate gene is causally involved in lipid homeostasis, cancer, or viral defense. EDITGENE provides comprehensive CRISPR services to enable precise genetic manipulation and functional validation.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of SREBP signaling pathway research.
Frequently Asked Questions About negative regulation of SREBP signaling pathway
What is GO:2000639?
GO:2000639 is a Gene Ontology term for negative regulation of SREBP signaling pathway, describing any process that stops, prevents, or reduces the SREBP signaling pathway, which controls lipid synthesis.
What genes are involved in negative regulation of SREBP signaling?
Key genes include SREBP1, SREBP2, SCAP, miR-29, CDK8, AMPK, and components of the PI3K/AKT/mTOR pathway.
How is SREBP signaling negatively regulated?
It can be negatively regulated by microRNAs like miR-29, kinases like CDK8 that promote degradation, and metabolic sensors like AMPK that inhibit SREBP activity.
Why is negative regulation of SREBP important in cancer?
In cancer, negative regulation of SREBP can suppress tumor growth by limiting lipid availability; its dysregulation leads to enhanced lipogenesis supporting proliferation.
What diseases are associated with SREBP negative regulation?
Diseases include cancer (e.g., glioblastoma, esophageal squamous cell carcinoma), metabolic disorders, and viral infections.
How can I study negative regulation of SREBP signaling?
Use CRISPR knockout, point mutation, overexpression, RNA-seq, lipidomics, and reporter assays to assess pathway activity.
What is the role of glutamine in SREBP negative regulation?
Glutamine sensing licenses cholesterol synthesis by regulating SREBP activation, linking amino acid metabolism to lipid homeostasis.
Does AMPK negatively regulate SREBP?
Yes, AMPK activation inhibits SREBP and reduces lipid levels, as shown in dietary choline studies.
How does miR-29 regulate SREBP?
miR-29 targets SCAP and SREBP-1, modulating a feedback loop with EGFR signaling in glioblastoma.
What CRISPR models are available for SREBP research?
EDITGENE provides knockout, point mutation, knock-in, overexpression, and library screening services for genes in the SREBP pathway.
Conclusion
Negative regulation of SREBP signaling (GO:2000639) is a critical biological process that maintains lipid homeostasis and prevents pathological lipid accumulation. Its dysregulation is implicated in cancer, metabolic disorders, and viral infections, making it a promising therapeutic target. Understanding the molecular players and mechanisms, from microRNAs to kinases and metabolic sensors, provides a foundation for developing targeted interventions. CRISPR-based models and advanced omics technologies are invaluable for dissecting this pathway and identifying new regulatory nodes.
References
- 1. Liu S et al.. 2025. Negative regulation of SREBP-1/FAS signaling molecules activates the RIG-1/TBK1-mediated IFN-I pathway to inhibit BVDV replication.. Antiviral Res 233:106054 PMID: 39653278
- 2. Garcia BM et al.. 2024. Glutamine sensing licenses cholesterol synthesis.. EMBO J 43(23):5837-5856 PMID: 39433901
- 3. Liu Y et al.. 2025. ZKSCAN5 transcriptional regulation of APOC1 modulates ferroptosis via PI3K/AKT/SREBP2/SLC1A5 axis.. J Transl Med 23(1):1020 PMID: 41029397
- 4. Tao M et al.. 2021. LPCAT1 reprogramming cholesterol metabolism promotes the progression of esophageal squamous cell carcinoma.. Cell Death Dis 12(9):845 PMID: 34518524
- 5. Ru P et al.. 2016. Feedback Loop Regulation of SCAP/SREBP-1 by miR-29 Modulates EGFR Signaling-Driven Glioblastoma Growth.. Cell Rep 16(6):1527-1535 PMID: 27477273
- 6. Lu J et al.. 2023. Dietary choline activates the Ampk/Srebp signaling pathway and decreases lipid levels in Pacific white shrimp (Litopenaeus vannamei).. Anim Nutr 15:58-70 PMID: 37818178
- 7. Zhao X et al.. 2012. Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1.. J Clin Invest 122(7):2417-27 PMID: 22684109
- 8. Aoki M et al.. 2017. Oncogenic Roles of the PI3K/AKT/mTOR Axis.. Curr Top Microbiol Immunol 407:153-189 PMID: 28550454
