PLA2G4A

Detailed Information

The PLA2G4A gene is located on human chromosome 1q25 and contains 18 exons. It encodes cytosolic phospholipase A2 (cPLA2α), a protein of approximately 85 kDa. Through selective promoters and alternative splicing, the gene produces multiple transcript variants, with the major isoform composed of 749 amino acids and three essential functional domains: an N-terminal calcium-dependent lipid-binding C2 domain, a central catalytic domain, and a C-terminal phosphorylation regulatory region. The C2 domain confers unique calcium sensitivity—when intracellular calcium concentration ([Ca²⁺]i) rises above 500 nM, this domain binds phosphatidylserine in cell membranes, driving enzyme translocation from the cytosol to the Golgi, endoplasmic reticulum, and nuclear envelope. The catalytic domain contains a highly conserved Ser228/Asp549 catalytic dyad, responsible for hydrolyzing the ester bond at the sn-2 position of glycerophospholipids.

Functions and Enzymatic Activities

cPLA2α, encoded by PLA2G4A, is a pivotal regulator of phospholipid metabolism, exhibiting multiple enzymatic activities. Its core role is calcium-dependent phospholipase A2 activity, which specifically hydrolyzes arachidonic acid (AA) at the sn-2 position of glycerophospholipids. This reaction generates two key signaling molecules: free AA and lysophospholipids. AA is further metabolized via cyclooxygenase (COX) pathways into prostaglandins (PGs) and thromboxane A2 (TXA2), or via lipoxygenase (LOX) pathways into leukotrienes (LTs) and lipoxins. These eicosanoids play central roles in inflammation, vascular homeostasis, and pain perception. Lysophospholipids, on the other hand, may be converted into platelet-activating factor (PAF) or serve as precursors for lysophosphatidic acid (LPA), which regulates cell proliferation. Additionally, under certain conditions, cPLA2α displays phospholipase A1 activity (hydrolyzing sn-1 acyl chains) and O-acyltransferase activity (catalyzing fatty acid transfer to glycerol), thereby participating in monoacylglycerol synthesis.

Regulation of cPLA2α

cPLA2α activity is tightly regulated by multiple mechanisms. Besides calcium-mediated membrane translocation, phosphorylation is a key mode of control. MAPK signaling enhances enzyme activity via phosphorylation at Ser505, while CaMKII phosphorylation at Ser515 promotes Golgi localization. Membrane lipid composition also modulates activity—phosphatidylinositol 4,5-bisphosphate (PIP2) enhances cPLA2α via allosteric effects, whereas sphingolipids exert inhibition. Such multilayered regulation ensures precise control of eicosanoid production across different physiological conditions.

Disease Associations and Pathological Mechanisms

Inflammatory Diseases

PLA2G4A is a central regulator of inflammation, and gain-of-function mutations are associated with multiple autoinflammatory diseases. GWAS identified a promoter SNP (rs10798059) strongly linked to rheumatoid arthritis (RA) risk (OR=1.28, p=3.2×10⁻⁸). Mechanistically, the risk allele increases NF-κB binding affinity to the PLA2G4A promoter, raising synovial cPLA2α expression 2.3-fold and enhancing PGE2 and LTB4 production, which drives joint inflammation and bone erosion. In asthma, epithelial overexpression of cPLA2α elevates LTC4 synthesis, causing bronchoconstriction and mucus hypersecretion. Clinical studies report cPLA2α activity in bronchoalveolar lavage fluid of asthma patients is 3.5-fold higher than in controls, correlating negatively with FEV1 decline (r=-0.41, p<0.001).

Metabolic Diseases

PLA2G4A contributes to insulin resistance and adipose tissue inflammation. Adipocyte-specific cPLA2α knockout mice retain insulin sensitivity under high-fat diets, due to reduced PGE2 production and decreased macrophage infiltration. Clinically, PLA2G4A mRNA is 2.1-fold higher in subcutaneous adipose tissue of type 2 diabetes patients versus controls, positively correlating with fasting insulin (r=0.37, p=0.008). cPLA2α also plays a role in hepatic steatosis: by releasing AA, it promotes 4-HNE production, mitochondrial dysfunction, and triglyceride accumulation. In NAFLD biopsies, cPLA2α protein correlates positively with steatosis severity (r=0.49) and fibrosis stage (r=0.52).

Cancer Development

PLA2G4A’s role in cancer is complex and context-dependent. In lung cancer, PLA2G4A mRNA (p<0.05) and protein (p<0.001) are significantly upregulated, correlating with poor prognosis (HR=1.84, 95%CI 1.32–2.56). Mechanistically, cPLA2α drives tumor progression via PGE2-mediated EP2/EP4-cAMP-PKA signaling, suppressing anti-tumor immunity, and AA-derived HETEs, which promote proliferation and migration. Notably, its C2 domain can bind p53, blocking nuclear localization and transcriptional activity, thus impairing DNA repair.

Ferroptosis Regulation

Recent studies highlight PLA2G4A as a key regulator of ferroptosis, an iron-dependent lipid peroxidation-driven form of cell death. Knockdown of PLA2G4A in lung cancer cells elevates Fe²⁺ levels 1.8-fold, increases lipid peroxidation products 2.3-fold, and reduces GPX4 activity by 65%, enhancing sensitivity to erastin by 10.7-fold. Mechanistically, cPLA2α contributes through two pathways: (1) hydrolyzing phospholipids to release PUFAs, substrates for lipid peroxidation; (2) upregulating SLC7A11 expression, which maintains antioxidant defenses. Knockdown reduces SLC7A11 by ~60%. Clinical lung adenocarcinoma samples confirm a positive correlation between PLA2G4A and SLC7A11 (r=0.23, p<0.001). This suggests that PLA2G4A inhibition could sensitize tumors to ferroptosis-inducing therapy.

Therapeutic Target Development and Challenges

Several inhibitors are in development. Pyrrolidone derivatives (e.g., AX059) competitively inhibit catalytic activity with IC50 = 0.2 μM. In collagen-induced arthritis, AX059 reduced joint swelling by 68% and synovial PGE2 by 82%. Indole derivative GY397 acts allosterically, suppressing airway hyperreactivity in asthma by 75%. Some NSAIDs indirectly inhibit cPLA2α—ibuprofen reduces Ca²-mediated membrane translocation, while indomethacin limits AA release.

Therapeutic strategies often combine PLA2G4A inhibitors with ferroptosis inducers. AAV-848 plus erastin reduced lung tumor xenografts by 92% (vs. 45% with monotherapy) and extended survival. This synergy arises from the downregulation of SLC7A11 and altered PUFA availability.

Advances in chemical biology tools expand PLA2G4A research. Photoactivatable probes enable live-cell dynamics tracking, while PROTACs induce targeted degradation. Personalized therapy based on PLA2G4A genotypes (e.g., rs10798059 in RA) and expression signatures (PLA2G4A/SLC7A11 co-expression in lung cancer) holds promise. Multi-omics revealed novel roles: CDK5 phosphorylation at Ser728 links cPLA2α to mitochondrial phospholipid remodeling, while lipidomics implicates cardiolipin hydrolysis in mitophagy. Future strategies combining PLA2G4A inhibitors with advanced delivery systems (e.g., exosomes, prodrugs) may unlock new therapeutic frontiers in inflammation, cancer, and metabolism.

Reference

1. Valdes AM, Spector TD. The genetic epidemiology of osteoarthritis. Curr Opin Rheumatol. 2010 Mar;22(2):139-43.

2. McAlindon ME. Cryptogenic multifocal ulcerating stenosing enteritis and other under-recognised small bowel inflammatory enteropathies. Curr Opin Gastroenterol. 2022 May 1;38(3):279-284.