GO:0140615 ATP-dependent citrate lyase complex: Components, Assembly and Research Methods, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0140615 (ATP-dependent citrate lyase complex) is a cellular component defined as a protein complex that catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA.
• The complex contains ATP citrate lyase (ACLY), which links carbohydrate metabolism to lipid synthesis and histone acetylation.
• ACLY is regulated by acetylation, ubiquitination, and mTORC2-AKT signaling, affecting its stability and activity.
• The complex supports de novo lipogenesis, brown adipogenesis, oocyte maturation, and vascular remodeling.
• Dysregulation of ACLY is implicated in cancers, metabolic disorders, and cardiovascular diseases.
• CRISPR knockout, knock-in, and overexpression models are essential to dissect ACLY complex function in health and disease.
Description
The ATP-dependent citrate lyase complex (GO:0140615) is a cellular component that catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA, a key reaction connecting glucose metabolism to lipid biosynthesis and protein acetylation. This complex is essential for de novo lipogenesis in lipogenic tissues and for providing acetyl-CoA for histone acetylation, thereby influencing gene expression. Researchers study this complex to understand metabolic reprogramming in cancer, immune cell exhaustion, and vascular diseases. The complex is dynamically regulated by post-translational modifications and signaling pathways such as mTORC2-AKT, which phosphorylates ACLY to drive brown adipogenesis and lipogenesis. Because ACLY is a central metabolic node, its dysfunction is linked to tumor growth, oocyte maturation defects, and systemic vascular remodeling. Thus, GO:0140615 represents a critical interface between metabolism, epigenetics, and disease.
ATP-dependent citrate lyase complex At A Glance
| GO ID | GO:0140615 |
|---|---|
| GO term | ATP-dependent citrate lyase complex |
| Ontology | cellular_component |
| Synonym | citrate lyase complex, citrate synthase complex |
| Major function | Catalyzes cleavage of citrate into oxaloacetate and acetyl-CoA |
| Associated enzyme | ATP citrate lyase (ACLY) |
| Pathways | Lipid biosynthesis, histone acetylation, glucose metabolism |
| Disease relevance | Cancer, metabolic disorders, vascular diseases |
What Is GO:0140615?
The ATP-dependent citrate lyase complex is a protein complex that catalyzes the ATP-dependent cleavage of citrate into oxaloacetate and acetyl-CoA. This definition is based on the Gene Ontology cellular component term GO:0140615, which describes a molecular machine dedicated to this specific metabolic reaction.
Why Is ATP-dependent citrate lyase complex Important in Cell Biology?
The ATP-dependent citrate lyase complex is important because it occupies a central position in cellular metabolism, converting citrate into acetyl-CoA for lipid synthesis and protein acetylation. This complex is required for de novo lipogenesis in brown adipocytes and for oocyte maturation, and its activity supports cancer cell proliferation and immune cell function. Dysregulation of the complex contributes to tumor growth, vascular remodeling, and metabolic diseases, making it a therapeutic target.
• Provides acetyl-CoA for de novo lipogenesis in lipogenic tissues.
• Supports histone acetylation and epigenetic regulation of gene expression.
• Required for oocyte maturation and female fertility.
• Drives brown adipogenesis and adaptive thermogenesis.
• Promotes tumor growth and metastasis in multiple cancers.
• Mediates vascular remodeling in systemic and pulmonary vascular diseases.
• Regulated by acetylation, ubiquitination, and mTORC2-AKT signaling.
• Target for small-molecule inhibitors in cancer therapy.
• Links nutrient availability to CD8+ T cell exhaustion.
• Involved in KRAS-LKB1 co-mutated lung cancer invasion.
Structure and Composition of ATP-dependent citrate lyase complex
Core Enzyme: ATP Citrate Lyase (ACLY)
In simple terms: The main worker in this complex is an enzyme called ACLY.
The ATP-dependent citrate lyase complex contains ATP citrate lyase (ACLY) as its catalytic subunit, which cleaves citrate into oxaloacetate and acetyl-CoA in an ATP-dependent manner. ACLY is a homotetramer in solution and is highly expressed in lipogenic tissues.
Assembly and Post-Translational Modifications
In simple terms: The complex is put together and modified by chemical tags that change its stability.
ACLY is stabilized by acetylation, which prevents its ubiquitination and degradation, thereby promoting lipid biosynthesis and tumor growth. Conversely, selective autophagic degradation of ACLY maintains citrate homeostasis during oocyte maturation.
Regulatory Subunits and Interactors
In simple terms: Other proteins can attach to ACLY and control its activity.
mTORC2-AKT signaling phosphorylates ACLY at S455, which is required for brown adipogenesis and de novo lipogenesis. Additionally, PSMD14-mediated deubiquitination of LDHA upregulates ACLY expression via H3K18 lactylation, linking glycolysis to ACLY transcription.
Subcellular Localization
In simple terms: The complex is found in the main fluid of the cell, where metabolism happens.
ACLY localizes predominantly to the cytosol, where it generates acetyl-CoA for lipogenesis and acetylation reactions. It can also be found in the nucleus, contributing to histone acetylation and gene regulation.
Dynamic Regulation by Nutrients
In simple terms: What you eat and how your cells use energy can change how this complex works.
Nutrient-driven histone code determines exhausted CD8+ T cell fates, with ACLY-dependent acetyl-CoA production influencing histone acetylation and T cell exhaustion. In vascular diseases, ACLY drives metabolic and epigenetic changes that promote remodeling.
Key Genes Involved in GO:0140615 ATP-dependent citrate lyase complex
The following genes and proteins are key components or regulators of the ATP-dependent citrate lyase complex and its associated pathways.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ACLY | Catalytic subunit of the complex; cleaves citrate to acetyl-CoA | Central to lipogenesis, histone acetylation, cancer, and metabolic diseases |
| AKT1 | Phosphorylates ACLY at S455 downstream of mTORC2 | Regulates brown adipogenesis and lipogenesis |
| MTOR | Component of mTORC2 that activates AKT | Controls ACLY phosphorylation and lipid synthesis |
| LDHA | Produces lactate that drives H3K18 lactylation and ACLY expression | Links glycolysis to ACLY transcription in pancreatic cancer |
| PSMD14 | Deubiquitinates LDHA, indirectly upregulating ACLY | Promotes lipid synthesis and cancer progression |
| SNAI1 | Snail acetylation by autophagy-derived acetyl-CoA promotes invasion | Influences metastasis in KRAS-LKB1 co-mutated lung cancer |
| LKB1 | Tumor suppressor; co-mutation with KRAS affects ACLY-dependent invasion | Context for Snail acetylation and metastasis |
| KRAS | Oncogene; co-mutation with LKB1 alters acetyl-CoA metabolism | Drives aggressive lung cancer phenotypes |
| H3-18 | Histone H3 lysine 18 lactylation | Epigenetic mark that upregulates ACLY expression |
| H3 | Histone H3 acetylation | Nutrient-driven histone code in T cell exhaustion |
| CD8A | Marker of CD8+ T cells | ACLY-dependent histone acetylation determines exhausted T cell fates |
| ATG5 | Autophagy-related protein | Selective autophagic degradation of ACLY in oocyte maturation |
| MAP1LC3B | Autophagosome marker | Involved in ACLY degradation during oocyte maturation |
| SREBF1 | Transcription factor for lipogenic genes | Downstream of ACLY-mediated lipogenesis |
| FASN | Fatty acid synthase | Works with ACLY in de novo lipogenesis |
| SCD | Stearoyl-CoA desaturase | Lipogenic enzyme downstream of ACLY |
| ACACA | Acetyl-CoA carboxylase | Lipogenic enzyme cooperating with ACLY |
How Is ATP-dependent citrate lyase complex Regulated?
The ATP-dependent citrate lyase complex is regulated at multiple levels. Acetylation of ACLY stabilizes the protein by preventing ubiquitination, thereby promoting lipid biosynthesis and tumor growth. Selective autophagic degradation of ACLY maintains citrate homeostasis during oocyte maturation. mTORC2-AKT signaling phosphorylates ACLY at S455, driving brown adipogenesis and de novo lipogenesis. Additionally, PSMD14-mediated deubiquitination of LDHA upregulates ACLY expression via H3K18 lactylation, linking glycolysis to ACLY transcription in pancreatic cancer. Nutrient availability influences histone acetylation and CD8+ T cell exhaustion through ACLY-dependent acetyl-CoA production.
ATP-dependent citrate lyase complex and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ACLY | Cancer, metabolic disorders, vascular diseases | ACLY knockout or overexpression in cancer cell lines |
| ACLY | Oocyte maturation defects | Oocyte-specific Acly knockout mice |
| ACLY | Pulmonary hypertension | ACLY inhibitor in rodent models |
| LDHA/PSMD14 | Pancreatic cancer | LDHA or PSMD14 knockout in pancreatic cancer cells |
| KRAS/LKB1 | Lung cancer metastasis | KRAS-LKB1 co-mutant lung cancer models |
Cancer
ACLY is overexpressed or hyperactivated in many cancers, where it supports de novo lipogenesis and histone acetylation to promote tumor growth. Acetylation stabilizes ACLY, enhancing lipid biosynthesis and tumor progression. In pancreatic cancer, PSMD14-mediated LDHA deubiquitination upregulates ACLY via H3K18 lactylation, driving lipid synthesis and cancer progression. In KRAS-LKB1 co-mutated lung cancer, autophagy-derived acetyl-CoA promotes Snail acetylation and metastasis.
Metabolic and Reproductive Disorders
Selective autophagic degradation of ACLY maintains citrate homeostasis and promotes oocyte maturation, suggesting that dysregulation may impair fertility. ACLY also drives brown adipogenesis and de novo lipogenesis, linking it to obesity and metabolic syndrome.
Vascular Diseases
ATP citrate lyase drives vascular remodeling in systemic and pulmonary vascular diseases through metabolic and epigenetic changes, making it a potential therapeutic target.
Immune Exhaustion
Nutrient-driven histone code determines exhausted CD8+ T cell fates, with ACLY-dependent acetyl-CoA production influencing T cell exhaustion and immunotherapy responses.
From ATP-dependent citrate lyase complex-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does ACLY loss impair lipogenesis? | ACLY knockout cell lines (e.g., HepG2, A549) |
| Does ACLY acetylation affect stability? | Point mutation of ACLY acetylation sites (K540, K546, etc.) |
| Does ACLY S455 phosphorylation drive adipogenesis? | Knock-in of phospho-deficient or phospho-mimetic ACLY |
| Does ACLY degradation affect oocyte maturation? | Tagged ACLY knock-in for autophagy studies |
| Does ACLY overexpression promote tumor growth? | ACLY overexpression in cancer cell lines and xenografts |
| Does ACLY inhibition reverse vascular remodeling? | ACLY knockout or inhibitor in pulmonary artery smooth muscle cells |
How to Study the ATP-dependent citrate lyase complex Process
| Method | What It Measures | Typical Application |
|---|---|---|
| 13C metabolic flux | Acetyl-CoA and lipid synthesis | Assessing ACLY activity in cancer cells |
| ChIP-seq | Histone acetylation and lactylation | Epigenetic regulation by ACLY |
| Immunoblotting | ACLY protein levels and modifications | Post-translational regulation |
| CRISPR knockout | Gene function loss | ACLY dependency in cancer |
| Autophagy flux assay | ACLY degradation | Oocyte maturation studies |
| Phospho-specific antibodies | ACLY S455 phosphorylation | mTORC2-AKT signaling |
| Lactylation assays | H3K18 lactylation | Pancreatic cancer progression |
| Xenograft models | Tumor growth | ACLY overexpression or knockout |
Metabolic Flux Analysis
Metabolic flux analysis using 13C-labeled citrate or glucose can measure ACLY-dependent acetyl-CoA production and lipogenesis.
Chromatin Immunoprecipitation (ChIP)
ChIP for histone acetylation marks (e.g., H3K27ac, H3K18la) can assess the impact of ACLY-derived acetyl-CoA on gene expression.
Proteomics and Immunoblotting
Immunoblotting for ACLY, phospho-ACLY (S455), and acetylation levels can reveal post-translational regulation.
CRISPR Screening
Genome-wide CRISPR knockout screens can identify synthetic lethal interactions with ACLY inhibition in cancer cells.
How CRISPR Can Be Used to Study GO:0140615 ATP-dependent citrate lyase complex
Knockout
CRISPR knockout of ACLY in cancer cell lines reduces de novo lipogenesis and inhibits tumor growth, validating its role in metabolic reprogramming.
Point Mutation
Point mutations of ACLY acetylation sites (e.g., K540R, K546R) prevent acetylation and destabilize the protein, revealing the importance of acetylation for lipid biosynthesis.
Knock-in
Knock-in of phospho-mimetic (S455D) or phospho-deficient (S455A) ACLY can dissect the role of mTORC2-AKT signaling in brown adipogenesis.
Overexpression
Overexpression of ACLY in cancer cells promotes lipid synthesis and tumor growth, providing a model to test ACLY inhibitors.
How EDITGENE Supports ATP-dependent citrate lyase complex Research
Researchers studying ATP-dependent citrate lyase complex-related genes often need to determine whether a candidate gene is causally involved in lipid metabolism, epigenetic regulation, or disease progression. EDITGENE provides comprehensive CRISPR services to generate precisely engineered cell models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for ATP-dependent citrate lyase complex research.
Frequently Asked Questions About ATP-dependent citrate lyase complex
What is the ATP-dependent citrate lyase complex?
It is a protein complex (GO:0140615) that catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA, linking glucose metabolism to lipid synthesis and acetylation.
What genes are involved in the ATP-dependent citrate lyase complex?
The core gene is ACLY, which encodes ATP citrate lyase. Regulators include AKT1, MTOR, LDHA, and PSMD14.
What is the function of ACLY in cancer?
ACLY supports de novo lipogenesis and histone acetylation, promoting tumor growth and metastasis in multiple cancers.
How is ACLY regulated?
ACLY is regulated by acetylation, ubiquitination, autophagy, and mTORC2-AKT phosphorylation.
What diseases are associated with ACLY dysfunction?
ACLY is implicated in cancers, metabolic disorders, vascular remodeling, and oocyte maturation defects.
What is the role of ACLY in oocyte maturation?
Selective autophagic degradation of ACLY maintains citrate homeostasis and promotes oocyte maturation.
How does ACLY affect histone acetylation?
ACLY produces acetyl-CoA, which is used for histone acetylation, influencing gene expression and T cell exhaustion.
What are ACLY inhibitors?
ACLY inhibitors are small molecules that target the enzyme's activity and are being developed as therapeutic agents for cancer and metabolic diseases.
What is the link between ACLY and pancreatic cancer?
PSMD14-mediated LDHA deubiquitination upregulates ACLY via H3K18 lactylation, promoting lipid synthesis and pancreatic cancer progression.
How can CRISPR be used to study ACLY?
CRISPR knockout, point mutation, knock-in, and overexpression models allow precise dissection of ACLY function in metabolism and disease.
Conclusion
The ATP-dependent citrate lyase complex (GO:0140615) is a central metabolic machine that converts citrate to acetyl-CoA, fueling lipogenesis and epigenetic regulation. Its dysregulation is linked to cancer, metabolic disorders, and vascular diseases, making it a prime therapeutic target. CRISPR-based models are indispensable for understanding its precise roles and for developing targeted interventions.
References
- 1. Ma S et al.. 2025. Nutrient-driven histone code determines exhausted CD8(+) T cell fates.. Science 387(6734):eadj3020 PMID: 39666821
- 2. He H et al.. 2023. Selective autophagic degradation of ACLY (ATP citrate lyase) maintains citrate homeostasis and promotes oocyte maturation.. Autophagy 19(1):163-179 PMID: 35404187
- 3. Grobs Y et al.. 2024. ATP citrate lyase drives vascular remodeling in systemic and pulmonary vascular diseases through metabolic and epigenetic changes.. Sci Transl Med 16(777):eado7824 PMID: 39661707
- 4. Martinez Calejman C et al.. 2020. mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis.. Nat Commun 11(1):575 PMID: 31996678
- 5. Lin R et al.. 2013. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth.. Mol Cell 51(4):506-518 PMID: 23932781
- 6. Granchi C. 2022. ATP-citrate lyase (ACLY) inhibitors as therapeutic agents: a patenting perspective.. Expert Opin Ther Pat 32(7):731-742 PMID: 35436171
- 7. Lu RS et al.. 2025. PSMD14-Mediated LDHA Deubiquitination Upregulates ACLY Expression via H3K18 Lactylation to Promote Lipid Synthesis and Pancreatic Cancer Progression.. Adv Sci (Weinh) 12(44):e05762 PMID: 41051446
- 8. Han JH et al.. 2022. Snail acetylation by autophagy-derived acetyl-coenzyme A promotes invasion and metastasis of KRAS-LKB1 co-mutated lung cancer cells.. Cancer Commun (Lond) 42(8):716-749 PMID: 35838183
