PLA1A

PLA1A (PS-PLA1) is a secreted phospholipase A1 of the pancreatic lipase gene family that generates the bioactive lipid mediator 2-acyl-lysophosphatidylserine (lysoPS) by selectively cleaving the sn-1 ester bond of phosphatidylserine, with substrate specificity determined by its unusually short lid and deleted β9 loop (PMID:10196188, PMID:12069807, PMID:17101204). The lysoPS produced by PLA1A signals through GPR34 to drive peritoneal plasma cell and memory B cell accumulation at the omentum, through GPR174/cAMP/PKA to suppress lung adenocarcinoma proliferation and EMT, and through MAPK pathway suppression to restrain macrophage M1 polarization (PMID:39412501, PMID:35358472, PMID:35650027). PLA1A is a non-redundant source of lysoPS on apoptotic cells, supporting GPR34-dependent efferocytosis and cross-presentation by splenic cDC1s (PMID:41212150). Independent of its lipase product, PLA1A participates in antiviral innate immunity by facilitating TBK1 recruitment to mitochondria and MAVS interaction, and is co-opted during HCV infection to bridge viral envelope (E2/NS2) and replication (NS5A) complexes required for virion assembly (PMID:30016790, PMID:25505071).

1. 1999 High

   Establishing the enzymatic identity of PLA1A: the enzyme was shown to specifically hydrolyze the sn-1 position of PS and lysoPS, and the C-terminal domain was required for diacyl-PS recognition, defining PLA1A as a PS-selective phospholipase A1.

   Evidence Recombinant protein expression and in vitro enzyme assays with domain-deletion mutants and defined lipid substrates

   PMID:10196188

   Open questions at the time

   • No crystal structure of PLA1A itself
   • Regulation of secretion and tissue-specific expression not addressed
   • In vivo substrate preference not tested
2. 2002 Medium

   Structural determinants of substrate selectivity were identified: comparative analysis across the pancreatic lipase family revealed that PLA1A's short lid and deleted β9 loop explain its exclusive PLA1 activity and inability to hydrolyze triacylglycerols.

   Evidence Amino acid sequence alignment and comparative structural modeling with lipase gene family members

   PMID:12069807

   Open questions at the time

   • No direct mutagenesis of lid or β9 loop in PLA1A to confirm causality
   • No solved 3D structure of PLA1A
3. 2003 High

   In vivo overexpression demonstrated a physiological role for PLA1A in lipoprotein remodeling: PLA1A increased HDL size and cholesterol content and reciprocally regulated SR-BI versus ABCA1 cholesterol efflux, linking its phospholipase activity to HDL metabolism.

   Evidence Adenoviral PLA1A overexpression in apoA-I transgenic mice with serum lipid profiling and efflux assays

   PMID:14594995

   Open questions at the time

   • Loss-of-function in vivo data for HDL phenotype not provided
   • Whether lysoPS or another product mediates the efflux changes is unclear
   • Human relevance not established
4. 2006 High

   Replication and consolidation confirmed PLA1A as the principal extracellular enzyme generating 2-acyl-lysoPS from PS, solidifying the link between its structural features and enzymatic specificity.

   Evidence In vitro enzyme assays with structural and sequence analysis across the lipase gene family

   PMID:17101204

   Open questions at the time

   • Physiological concentrations of lysoPS product in tissues not measured
   • No direct structural data (crystal/cryo-EM) for PLA1A
5. 2014 High

   A non-canonical role in viral assembly was uncovered: PLA1A was shown to be upregulated during HCV infection and required specifically for virion assembly, physically bridging envelope protein E2, NS2, and the replication protein NS5A.

   Evidence siRNA knockdown, reciprocal co-IP of PLA1A with E2/NS2/NS5A, and step-specific viral propagation assays

   PMID:25505071

   Open questions at the time

   • Whether PLA1A's lipase activity is required for viral assembly or only its scaffolding function
   • Mechanism by which PLA1A stabilizes NS2–E2 and NS2–NS5A complexes not defined
6. 2018 High

   PLA1A was positioned in antiviral innate immune signaling upstream of TBK1: it facilitates TBK1 recruitment to mitochondria and TBK1–MAVS interaction, promoting IFN-β induction independently of IRF3-driven transcription.

   Evidence siRNA knockdown, TBK1/IRF3 reporter assays, mitochondrial fractionation, and TBK1 phosphorylation analysis

   PMID:30016790

   Open questions at the time

   • Direct physical interaction between PLA1A and TBK1 or MAVS not demonstrated
   • Whether lipase activity is required for this innate immune function is unknown
   • Mechanism of mitochondrial morphology changes not resolved
7. 2019 Medium

   Domain-mapping refined the HCV assembly model: PLA1A interacts most closely with E2 lumenal domains and engages NS5A via its domain 1 C-terminus, establishing architecture of the oligomeric assembly complex.

   Evidence Domain deletion/truncation co-IP and proximity ligation assay in HCV-infected cells

   PMID:31161554

   Open questions at the time

   • Single-lab study without independent replication
   • Stoichiometry and 3D organization of the complex unknown
   • Whether NS5A domain 1 interaction competes with replication function not tested
8. 2021 Medium

   A paracrine signaling cascade was delineated in synoviocytes: PLA1A-generated lysoPS is converted to LPA by autotaxin, which then acts on LPA receptors to drive IL-8 secretion, linking PLA1A to pro-inflammatory lipid signaling in joints.

   Evidence Recombinant PLA1A stimulation of primary fibroblast-like synoviocytes with ATX inhibitor, LPA receptor antagonist, and heparin blockade

   PMID:34884486

   Open questions at the time

   • Single-lab pharmacological study without genetic confirmation
   • In vivo relevance in arthritis models not tested
   • Direct measurement of lysoPS and LPA intermediates not shown
9. 2022 Medium

   Two studies established PLA1A as an immunomodulatory and tumor-suppressive enzyme acting through its lysoPS product: in macrophages, PLA1A suppresses M1 polarization via MAPK pathway inhibition; in lung adenocarcinoma, PLA1A/lysoPS signals through GPR174–cAMP/PKA to arrest cell cycle and inhibit EMT.

   Evidence Stable knockdown/overexpression in RAW264.7 with MAPK inhibitor rescue; PLA1A overexpression in LUAD cell lines and xenograft models with GPR174/cAMP/PKA pathway analysis

   PMID:35358472 PMID:35650027

   Open questions at the time

   • Both from single labs; independent replication needed
   • Endogenous PLA1A loss-of-function in tumor models not tested
   • Whether anti-inflammatory and anti-tumor effects are separable or share a common lysoPS receptor axis is unclear
10. 2024 High

    Conditional knockout in vivo established stromal PLA1A as a non-redundant source of lysoPS that signals via GPR34 to maintain peritoneal plasma cells and memory B cells at the omentum, defining a physiological lipid mediator niche for humoral immune memory.

    Evidence Conditional PLA1A knockout in stromal cells, adoptive transfer, chimera experiments, and ex vivo migration assays

    PMID:39412501

    Open questions at the time

    • Whether PLA1A–GPR34 axis regulates other immune cell types at other mucosal sites not tested
    • Quantitative lysoPS gradients in vivo not measured
11. 2025 Medium

    PLA1A was shown to be the dominant enzyme generating lysoPS on apoptotic cells in vivo, non-redundant with ABHD16A, supporting GPR34-dependent efferocytosis and cross-presentation by splenic cDC1 dendritic cells.

    Evidence PLA1A knockout mice, OT-I adoptive transfer, apoptotic cell uptake assays

    PMID:41212150

    Open questions at the time

    • Single-lab study
    • Whether PLA1A acts cell-autonomously on apoptotic cells or is supplied by phagocytes not resolved
    • Molecular mechanism linking lysoPS/GPR34 to enhanced cross-presentation not defined

• Key open questions include whether PLA1A's lipase activity is required for its non-canonical roles in HCV assembly and TBK1 recruitment, the identity of its physiological regulators, and the structural basis of its PS selectivity at atomic resolution.
• No crystal or cryo-EM structure of PLA1A
• Catalytic vs scaffolding function not genetically separated in viral/innate immune contexts
• Physiological regulation of PLA1A expression and secretion poorly defined