GO:0036150 phosphatidylserine acyl-chain remodeling: Lipid Remodeling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0036150 phosphatidylserine acyl-chain remodeling is the biological process that changes the fatty acid composition of phosphatidylserine through sequential deacylation and re-acylation reactions.
• This remodeling generates phosphatidylserine molecular species with distinct acyl chains, which can influence membrane curvature, lipid packing, and protein interactions.
• Key enzymes include phospholipase A2 (PLA2) and lysophosphatidylserine acyltransferases (LPSATs), which remove and add acyl chains, respectively.
• Acyl-chain remodeling of aminophospholipids, including phosphatidylserine, has been demonstrated in yeast and mammalian cells using mass spectrometry and isotope labeling.
• Dysregulation of phosphatidylserine remodeling has been linked to cancer, neurodegeneration, and metabolic disorders, making it a potential therapeutic target.
• CRISPR-based knockout, knock-in, and overexpression models are powerful tools to study the causal roles of remodeling enzymes in health and disease.
Description
Phosphatidylserine (PS) is a glycerophospholipid that is enriched in the inner leaflet of the plasma membrane and plays critical roles in cell signaling, apoptosis, and membrane trafficking. The acyl chains of PS are not static; they undergo a process known as acyl-chain remodeling, which is defined by the Gene Ontology term GO:0036150. This process involves the sequential removal and re-esterification of fatty acids, resulting in PS molecules with different acyl chain compositions. The remodeling of PS is part of a broader lipid remodeling network that includes phosphatidylethanolamine and phosphatidylcholine, and it is essential for maintaining membrane homeostasis and function. Researchers study PS acyl-chain remodeling to understand how membrane lipid diversity is generated and how it impacts cellular processes such as signal transduction, membrane fusion, and protein sorting. The importance of PS acyl-chain remodeling extends to human health. Alterations in lipid remodeling enzymes have been implicated in cancer, where changes in membrane lipid composition can affect oncogenic signaling and drug resistance. For example, lysophosphatidylcholine acyltransferase 1 (LPCAT1), an enzyme involved in phospholipid remodeling, has been shown to suppress KRAS nanoclustering and function, highlighting the interplay between lipid remodeling and oncogenesis. Similarly, caveolin-1 and cavin1, which are involved in caveolae formation, contribute to a unique lipid environment that may depend on PS remodeling. Understanding the molecular players and regulatory mechanisms of PS acyl-chain remodeling is therefore crucial for developing new therapeutic strategies. Recent advances in lipidomics and mass spectrometry have enabled detailed characterization of PS molecular species and their remodeling pathways. Studies using electrospray ionization tandem mass spectrometry (ESI-MS/MS) have revealed acyl chain-based sorting and remodeling of distinct lipid species en route to the plasma membrane in yeast. Isotope labeling combined with mass spectrometry has provided insights into the dynamics of aminophospholipid acyl chain remodeling. These techniques, coupled with genetic tools such as CRISPR, allow researchers to dissect the functions of specific remodeling enzymes and their contributions to cellular physiology and disease.
phosphatidylserine acyl-chain remodeling At A Glance
| GO ID | GO:0036150 |
|---|---|
| GO term | phosphatidylserine acyl-chain remodeling |
| Ontology | biological_process |
| Synonym | phosphatidyl-L-serine acyl-chain remodeling; phosphatidylserine acyl-chain remodelling |
| Definition | Remodeling the acyl chains of phosphatidylserine, through sequential deacylation and re-acylation reactions, to generate phosphatidylserine containing different types of fatty acid acyl chains. |
| Major function | Modifies the fatty acid composition of phosphatidylserine, influencing membrane fluidity, curvature, and protein-lipid interactions. |
| Related processes | Phosphatidylethanolamine acyl-chain remodeling, phosphatidylcholine remodeling, Lands cycle. |
| Key enzymes | Phospholipase A2 (PLA2), lysophosphatidylserine acyltransferase (LPSAT). |
| Cellular location | Endoplasmic reticulum, Golgi apparatus, and mitochondria-associated membranes. |
What Is GO:0036150?
GO:0036150 phosphatidylserine acyl-chain remodeling is the biological process in which the fatty acid chains attached to phosphatidylserine are modified through a cycle of deacylation and re-acylation. This process converts phosphatidylserine molecules into different molecular species with varying acyl chain lengths and degrees of saturation, thereby altering the physical properties of the lipid and its interactions with proteins.
Why Is phosphatidylserine acyl-chain remodeling Important in Cell Biology?
Phosphatidylserine acyl-chain remodeling is critical for generating the diverse array of PS molecular species found in cellular membranes. This diversity is essential for membrane function, including the formation of lipid microdomains, regulation of membrane protein activity, and participation in signaling events such as apoptosis and blood coagulation. Disruptions in PS remodeling have been associated with various diseases, including cancer and neurodegenerative disorders, underscoring its physiological significance.
• Maintains membrane lipid diversity and asymmetry, which are vital for cell signaling and membrane trafficking.
• Regulates the biophysical properties of membranes, such as fluidity, thickness, and curvature, affecting protein function.
• Plays a role in the generation of lipid second messengers and in apoptosis, where PS exposure is a key signal.
• Influences oncogenic signaling pathways, as shown by the impact of lipid remodeling on KRAS function.
• Contributes to mitochondrial dynamics and function through remodeling of aminophospholipids.
• Is implicated in metabolic disorders and neurodegeneration, where lipid homeostasis is disrupted.
• Provides potential biomarkers for disease diagnosis and progression.
• Offers targets for therapeutic intervention in cancer and other diseases.
• Helps understand the evolutionary conservation of lipid remodeling pathways from yeast to humans.
• Enables the development of advanced lipidomics technologies to study lipid species in health and disease.
What Happens During phosphatidylserine acyl-chain remodeling?
Deacylation: Removal of the sn-2 acyl chain
In simple terms: First, an enzyme cuts off one of the fatty acid tails from phosphatidylserine.
The remodeling cycle begins with the hydrolysis of the acyl chain at the sn-2 position of phosphatidylserine, catalyzed by phospholipase A2 (PLA2) enzymes. This reaction produces lysophosphatidylserine (lysoPS), a intermediate with only one acyl chain. The activity of PLA2 is regulated by various factors, including calcium and phosphorylation. In yeast, the remodeling of aminophospholipids, including PS, has been shown to involve deacylation steps that generate lysoPS species.
Re-acylation: Addition of a new acyl chain
In simple terms: Then, another enzyme attaches a new fatty acid tail to the lysophosphatidylserine.
Lysophosphatidylserine acyltransferases (LPSATs) catalyze the transfer of an acyl chain from an acyl-CoA donor to lysoPS, regenerating phosphatidylserine with a different acyl chain composition. This step is crucial for incorporating specific fatty acids, such as arachidonic acid or docosahexaenoic acid, into PS. The re-acylation step is part of the Lands cycle and is essential for generating the diverse PS molecular species observed in cells. Studies using isotope-labeled lipid species have provided detailed information on the acyl chain remodeling of aminophospholipids, including PS.
Substrate specificity and acyl chain selection
In simple terms: Different enzymes choose which fatty acids to add or remove, creating variety.
The specificity of PLA2 and LPSAT enzymes determines which acyl chains are removed and added, leading to the generation of distinct PS molecular species. For example, some LPSATs prefer polyunsaturated fatty acyl-CoAs, while others prefer saturated or monounsaturated acyl-CoAs. This specificity is critical for producing PS species with specific functions in membrane organization and signaling. In yeast, acyl chain-based sorting and remodeling of distinct molecular species en route to the plasma membrane has been observed, indicating that the acyl chain composition influences lipid trafficking.
Integration with other lipid remodeling pathways
In simple terms: This process is connected to remodeling of other lipids like phosphatidylethanolamine.
Phosphatidylserine acyl-chain remodeling is interconnected with the remodeling of other aminophospholipids, such as phosphatidylethanolamine (PE). Studies have shown that EBF2 regulates cardiolipin and phosphatidylethanolamine remodeling and mitochondrial dynamics in brown fat, suggesting that similar regulatory mechanisms may apply to PS remodeling. Additionally, the phosphorylation of fatty acid synthase complex controls fatty acyl chain length, which can impact the availability of acyl-CoAs for remodeling reactions.
Techniques for studying PS remodeling
In simple terms: Scientists use mass spectrometry and isotopes to track these changes.
Advanced lipidomics techniques, such as electrospray ionization tandem mass spectrometry (ESI-MS/MS), allow the identification and quantification of PS molecular species and their remodeling intermediates. The use of exogenous heavy isotope-labeled lipid species provides detailed information on the dynamics of aminophospholipid acyl chain remodeling, enabling researchers to trace the incorporation and removal of specific acyl chains. These methods are essential for understanding the enzymes and pathways involved in PS remodeling.
Key Genes Involved in GO:0036150 phosphatidylserine acyl-chain remodeling
The following genes and proteins are key players in phosphatidylserine acyl-chain remodeling, including enzymes that catalyze deacylation and re-acylation, as well as regulatory factors.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PLA2G4A | Phospholipase A2 that hydrolyzes the sn-2 acyl chain of phosphatidylserine | Studied for its role in eicosanoid production and inflammation; potential target in cancer. |
| PLA2G6 | Calcium-independent phospholipase A2 involved in phospholipid remodeling | Mutations linked to neurodegeneration; model for studying lipid remodeling in disease. |
| LPCAT1 | Lysophosphatidylcholine acyltransferase 1; may also acetylate lysoPS | Suppresses KRAS nanoclustering; implicated in cancer lipid metabolism. |
| LPCAT3 | Lysophosphatidylcholine acyltransferase 3; involved in phospholipid remodeling | Regulates membrane lipid composition and ER stress; potential role in metabolic diseases. |
| MBOAT1 | Membrane-bound O-acyltransferase that may acylate lysoPS | Candidate LPSAT; studied for its role in phospholipid diversity. |
| MBOAT2 | Membrane-bound O-acyltransferase family member | Potential lysophosphatidylserine acyltransferase; research on substrate specificity. |
| AGPAT1 | 1-acylglycerol-3-phosphate O-acyltransferase 1 | Involved in phosphatidic acid remodeling; may indirectly affect PS acyl chains. |
| AGPAT2 | 1-acylglycerol-3-phosphate O-acyltransferase 2 | Mutations cause congenital generalized lipodystrophy; links lipid remodeling to metabolic disease. |
| LPGAT1 | Lysophosphatidylglycerol acyltransferase 1 | May contribute to aminophospholipid remodeling; studied in yeast and mammals. |
| TAFAZZIN | Transacylase involved in cardiolipin remodeling | Mutations cause Barth syndrome; highlights importance of acyl chain remodeling in mitochondria. |
| EBF2 | Transcription factor regulating cardiolipin and PE remodeling | Regulates mitochondrial dynamics in brown fat; may influence PS remodeling. |
| FASN | Fatty acid synthase; provides acyl-CoAs for remodeling | Phosphorylation controls acyl chain length; affects substrate availability for remodeling. |
| CAV1 | Caveolin-1; structural protein of caveolae | Contributes to unique lipid environment; may interact with PS remodeling. |
| CAVIN1 | Cavin1; caveolae-associated protein | Acts synergistically with CAV1 to generate lipid environment; potential link to PS. |
| KRAS | Small GTPase; oncogene | Lipid remodeling affects KRAS nanoclustering and function; allele-specific responses. |
| LCAT | Lecithin-cholesterol acyltransferase | Involved in lipoprotein metabolism; may have phospholipase A2 activity. |
| PLSCR1 | Phospholipid scramblase 1 | Facilitates PS exposure; may influence remodeling by altering substrate accessibility. |
| ABCA1 | ATP-binding cassette transporter A1 | Transports phospholipids and cholesterol; may affect PS distribution and remodeling. |
How Is phosphatidylserine acyl-chain remodeling Regulated?
Phosphatidylserine acyl-chain remodeling is regulated at multiple levels. The activity of phospholipase A2 enzymes can be controlled by calcium signaling, phosphorylation, and interaction with regulatory proteins. For example, the phosphorylation of the fatty acid synthase complex controls fatty acyl chain length, thereby influencing the pool of acyl-CoAs available for re-acylation reactions. Additionally, transcription factors such as EBF2 regulate the expression of genes involved in lipid remodeling, including those for cardiolipin and phosphatidylethanolamine, and may similarly affect PS remodeling. The interplay between different lipid remodeling pathways ensures membrane lipid homeostasis and allows cells to adapt to changing conditions.
phosphatidylserine acyl-chain remodeling and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| LPCAT1 | Cancer (KRAS-driven) | Knockout and overexpression in cancer cell lines; KRAS nanoclustering assays. |
| PLA2G6 | Neurodegeneration (infantile neuroaxonal dystrophy) | Knockout mice or patient-derived iPSCs; lipidomic analysis. |
| AGPAT2 | Congenital generalized lipodystrophy | Knockout adipocytes; lipid remodeling assays. |
| EBF2 | Metabolic disorders (brown fat function) | Knockout mice; mitochondrial dynamics and lipidomics. |
| KRAS | Cancer (allele-specific lipid metabolism) | Point mutation knock-in (G12C, G12D); lipid metabolism profiling. |
Cancer
Alterations in phosphatidylserine acyl-chain remodeling have been implicated in cancer. LPCAT1, an enzyme involved in phospholipid remodeling, suppresses nanoclustering and function of KRAS, a key oncogene. Furthermore, KRAS G12C and KRAS G12D mutants respond to lipid metabolism in an allele-specific manner, suggesting that targeting lipid remodeling pathways could be a therapeutic strategy for KRAS-driven cancers. The lipid environment of caveolae, which depends on caveolin-1 and cavin1, may also influence oncogenic signaling.
Neurodegeneration
Defects in phospholipid remodeling enzymes, such as PLA2G6, are associated with neurodegenerative disorders like infantile neuroaxonal dystrophy. Disruption of PS remodeling can lead to altered membrane properties and impaired neuronal function. Lipidomic studies have revealed changes in aminophospholipid species in neurodegenerative conditions, highlighting the importance of PS remodeling in brain health.
Metabolic disorders
Phosphatidylserine remodeling is linked to metabolic diseases. Mutations in AGPAT2 cause congenital generalized lipodystrophy, a severe metabolic disorder, indicating that acyl chain remodeling of phospholipids is critical for adipose tissue function. Additionally, EBF2 regulates cardiolipin and phosphatidylethanolamine remodeling in brown fat, affecting mitochondrial dynamics and energy metabolism. These findings suggest that PS remodeling may also play a role in obesity and diabetes.
From phosphatidylserine acyl-chain remodeling-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does knockout of a candidate remodeling enzyme alter PS acyl chain composition? | CRISPR knockout cell lines; lipidomics by ESI-MS/MS. |
| Does a specific point mutation in an enzyme affect substrate specificity? | CRISPR point mutation knock-in; enzyme activity assays. |
| Does overexpression of a remodeling enzyme change membrane properties? | CRISPR overexpression (e.g., CRISPRa) or lentiviral overexpression; imaging and lipidomics. |
| How does a tagged enzyme localize within cells? | CRISPR knock-in of fluorescent or epitope tags; live-cell imaging. |
| What is the role of a gene in disease progression? | Knockout or knock-in in disease models (e.g., cancer xenografts); phenotypic analysis. |
| Can we identify novel regulators of PS remodeling? | CRISPR library screening; lipidomics and transcriptomics. |
How to Study the phosphatidylserine acyl-chain remodeling Process
| Method | What It Measures | Typical Application |
|---|---|---|
| ESI-MS/MS lipidomics | Molecular species of PS and intermediates | Profiling acyl chain composition in cells and tissues. |
| Isotope labeling | Dynamics of acyl chain incorporation/removal | Tracing remodeling pathways. |
| CRISPR knockout | Loss-of-function effects on lipid remodeling | Identifying essential enzymes. |
| CRISPR activation (CRISPRa) | Overexpression effects on lipid composition | Gain-of-function studies. |
| Fluorescence microscopy | Subcellular localization of lipids and proteins | Visualizing membrane dynamics. |
| Phosphoproteomics | Phosphorylation of lipid metabolism enzymes | Identifying regulatory phosphorylation sites. |
| RNA-seq | Transcriptional changes in lipid remodeling genes | Assessing gene expression under conditions. |
| Bioinformatics pathway analysis | Enrichment of lipid metabolism pathways | Interpreting omics data. |
Lipidomics and Mass Spectrometry
Electrospray ionization tandem mass spectrometry (ESI-MS/MS) is the gold standard for analyzing PS molecular species and their acyl chain composition. This technique allows the identification and quantification of individual lipid species, including lysoPS intermediates, and can be combined with isotope labeling to trace remodeling dynamics.
Isotope Labeling
Exogenous heavy isotope-labeled lipid species can be used to monitor the incorporation and removal of acyl chains in phosphatidylserine. This approach provides detailed information on the enzymatic steps and kinetics of acyl chain remodeling.
CRISPR-Based Genetic Screens
CRISPR knockout and activation screens can identify genes that regulate PS acyl-chain remodeling. By coupling these screens with lipidomic readouts, researchers can discover novel enzymes and regulatory factors.
Fluorescence Imaging
Fluorescently tagged lipid-binding domains or antibodies can visualize PS distribution and dynamics in live cells. This helps to correlate acyl chain remodeling with changes in membrane organization and protein localization.
How CRISPR Can Be Used to Study GO:0036150 phosphatidylserine acyl-chain remodeling
Knockout
CRISPR knockout of genes encoding phospholipases or acyltransferases can abolish specific steps in PS acyl-chain remodeling. For example, knocking out LPCAT1 in cancer cells can alter PS species and affect KRAS signaling. Knockout models are essential for determining the necessity of a gene in the remodeling process.
Point Mutation
Introducing point mutations in catalytic residues of remodeling enzymes via CRISPR can dissect their enzymatic activity and substrate specificity. For instance, mutating the active site of a lysophosphatidylserine acyltransferase can reveal its role in acyl chain selection.
Knock-in
CRISPR knock-in of tags (e.g., GFP, HA) allows visualization and immunoprecipitation of remodeling enzymes to study their localization and interactions. Knock-in of disease-associated mutations can model human disorders linked to PS remodeling defects.
Overexpression
CRISPR activation (CRISPRa) or lentiviral overexpression can increase the levels of remodeling enzymes, enabling gain-of-function studies. Overexpression of LPCAT1, for example, can suppress KRAS nanoclustering, demonstrating the impact of lipid remodeling on oncogenic signaling.
How EDITGENE Supports phosphatidylserine acyl-chain remodeling Research
Researchers studying phosphatidylserine acyl-chain remodeling-related genes often need to determine whether a candidate gene is causally involved in lipid metabolism, membrane dynamics, or disease. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this research, from gene knockout to precise point mutations and overexpression models.
Contact EDITGENE today to design your custom CRISPR model for phosphatidylserine acyl-chain remodeling research.
Frequently Asked Questions About phosphatidylserine acyl-chain remodeling
What is phosphatidylserine acyl-chain remodeling?
Phosphatidylserine acyl-chain remodeling is the biological process (GO:0036150) that modifies the fatty acid chains of phosphatidylserine through deacylation and re-acylation, generating diverse PS molecular species.
What genes are involved in phosphatidylserine acyl-chain remodeling?
Key genes include PLA2G4A, PLA2G6, LPCAT1, LPCAT3, MBOAT1, MBOAT2, and AGPAT1/2, which encode enzymes that remove or add acyl chains to PS.
How is phosphatidylserine acyl-chain remodeling studied?
It is studied using lipidomics (ESI-MS/MS), isotope labeling, CRISPR screens, and fluorescence imaging to track lipid species and enzyme functions.
Why is phosphatidylserine acyl-chain remodeling important?
It regulates membrane properties, cell signaling, and is implicated in cancer, neurodegeneration, and metabolic disorders.
What diseases are associated with defects in phosphatidylserine remodeling?
Diseases include cancer (e.g., KRAS-driven), neurodegeneration (e.g., PLA2G6 mutations), and lipodystrophy (AGPAT2 mutations).
Which enzymes catalyze phosphatidylserine acyl-chain remodeling?
Phospholipase A2 (PLA2) removes acyl chains, and lysophosphatidylserine acyltransferases (LPSATs) add new ones.
Can CRISPR be used to study phosphatidylserine acyl-chain remodeling?
Yes, CRISPR knockout, knock-in, point mutation, and overexpression models are powerful tools to dissect gene function in this process.
What is the role of LPCAT1 in phosphatidylserine remodeling?
LPCAT1 is a phospholipid remodeling enzyme that can suppress KRAS nanoclustering and function, linking PS remodeling to cancer signaling.
How does phosphatidylserine remodeling affect membrane function?
It alters membrane fluidity, curvature, and lipid-protein interactions, impacting processes like signal transduction and membrane trafficking.
What are the latest advances in phosphatidylserine remodeling research?
Recent advances include detailed lipidomic profiling, isotope tracing, and the discovery of allele-specific lipid metabolism in KRAS mutants.
Conclusion
Phosphatidylserine acyl-chain remodeling (GO:0036150) is a fundamental biological process that generates lipid diversity and regulates membrane function. Through the coordinated action of phospholipases and acyltransferases, cells can dynamically adjust the acyl chain composition of PS to meet physiological demands. Dysregulation of this process contributes to cancer, neurodegeneration, and metabolic diseases, making it a promising target for therapeutic intervention. Continued research using advanced lipidomics and CRISPR-based models will further elucidate the molecular mechanisms and disease relevance of PS remodeling.
References
- 1. Schneiter R et al.. 1999. Electrospray ionization tandem mass spectrometry (ESI-MS/MS) analysis of the lipid molecular species composition of yeast subcellular membranes reveals acyl chain-based sorting/remodeling of distinct molecular species en route to the plasma membrane.. J Cell Biol 146(4):741-54 PMID: 10459010
- 2. Rajakumari S et al.. 2025. EBF2 regulates cardiolipin and phosphatidylethanolamine remodeling and mitochondrial dynamics in brown fat.. J Lipid Res 66(10):100888 PMID: 40865612
- 3. Kainu V et al.. 2008. Electrospray ionization mass spectrometry and exogenous heavy isotope-labeled lipid species provide detailed information on aminophospholipid acyl chain remodeling.. J Biol Chem 283(6):3676-3687 PMID: 18056998
- 4. Arora N et al.. 2024. Lysophosphatidylcholine acyltransferase 1 suppresses nanoclustering and function of KRAS.. bioRxiv PMID: 38853864
- 5. Kim KH et al.. 2026. Decoding Membrane Lipids: Analytical Barriers and Technological Advances in Modern Lipidomics.. Int J Mol Sci 27(3) PMID: 41683891
- 6. Martínez-Montañés F et al.. 2020. Phosphoproteomic Analysis across the Yeast Life Cycle Reveals Control of Fatty Acyl Chain Length by Phosphorylation of the Fatty Acid Synthase Complex.. Cell Rep 32(6):108024 PMID: 32783946
- 7. Zhou Y et al.. 2021. Caveolin-1 and cavin1 act synergistically to generate a unique lipid environment in caveolae.. J Cell Biol 220(3) PMID: 33496726
- 8. Arora N et al.. 2026. KRAS G12C and KRAS G12D respond to lipid metabolism in an allele-specific manner.. J Lipid Res 67(7):101079 PMID: 42303154
