Affinage

PLA2G4A

Cytosolic phospholipase A2 · UniProt P47712

Length
749 aa
Mass
85.2 kDa
Annotated
2026-06-10
35 papers in source corpus 14 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLA2G4A (cytosolic phospholipase A2-alpha, cPLA2-alpha) is the principal Ca2+-dependent enzyme that liberates arachidonic acid (AA) from membrane phospholipids to fuel eicosanoid biosynthesis across inflammation, immune defense, reproduction, and cancer (PMID:12676927, PMID:15475363). Calcium elevation drives its C2 domain to insert into lipid membranes, with the calcium-binding loops CBL1 and CBL3 penetrating the phospholipid tail region and positioning bound Ca2+ ions adjacent to the headgroup phosphate (PMID:15994899); this Ca2+-triggered translocation relocates cPLA2-alpha to the trans-Golgi where it co-localizes specifically with COX-1 to couple AA release to prostaglandin synthesis (PMID:12711701). In innate immunity, cPLA2-alpha is required for neutrophil AA release, PAF biosynthesis, and efficient bacterial killing and pulmonary defense, while being dispensable for NADPH oxidase activation, granule secretion, and phagocytosis (PMID:15475363, PMID:17185330). PLA2G4A expression and activity are controlled at multiple levels: transcriptionally by ATF6alpha, the NRF2-PIR circuit, and GSK3beta/NF-kappaB, and post-translationally by PTRF, which stabilizes the protein against proteasomal degradation (PMID:35547748, PMID:35089606, PMID:41400081, PMID:42047940). Through these inputs, cPLA2-alpha-mediated AA/PGE2 production suppresses ferroptosis in prostate and colorectal cancer and reprograms the tumor immune microenvironment by polarizing CD39+ gamma-delta Tregs (PMID:35089606, PMID:34283812, PMID:41400081). In the nervous system, excessive cPLA2-alpha activity causes lysosomal membrane permeabilization that blocks autophagy flux and drives neuronal death following traumatic brain injury and in Alzheimer's models (PMID:31238788, PMID:42047940).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2003 High

    Establishing which phospholipase carries out stimulus-coupled arachidonic acid release resolved cPLA2-alpha as the obligate effector downstream of secretory PLA2s and ERK/PKC signaling.

    Evidence cPLA2-alpha-knockout mesangial cells with isoform-specific adenoviral re-expression and pharmacological MEK/PKC/Ca2+ blockade, AA release assays

    PMID:12676927

    Open questions at the time
    • Did not resolve how sPLA2 activity mechanistically depends on cPLA2-alpha
    • Restricted to mesangial cells under oxidative stress
  2. 2003 Medium

    Defining where the activated enzyme acts showed that Ca2+ drives cPLA2-alpha to the trans-Golgi to co-localize with COX-1, providing a spatial basis for AA-to-prostaglandin coupling.

    Evidence Confocal microscopy after Ca2+ ionophore stimulation with Golgi-subcompartment and COX markers, brefeldin A perturbation in A549 cells

    PMID:12711701

    Open questions at the time
    • Single cell line
    • Did not establish the targeting determinant for trans-Golgi versus other membranes
  3. 2004 High

    Dissecting cPLA2-alpha's immune role showed it is specifically required for neutrophil AA/PAF generation and antibacterial defense but not for the oxidative burst, separating lipid signaling from other effector functions.

    Evidence Gene-disrupted mice plus pharmacological inhibition in human neutrophils, AA/PAF assays, bacterial killing, in vivo E. coli pulmonary infection

    PMID:15475363

    Open questions at the time
    • Partial rescue by exogenous AA/PAF left other contributing pathways unresolved
  4. 2005 High

    Determining how cPLA2-alpha engages membranes showed the C2 domain inserts CBL loops into the lipid tail region with Ca2+ ions at the phosphate, explaining the calcium dependence of translocation.

    Evidence X-ray reflectivity of the C2 domain on lipid monolayers with domain mutants and Ca2+-free controls

    PMID:15994899

    Open questions at the time
    • Isolated C2 domain rather than full-length enzyme
    • Model membrane rather than native bilayer
  5. 2006 High

    Testing functional specificity confirmed PKC, not cPLA2-alpha, drives NADPH oxidase and proton channel gating, sharpening the boundary of cPLA2-alpha's effector functions.

    Evidence Knockout mice and three independent inhibitors in eosinophils/granulocytes with perforated-patch electrophysiology

    PMID:17185330

    Open questions at the time
    • Negative result for a specific pathway; does not address other granulocyte functions
  6. 2006 Medium

    Linking cPLA2-alpha to reproduction showed hCG induces its expression via cAMP signaling in ovulatory granulosa cells, implicating it in prostaglandin production during ovulation.

    Evidence Timed hCG injection in bovine model, RT-PCR/Western/IHC, in vitro forskolin stimulation

    PMID:16510840

    Open questions at the time
    • Correlative expression; did not demonstrate functional requirement in ovulation
    • Single species
  7. 2019 High

    Identifying a pathological consequence of excess activity showed cPLA2-alpha drives lysosomal membrane permeabilization that blocks autophagy and kills neurons after brain injury.

    Evidence Lysosomal lipidomics, AACOCF3 inhibition, in vitro neuron assays, in vivo CCI mouse model with autophagy/neuronal-death readouts

    PMID:31238788

    Open questions at the time
    • Used pharmacological rather than genetic loss-of-function in vivo
    • Mechanism linking AA release to LMP not fully resolved
  8. 2021 Medium

    Connecting cPLA2-alpha to tumor immunity showed its AA pathway polarizes CD39+ gamma-delta Tregs to suppress anti-tumor responses in colorectal cancer.

    Evidence Quantitative mass spectrometry, co-culture, orthotopic murine CRC model with Pla2g4a overexpression, flow cytometry

    PMID:34283812

    Open questions at the time
    • Relied on overexpression
    • Downstream AA metabolite mediating Treg polarization not pinpointed
  9. 2022 Medium

    Defining upstream control identified two regulatory layers: PTRF stabilizes cPLA2-alpha protein against proteasomal degradation, and ATF6alpha transcriptionally activates it, with both axes feeding AA/ferroptosis outcomes.

    Evidence ChIP, Co-IP, luciferase, proteasome inhibition, genetic KO/KD in neurons and prostate cancer cells with AA/PGE2 ELISA and in vivo models

    PMID:35089606 PMID:35547748

    Open questions at the time
    • Single labs for each axis
    • How PTRF binding physically blocks degradation unresolved
  10. 2026 Medium

    Extending transcriptional regulation, the NRF2-PIR circuit and GSK3beta/NF-kappaB were shown to set PLA2G4A levels that tune the cellular lipidome toward or away from ferroptosis and govern lysosomal integrity in neurodegeneration.

    Evidence NRF2/PIR ChIP, lipidomics, genetic deletion and PLA2G4A rescue in CRC and AOM/DSS models; GSK3alpha/beta and PLA2G4A knockdown plus AS1842856 in APP/PS1 mice and N2a cells

    PMID:41400081 PMID:42047940

    Open questions at the time
    • Each regulatory axis from a single lab
    • Whether these inputs converge on the same enzyme pool unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple transcriptional and post-translational inputs are integrated to direct cPLA2-alpha between protective and pathological (e.g., Golgi-COX coupling versus lysosomal permeabilization) membrane targets remains unresolved.
  • No unified model linking specific upstream regulators to subcellular targeting outcomes
  • Structural basis for differential membrane targeting beyond the C2 domain not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0008289 lipid binding 1
Localization
GO:0005764 lysosome 1 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-5357801 Programmed Cell Death 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2
Partners
CENPFCOX-1PTRF

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 PLA2G4A/cPLA2-alpha activation causes lysosomal membrane permeabilization (LMP) in neurons, leading to inhibition of autophagy flux and neuronal cell death following traumatic brain injury; pharmacological inhibition of PLA2G4A attenuated TBI-induced LMP, autophagy impairment, and neuronal loss in vivo, and limited amyloid-β-induced LMP in vitro. LC-MS/MS lysosomal membrane lipid profiling, pharmacological inhibition (AACOCF3), in vitro cell line and primary neuron assays, in vivo CCI mouse model with LC3/autophagy flux markers and neuronal death quantification Autophagy High 31238788
2003 cPLA2-alpha (PLA2G4A) is the primary enzyme responsible for arachidonic acid (AA) release in mesangial cells under oxidative stress; secretory PLA2s (group IIa and V) act as upstream regulators that depend on cPLA2-alpha activity and ERK1/2 and PKC signaling pathways to effect AA release. Genetic knockout mesangial cells (MC-/-) lacking cPLA2-alpha with recombinant adenovirus re-expression of specific PLA2 isoforms; pharmacological inhibition of MEK-1 (U0126), PKC (GF109203x), and calcium chelation (BAPTA-AM); AA release assays The Journal of biological chemistry High 12676927
2004 cPLA2-alpha (PLA2G4A) is necessary for neutrophil arachidonate release and platelet-activating factor (PAF) biosynthesis, but not for NADPH oxidase activation, granule secretion, or phagocytosis; cPLA2-alpha is required for efficient bacterial killing in vitro (partially rescued by exogenous AA or PAF) and for pulmonary innate immune defense in vivo. Pharmacological inhibition (Pyrrolidine-1) in human neutrophils; cPLA2-alpha gene-disrupted mice; AA release assays, PAF biosynthesis assays, NADPH oxidase activation, bacterial killing assays, in vivo E. coli pulmonary infection model The Journal of biological chemistry High 15475363
2005 The C2 domain of cPLA2-alpha (PLA2G4A) binds to phospholipid monolayers in a Ca2+-dependent manner, with the calcium-binding loops CBL1 and CBL3 penetrating 2 Å into the lipid tail region; Ca2+-bound protein places its Ca2+ ions within 1 Å of the lipid phosphate group, and binding involves loss of headgroup-associated water molecules (entropic contribution) alongside electrostatic and hydrophobic interactions. X-ray reflectivity of cPLA2-alpha C2 domain adsorbed onto Langmuir monolayers of SOPC; domain mutants and calcium-free controls; crystallographic structure-based electron density profile analysis Biophysical journal High 15994899
2003 In response to Ca2+ elevation, cPLA2-alpha (PLA2G4A) translocates from cytosol and nuclei to the trans-Golgi stack and trans-Golgi network in A549 lung epithelial cells, where it co-localizes specifically with cyclooxygenase-1 (COX-1) but not COX-2; this Golgi association was confirmed by sensitivity to brefeldin A. High-resolution confocal microscopy with Ca2+ ionophore A23187 stimulation; double staining with Golgi subcompartment markers and rhodamine-wheat germ agglutinin; brefeldin A disruption assay Journal of cell science Medium 12711701
2006 cPLA2-alpha (PLA2G4A) is not required for PMA-stimulated NADPH oxidase activation or voltage-gated proton channel enhanced gating in human eosinophils or murine granulocytes; PKC activity (not cPLA2-alpha) is required for sustained activation of both proton channels and NADPH oxidase. cPLA2-alpha gene knockout mice; three specific cPLA2-alpha inhibitors (Wyeth-1, pyrrolidine-2, AACOCF3) in human eosinophils; perforated-patch electrophysiology; PKC inhibitors (GFX, staurosporine); okadaic acid phosphatase inhibition The Journal of physiology High 17185330
2022 PTRF (Polymerase I and transcript release factor) stabilizes PLA2G4A protein by decreasing its proteasome-mediated degradation; PTRF overexpression enhances PLA2G4A activity and stability, promoting lipid metabolism reprogramming, mitochondrial bioenergetics changes, oxidative damage, autophagy, lipid peroxidation, and ferroptosis in neuronal cells after cerebral ischemia-reperfusion injury. HIF-1α and STAT3 regulate PTRF expression by binding its promoter. ChIP assay, luciferase assay, Co-IP, lentiviral-sgRNA knockout, AAV-shRNA knockdown in primary neurons and in vivo mouse I/R model; proteasome inhibition experiments; Western blot for PLA2G4A stability Theranostics Medium 35547748
2022 ATF6α transcriptionally activates PLA2G4A expression (confirmed by ChIP), leading to increased AA release and PGE2 production; this ATF6α-PLA2G4A axis protects prostate cancer cells against ferroptosis, and inhibition of ATF6α reduces PLA2G4A-mediated AA/PGE2 signaling to promote ferroptotic cell death. ChIP assay, Western blot, qPCR, AA and PGE2 ELISA assays; genetic and pharmacological ATF6α inhibition; cell death assays in prostate cancer cell lines The Prostate Medium 35089606
2006 PLA2G4A mRNA and protein expression is upregulated in bovine granulosa cells of ovulatory follicles in response to hCG via the adenylyl cyclase/cAMP pathway (confirmed by forskolin stimulation), implicating PLA2G4A in arachidonic acid release for prostaglandin biosynthesis during ovulation. In vivo bovine model with timed hCG injection; quantitative RT-PCR; Western blot; immunohistochemistry; in vitro forskolin stimulation of granulosa cells Biology of reproduction Medium 16510840
2021 PLA2G4A overexpression in colorectal cancer cells induces CD39+γδ Treg polarization through activation of the PLA2G4A/arachidonic acid metabolic pathway, which inhibits the anti-tumor immune response; this was demonstrated using in vitro co-culture and an orthotopic murine CRC model. Quantitative mass spectrometry, in vitro co-culture system, orthotopic murine CRC model with Pla2g4a-overexpressing CT26 cells, flow cytometry for CD39+γδ Treg quantification JCI insight Medium 34283812
2025 CENPF interacts physically with PLA2G4A (confirmed by molecular docking and Co-IP), and this interaction promotes glioma cell growth via mTORC1 and NF-κB pathways; silencing CENPF combined with PLA2G4A inhibitor AACOCF3 induced glioma cell apoptosis synergistically. Molecular docking, Co-IP, CENPF silencing (siRNA/shRNA), Western blot for mTORC1/NF-κB pathway proteins, CCK-8 proliferation assay, flow cytometry for apoptosis/cell cycle Cancer cell international Low 40025532
2025 Pirin (PIR) transcriptionally regulates PLA2G4A expression downstream of NRF2; PIR loss downregulates PLA2G4A (cPLA2α), increasing polyunsaturated fatty acid (PUFA)-containing phospholipids and shifting the lipidome toward a ferroptosis-permissive state. Restoration of PLA2G4A rescues ferroptosis resistance in PIR-deficient colorectal cancer cells, defining an NRF2-PIR-PLA2G4A circuit. NRF2 ChIP at PIR promoter, lipidomics, PIR genetic deletion (in vitro and intestinal epithelium-specific in vivo), PLA2G4A rescue experiments, pharmacological inhibition with AACOCF3, AOM/DSS tumorigenesis model Advanced science Medium 41400081
2019 ANXA10 upregulates PLA2G4A expression, which increases PGE2 production and activates STAT3 signaling, thereby facilitating epithelial-mesenchymal transition (EMT) and promoting metastasis in perihilar cholangiocarcinoma. mRNA sequencing after ANXA10 manipulation, Western blot, ELISA for PGE2, in vitro migration/invasion assays, in vivo metastasis model, correlation analysis of ANXA10 and PLA2G4A expression EBioMedicine Low 31492557
2026 GSK3β regulates PLA2G4A expression via an NF-κB-mediated transcriptional mechanism; pharmacological suppression of GSK3β with AS1842856 reduces NF-κB-driven PLA2G4A expression, restoring lysosomal membrane integrity and enhancing lysosomal degradation of amyloid-β in Alzheimer's disease models. Knockdown experiments established that GSK3β (but not GSK3α) specifically suppresses PLA2G4A. AS1842856 treatment in APP/PS1 mice and N2a-sw cells; GSK3α/β and PLA2G4A knockdown experiments; lysosomal integrity assays; cognitive function testing; Western blot for pathway proteins CNS neuroscience & therapeutics Medium 42047940
2025 The lncRNA PACERR interacts with an enhancer element affecting cPLA2/PLA2G4A transcriptional activation and escorts the cPLA2 protein to the nuclear membrane in response to HDL, where PLA2G4A releases arachidonic acid to further activate COX-2 and limit LXR/RXR-dependent ABCA1/ABCG1 transcription. PACERR antisense oligonucleotide silencing, humanized mouse model, RNA-protein interaction assays, ChIP/enhancer analysis, COX-2 and cholesterol efflux functional readouts bioRxivpreprint Low

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 PLA2G4A/cPLA2-mediated lysosomal membrane damage leads to inhibition of autophagy and neurodegeneration after brain trauma. Autophagy 147 31238788
2017 Long non-coding RNA SNHG14 promotes microglia activation by regulating miR-145-5p/PLA2G4A in cerebral infarction. Neuroscience 121 28215748
2003 Cross-talk between cytosolic phospholipase A2 alpha (cPLA2 alpha) and secretory phospholipase A2 (sPLA2) in hydrogen peroxide-induced arachidonic acid release in murine mesangial cells: sPLA2 regulates cPLA2 alpha activity that is responsible for arachidonic acid release. The Journal of biological chemistry 121 12676927
2022 Neuronal STAT3/HIF-1α/PTRF axis-mediated bioenergetic disturbance exacerbates cerebral ischemia-reperfusion injury via PLA2G4A. Theranostics 87 35547748
2004 Cytosolic phospholipase A2-alpha is necessary for platelet-activating factor biosynthesis, efficient neutrophil-mediated bacterial killing, and the innate immune response to pulmonary infection: cPLA2-alpha does not regulate neutrophil NADPH oxidase activity. The Journal of biological chemistry 84 15475363
2019 Annexin10 promotes extrahepatic cholangiocarcinoma metastasis by facilitating EMT via PLA2G4A/PGE2/STAT3 pathway. EBioMedicine 69 31492557
2006 Sustained activation of proton channels and NADPH oxidase in human eosinophils and murine granulocytes requires PKC but not cPLA2 alpha activity. The Journal of physiology 63 17185330
2022 ATF6α promotes prostate cancer progression by enhancing PLA2G4A-mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis. The Prostate 53 35089606
2005 X-ray reflectivity studies of cPLA2{alpha}-C2 domains adsorbed onto Langmuir monolayers of SOPC. Biophysical journal 44 15994899
2021 PLA2G4A promotes right-sided colorectal cancer progression by inducing CD39+γδ Treg polarization. JCI insight 42 34283812
2004 A study of a genetic association between the PTGS2/PLA2G4A locus and schizophrenia. Prostaglandins, leukotrienes, and essential fatty acids 35 15041036
2006 Expression of phospholipase A2 group IVA (PLA2G4A) is upregulated by human chorionic gonadotropin in bovine granulosa cells of ovulatory follicles. Biology of reproduction 33 16510840
2003 Association of cPLA2-alpha and COX-1 with the Golgi apparatus of A549 human lung epithelial cells. Journal of cell science 31 12711701
2020 LncRNA NEAT1 regulates chondrocyte proliferation and apoptosis via targeting miR-543/PLA2G4A axis. Human cell 26 33040229
2012 HERV-E-mediated modulation of PLA2G4A transcription in urothelial carcinoma. PloS one 26 23145155
2018 Inhibition of PLA2G4A Reduces the Expression of Lung Cancer-Related Cytokines. DNA and cell biology 20 30328712
2010 Effect of Ga-Al-As laser irradiation on COX-2 and cPLA2-alpha expression in compressed human periodontal ligament cells. Lasers in surgery and medicine 20 20662025
2012 The impact of PLA2G4A and PTGS2 gene polymorphisms, and red blood cell PUFAs deficit on niacin skin flush response in schizophrenia patients. Prostaglandins, leukotrienes, and essential fatty acids 19 23219238
2024 PLA2G4A and ACHE modulate lipid profiles via glycerophospholipid metabolism in platinum-resistant gastric cancer. Journal of translational medicine 17 38454407
2012 Association of PLA2G4A with myocardial infarction is modulated by dietary PUFAs. The American journal of clinical nutrition 15 22378731
2021 Acupuncture therapy protects PCOS patients with diabetes by regulating miR-32-3p/PLA2G4A pathway. American journal of translational research 14 34539997
2003 Association of a F479L variant in the cytosolic phospholipase A2 gene (PLA2G4A) with decreased glucose turnover and oxidation rates in Pima Indians. Molecular genetics and metabolism 14 12765847
2015 Association study of genetic variants in PLA2G4A, PLCG1, LAT, SYK, and TNFRS11A genes in NSAIDs-induced urticaria and/or angioedema patients. Pharmacogenetics and genomics 12 26398624
2021 Nuclear progesterone receptor regulates ptger4b and PLA2G4A expression in zebrafish (Danio rerio) ovulation. General and comparative endocrinology 10 34252451
2025 Xingxiao pills suppresses lung adenocarcinoma progression by modulating lipid metabolism and inhibiting the PLA2G4A-GLI1-SOX2 Axis. Phytomedicine : international journal of phytotherapy and phytopharmacology 8 40339555
2025 CENPF interaction with PLA2G4A promotes glioma growth by modulating mTORC1 and NF-κB pathways. Cancer cell international 6 40025532
2023 Lnc-PLA2G4A-4 facilitates the progression of hepatocellular carcinoma by inducing versican expression via sponging miR-23b-3p. Heliyon 5 37554815
2018 An association between the BanI polymorphism of the PLA2G4A gene for calcium-dependent phospholipase A2 and plasma glucose levels among females with schizophrenia. Prostaglandins, leukotrienes, and essential fatty acids 5 30103930
2012 PLA2G4A mutants modified protective effect of tea consumption against colorectal cancer. International journal of colorectal disease 2 22358383
2025 Pirin Transcriptionally Regulates PLA2G4A To Inhibit Ferroptosis in Colorectal Cancer via Lipid Profile Remodeling. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 41400081
2024 Link between mutations in ACVRL1 and PLA2G4A genes and chronic intestinal ulcers: A case report and review of literature. World journal of gastrointestinal surgery 1 38577076
2024 Copy number deletion of PLA2G4A affects the susceptibility and clinical phenotypes of schizophrenia. Schizophrenia (Heidelberg, Germany) 1 38816399
2026 A perspective: PLA2G4A as drug target for vascular inflammation in Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 0 41950067
2026 AS1842856 Reduces β-Amyloid Burden via Inhibiting PLA2G4A-Mediated Lysosomal Dysfunction in APP/PS1 Mice. CNS neuroscience & therapeutics 0 42047940
2007 Expression Analysis of cPLA2 Alpha Interacting TIP60 in Diabetic KKAy and Non-Diabetic C57BL Wild-Type Mice: No Impact of Transient and Stable TIP60 Overexpression on Glucose-Stimulated Insulin Secretion in Pancreatic Beta-Cells. The review of diabetic studies : RDS 0 18084672

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