GO:1905694 negative regulation of phosphatidic acid biosynthetic process: Lipid Signaling Control, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1905694 describes any process that stops, prevents, or reduces the frequency, rate, or extent of phosphatidic acid (PA) biosynthesis, a central lipid signaling node.
• Phosphatidic acid is a key intermediate in glycerophospholipid synthesis and a potent signaling lipid that regulates membrane curvature, enzyme recruitment, and ion channel activity [1,2].
• Negative regulation of PA biosynthesis is critical for balancing lipid homeostasis, controlling autophagy, and modulating mechanical sensitivity through PIEZO2 channels [1,7].
• Key proteins involved include lipin phosphatases (LPIN1/2/3), diacylglycerol kinases (DGK), phospholipase D (PLD), and PA-binding effectors such as mTOR and S6K [2,4,5].
• Dysregulation of PA metabolism is linked to cancer, metabolic disorders, and neurological conditions, making this pathway a target for therapeutic intervention [2,7].
• CRISPR-based knockout, knock-in, and overexpression models enable precise dissection of negative regulators of PA biosynthesis in human cells and animal models.
Description
Phosphatidic acid (PA) is a glycerophospholipid that serves as both a biosynthetic intermediate and a critical second messenger in eukaryotic cells. The biosynthetic process that generates PA is tightly controlled because PA levels influence membrane biogenesis, vesicular trafficking, and signal transduction [2,5]. GO:1905694, negative regulation of phosphatidic acid biosynthetic process, encompasses any mechanism that reduces the rate or extent of PA synthesis. This regulation is essential for cellular homeostasis, as excessive PA can disrupt membrane integrity and alter signaling cascades [1,2]. Researchers study this process to understand how cells balance lipid metabolism with growth, stress responses, and disease states [4,7]. The term is particularly relevant in cancer biology, neurobiology, and plant stress signaling, where PA acts as a node integrating hormonal and mechanical cues [1,4,6].
negative regulation of phosphatidic acid biosynthetic process At A Glance
| GO ID | GO:1905694 |
|---|---|
| GO term | negative regulation of phosphatidic acid biosynthetic process |
| Ontology | biological_process |
| Synonym | inhibition of phosphatidic acid biosynthesis; downregulation of phosphatidic acid formation; negative regulation of phosphatidic acid synthesis |
| Major function | Reduces the production of phosphatidic acid, a key lipid second messenger and biosynthetic intermediate |
| Related processes | Phospholipid biosynthesis, autophagy regulation, mechanical sensation, ABA signaling |
| Key enzymes | Lipin phosphatases (LPIN1/2/3), diacylglycerol kinases (DGK), phospholipase D (PLD) |
| Cellular location | Cytosol, endoplasmic reticulum, plasma membrane, nucleus |
What Is GO:1905694?
GO:1905694 is a biological process term defined as any process that stops, prevents, or reduces the frequency, rate, or extent of phosphatidic acid biosynthetic process. In other words, it covers molecular events that downregulate the production of PA, whether by inhibiting enzymes like diacylglycerol kinase or phospholipase D, or by activating phosphatases such as lipin that consume PA [2,5].
Why Is negative regulation of phosphatidic acid biosynthetic process Important in Cell Biology?
Negative regulation of PA biosynthesis is crucial because PA is not only a precursor for glycerophospholipids but also a signaling lipid that recruits effector proteins to membranes and modulates ion channels [1,2,5]. Uncontrolled PA production can lead to aberrant cell growth, impaired autophagy, and altered mechanical sensitivity [1,7]. Understanding this regulatory process provides insights into fundamental cell biology and offers potential therapeutic targets for cancer, metabolic diseases, and neurological disorders [2,4].
• Maintains lipid homeostasis by preventing excessive PA accumulation.
• Regulates autophagy through PA-binding proteins such as HS1BP3.
• Modulates mechanical sensitivity by controlling PIEZO2 channel activity.
• Integrates hormonal signals, including ABA, in plant stress responses.
• Influences membrane trafficking and vesicle formation.
• Affects cell proliferation and survival via mTOR signaling.
• Plays a role in platelet activation and thrombosis.
• Contributes to bacterial membrane phospholipid synthesis regulation.
• Dysregulation is implicated in cancer and metabolic disorders.
• Provides targets for CRISPR-based functional studies and drug discovery.
What Happens During negative regulation of phosphatidic acid biosynthetic process?
Inhibition of PA-synthesizing enzymes
In simple terms: The cell slows down the enzymes that make phosphatidic acid.
PA biosynthesis occurs via multiple routes, including the acylation of glycerol-3-phosphate and the phosphorylation of diacylglycerol by DGK, or the hydrolysis of phosphatidylcholine by PLD. Negative regulation can be achieved by direct inhibition or downregulation of these enzymes. For example, DGK activity is reduced under certain conditions, lowering PA production. In bacteria, PlsX and PlsY are involved in glycerophospholipid synthesis, and their regulation affects PA levels.
Activation of PA-consuming phosphatases
In simple terms: Enzymes that convert PA into other lipids are turned on.
Lipin phosphatases (LPIN1, LPIN2, LPIN3) dephosphorylate PA to yield diacylglycerol, thereby reducing PA levels. Activation of lipins, often through dephosphorylation and nuclear translocation, represents a major negative regulatory mechanism. This step is tightly linked to lipid homeostasis and energy metabolism.
Sequestration of PA by binding proteins
In simple terms: Proteins bind to PA and keep it from being used or from signaling.
PA interacts with a variety of proteins containing PA-binding domains, such as those with polybasic stretches or specific lipid-binding motifs. Proteins like mTOR, S6K, and PIEZO2 bind PA, and this binding can sequester PA away from biosynthetic pathways or modulate downstream signaling [1,5]. Negative regulation may involve increased expression of such PA-binding proteins, effectively reducing free PA available for signaling.
Feedback regulation via signaling pathways
In simple terms: Signals from other pathways tell the cell to stop making PA.
PA biosynthesis is subject to feedback inhibition by downstream products or by hormonal signals. In plants, abscisic acid (ABA) signaling involves PA, and negative regulation of PA production is necessary to attenuate the response. In mammalian cells, mTOR signaling can feedback to regulate lipid synthesis, including PA production. Additionally, autophagy-related proteins like HS1BP3 negatively regulate autophagy through modulation of PA levels.
Key Genes Involved in GO:1905694 negative regulation of phosphatidic acid biosynthetic process
The following genes and proteins are central to the negative regulation of phosphatidic acid biosynthetic process, based on their roles in PA metabolism and signaling.
| Gene | Major Role | Research Relevance |
|---|---|---|
| LPIN1 | Phosphatidic acid phosphatase; converts PA to DAG | Key negative regulator; knockout models show altered lipid metabolism |
| LPIN2 | Phosphatidic acid phosphatase | Implicated in Majeed syndrome; regulates PA levels |
| LPIN3 | Phosphatidic acid phosphatase | Contributes to PA homeostasis in specific tissues |
| DGKA | Diacylglycerol kinase; synthesizes PA from DAG | Inhibition reduces PA; target for negative regulation |
| DGKZ | Diacylglycerol kinase | Modulates PA signaling in immune cells |
| PLD1 | Phospholipase D; produces PA from PC | Downregulation decreases PA; linked to cancer |
| PLD2 | Phospholipase D | Regulates PA-dependent processes like vesicle trafficking |
| PIEZO2 | Mechanosensitive ion channel; inhibited by PA | PA binding modulates mechanical sensitivity |
| HS1BP3 | Negative regulator of autophagy; interacts with PA | Modulates autophagosome formation via PA |
| MTOR | Kinase; binds PA and regulates lipid synthesis | PA-binding affects mTOR signaling |
| RPS6KB1 | S6 kinase; PA-binding protein | Downstream effector of PA signaling |
| PLD | Phospholipase D family | PA production; negative regulation reduces PA |
| PIP5K | Phosphatidylinositol-4-phosphate 5-kinase; activated by PA | PA effector; negative regulation affects PIP2 synthesis |
| SNRK2 | Plant kinase; regulated by PA | ABA signaling; PA negatively regulates SNRK2 |
| PLDα1 | Plant phospholipase D | Produces PA in stress responses |
| PDK1 | Phosphoinositide-dependent kinase 1; PA-binding | PA modulates PDK1 signaling |
| RAF1 | Kinase; PA-binding protein | PA recruits RAF1 to membranes |
| K-Ras | Small GTPase; PA-binding | PA affects Ras signaling |
How Is negative regulation of phosphatidic acid biosynthetic process Regulated?
The negative regulation of PA biosynthesis is itself regulated at multiple levels. Transcriptional control of lipin and DGK genes, post-translational modifications such as phosphorylation, and feedback loops involving mTOR and AMPK all contribute [2,5]. In plants, ABA signaling modulates PA levels through phospholipase D and PA phosphatases. Autophagy-related proteins like HS1BP3 provide an additional layer of regulation by linking PA to autophagosome formation.
negative regulation of phosphatidic acid biosynthetic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| LPIN1 | Lipodystrophy, metabolic syndrome | Knockout mouse, hepatocyte cell lines |
| PLD1 | Cancer progression, metastasis | Overexpression in cancer cell lines, xenografts |
| PIEZO2 | Mechanical hypersensitivity, proprioception deficits | Knock-in mouse models, sensory neuron cultures |
| HS1BP3 | Autophagy dysregulation, neurodegenerative risk | Knockout cells, neuronal lines |
| DGKZ | Immune disorders, T-cell signaling | Knockout mice, Jurkat cells |
Cancer
Elevated PA levels and altered expression of PA-metabolizing enzymes are observed in various cancers. PLD and DGK are often overexpressed, promoting cell proliferation and survival. Negative regulation of PA biosynthesis, for example by activating lipin phosphatases, may counteract oncogenic signaling. Targeting this process could offer therapeutic strategies.
Metabolic disorders
Lipin phosphatases are critical for lipid homeostasis, and mutations in LPIN1 cause lipodystrophy and metabolic syndrome. Impaired negative regulation of PA biosynthesis can lead to insulin resistance and hepatic steatosis. Understanding these mechanisms may inform treatments for metabolic diseases.
Neurological and mechanical disorders
PA acts as an endogenous negative regulator of PIEZO2 channels, which are involved in mechanical sensation. Dysregulation of PA biosynthesis could affect touch, proprioception, and pain. Modulating PA levels might have therapeutic potential for mechanical hypersensitivity disorders.
Infectious and inflammatory diseases
Bacterial PlsX and PlsY are involved in glycerophospholipid synthesis, and their regulation affects membrane integrity. In platelets, PA is linked to protein phosphorylation and activation, influencing thrombosis. Negative regulation of PA biosynthesis may modulate inflammatory responses.
From negative regulation of phosphatidic acid biosynthetic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does LPIN1 knockout increase PA levels? | LPIN1 knockout HEK293 or HepG2 cells |
| How does PA binding to PIEZO2 affect mechanosensitivity? | PIEZO2 point-mutation knock-in mice |
| Can overexpression of HS1BP3 reduce autophagy? | HS1BP3 overexpression in HeLa cells |
| What is the role of DGKZ in T-cell activation? | DGKZ knockout Jurkat cells |
| Does PLD1 inhibition reduce cancer cell proliferation? | PLD1 knockout or inhibitor-treated cancer cells |
| How does ABA regulate PA levels in plants? | SNRK2 knockout Arabidopsis lines |
How to Study the negative regulation of phosphatidic acid biosynthetic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| LC-MS/MS lipidomics | PA species quantification | Assessing changes in PA levels after gene knockout |
| CRISPR knockout screening | Gene function on PA levels | Identifying negative regulators of PA biosynthesis |
| PA biosensor imaging | Real-time PA dynamics | Live-cell visualization of PA at membranes |
| Phosphoproteomics | Phosphorylation changes | Mapping signaling pathways regulating PA enzymes |
| Proximity labeling (BioID) | Protein interactors of PA enzymes | Discovering novel regulators |
| RNA-seq | Transcriptional changes | Measuring expression of PA metabolism genes |
| Immunoblotting | Protein expression and phosphorylation | Validating knockout or overexpression |
| Co-immunoprecipitation | Protein-protein interactions | Studying PA enzyme complexes |
Lipidomics and mass spectrometry
Quantitative lipidomics using LC-MS/MS allows precise measurement of PA species and other phospholipids. This method is essential to assess changes in PA levels upon genetic or pharmacological manipulation.
CRISPR screening
Genome-wide CRISPR knockout or activation screens can identify genes that negatively regulate PA biosynthesis. Coupling with PA-sensitive reporters or lipid staining enables high-throughput discovery.
Live-cell imaging of PA sensors
Genetically encoded PA biosensors (e.g., GFP-tagged PA-binding domains) allow real-time visualization of PA dynamics at subcellular locations. This helps study negative regulation in live cells.
Phosphoproteomics and interactomics
Mass spectrometry-based phosphoproteomics and proximity labeling can reveal signaling networks and protein-protein interactions that mediate negative regulation of PA synthesis.
How CRISPR Can Be Used to Study GO:1905694 negative regulation of phosphatidic acid biosynthetic process
Knockout
CRISPR knockout of genes such as LPIN1, DGKZ, or PLD1 can be used to study their roles in PA biosynthesis. Loss-of-function models reveal whether these genes are required for negative regulation and how their absence affects downstream processes like autophagy or proliferation.
Point Mutation
Introducing point mutations in PA-binding domains of effector proteins (e.g., PIEZO2) or catalytic residues of enzymes (e.g., LPIN1) allows precise dissection of molecular mechanisms. Such models help distinguish between catalytic activity and scaffolding functions.
Knock-in
Knock-in of tagged versions of PA-metabolizing enzymes (e.g., GFP-LPIN1) enables live-cell imaging and proteomic analysis. This approach provides insights into localization and dynamics of negative regulators.
Overexpression
CRISPR activation (CRISPRa) or cDNA overexpression can elevate levels of negative regulators like HS1BP3 or lipin phosphatases. Overexpression models are useful to test sufficiency in reducing PA levels and reversing disease phenotypes.
How EDITGENE Supports negative regulation of phosphatidic acid biosynthetic process Research
Researchers studying negative regulation of phosphatidic acid biosynthetic process-related genes often need to determine whether a candidate gene is causally involved in PA homeostasis or whether it is merely a bystander. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell models, enabling rigorous functional validation.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of phosphatidic acid biosynthetic process research.
Frequently Asked Questions About negative regulation of phosphatidic acid biosynthetic process
What is GO:1905694?
GO:1905694 is a Gene Ontology term for any process that stops, prevents, or reduces the frequency, rate, or extent of phosphatidic acid biosynthetic process.
What genes are involved in negative regulation of phosphatidic acid biosynthetic process?
Key genes include LPIN1, LPIN2, LPIN3, DGKA, DGKZ, PLD1, PLD2, HS1BP3, and PIEZO2, among others [1,2,5,7].
How is phosphatidic acid biosynthesis negatively regulated?
It is regulated by inhibiting PA-synthesizing enzymes like DGK and PLD, activating PA phosphatases like lipins, and sequestering PA by binding proteins [2,5].
Why is phosphatidic acid important in cell signaling?
PA is a lipid second messenger that recruits effector proteins to membranes and modulates ion channels, autophagy, and cell growth [1,2,5].
What diseases are linked to phosphatidic acid metabolism?
Dysregulation is linked to cancer, metabolic disorders, neurological conditions, and infectious diseases [1,2,3,8].
How can I study negative regulation of PA biosynthesis using CRISPR?
CRISPR knockout, knock-in, point mutation, and overexpression models can be used to manipulate genes like LPIN1 or PLD1 and measure PA levels.
What methods measure phosphatidic acid levels?
LC-MS/MS lipidomics, PA biosensors, and thin-layer chromatography are commonly used [2,5].
Is phosphatidic acid involved in autophagy?
Yes, PA regulates autophagy, and proteins like HS1BP3 negatively regulate autophagy through PA.
What is the role of lipin in PA regulation?
Lipin phosphatases convert PA to diacylglycerol, thereby reducing PA levels and negatively regulating its biosynthesis.
Can EDITGENE help create custom CRISPR models for PA research?
Yes, EDITGENE offers knockout, point mutation, knock-in, overexpression, and library screening services for genes in PA metabolism.
Conclusion
GO:1905694, negative regulation of phosphatidic acid biosynthetic process, represents a critical control point in lipid signaling and metabolism. By understanding the enzymes, binding proteins, and regulatory loops that reduce PA production, researchers can uncover new therapeutic targets for cancer, metabolic, and neurological diseases. CRISPR-based models provide powerful tools to dissect these mechanisms with precision.
References
- 1. Gabrielle M et al.. 2024. Phosphatidic acid is an endogenous negative regulator of PIEZO2 channels and mechanical sensitivity.. Nat Commun 15(1):7020 PMID: 39147733
- 2. Zhukovsky MA et al.. 2019. Phosphatidic acid in membrane rearrangements.. FEBS Lett 593(17):2428-2451 PMID: 31365767
- 3. Rex AN et al.. 2024. PlsX and PlsY: Additional roles beyond glycerophospholipid synthesis in Gram-negative bacteria.. mBio 15(12):e0296924 PMID: 39475235
- 4. Klimecka M et al.. 2020. Regulation of ABA-Non-Activated SNF1-Related Protein Kinase 2 Signaling Pathways by Phosphatidic Acid.. Int J Mol Sci 21(14) PMID: 32679718
- 5. Stace CL et al.. 2006. Phosphatidic acid- and phosphatidylserine-binding proteins.. Biochim Biophys Acta 1761(8):913-26 PMID: 16624617
- 6. Boss WF et al.. 2012. Phosphoinositide signaling.. Annu Rev Plant Biol 63:409-29 PMID: 22404474
- 7. Yin Z et al.. 2017. HS1BP3 provides a novel mechanism of negative autophagy regulation through membrane lipids.. Autophagy 13(5):779-780 PMID: 28323521
- 8. Gerrard JM et al.. 1985. Platelet protein phosphorylation.. Adv Exp Med Biol 192:235-48 PMID: 3010667
