Affinage

PTDSS1

Phosphatidylserine synthase 1 · UniProt P48651

Length
473 aa
Mass
55.5 kDa
Annotated
2026-06-10
31 papers in source corpus 9 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTDSS1 encodes phosphatidylserine synthase 1 (PSS1), a ~42 kDa integral membrane enzyme enriched in the mitochondria-associated membrane (MAM) and microsomal fractions that produces phosphatidylserine (PS) by base-exchange of the head group of phosphatidylcholine with serine (PMID:10432300, PMID:8898108). PSS1 activity is normally restrained by end-product feedback inhibition by PS, and heterozygous gain-of-function missense mutations abolish this feedback, increasing cellular PS synthesis and causing Lenz-Majewski syndrome (PMID:24241535). Beyond raising PS, dysregulated PSS1 reshapes broader phosphoinositide metabolism at membrane contact sites: gain-of-function mutants lower PI4P at the Golgi and plasma membrane by activating Sac1 and reduce membrane association of the PI4P-PS exchanger ORP8, while PS synthesis itself is coupled to PI4KA-generated PI4P that drives PS export from the ER (PMID:27044099). Catalytic activity is essential for these effects, as a catalytically inactive substitution abolishes the lipid and cellular phenotypes of mutant PSS1, and a loss-of-function residue substitution eliminates enzyme activity (PMID:35224839, PMID:37714410). Through its control of PS availability, PSS1 governs PS-dependent intercellular signaling: PS produced by PTDSS1 supports apoptotic-cell PS exposure recognized by macrophage MERTK to drive tumor-associated macrophage expansion (PMID:35425959), restrains interferon-responsive gene expression and MHC-I surface display to limit CD8+ T cell cytotoxicity (PMID:40929270), and maintains mitochondrial PS that suppresses mitophagy-linked ferroptotic and oxidative-stress programs (PMID:42026035).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1996 High

    Established the physical identity and subcellular home of the enzyme, showing PSS1 is a discrete ~42 kDa membrane protein whose activity resides in the MAM and microsomes rather than mitochondria or cytosol.

    Evidence Anti-pssA immunoprecipitation of enzyme activity plus subcellular fractionation in CHO/CDT-1 cells

    PMID:8898108

    Open questions at the time
    • No structural model of the membrane enzyme
    • Topology and active-site organization not defined
  2. 1999 High

    Defined the catalytic reaction and its metabolic reach, showing PSS1 uses phosphatidylcholine for serine base-exchange and that its output feeds PS-derived PE synthesis while suppressing the CDP-ethanolamine pathway.

    Evidence Stable cDNA overexpression with radiolabeled substrate incorporation in McArdle and CHO cells, comparing PSS1 vs PSS2

    PMID:10432300

    Open questions at the time
    • Feedback regulation not detected in this overexpression context
    • Did not resolve physiological control of flux at endogenous levels
  3. 2013 High

    Resolved how PSS1 is normally regulated and linked it to disease, demonstrating PS-mediated end-product feedback inhibition and that gain-of-function mutations relieving this inhibition cause Lenz-Majewski syndrome.

    Evidence Whole-exome sequencing plus PS synthesis and end-product inhibition assays in patient fibroblasts

    PMID:24241535

    Open questions at the time
    • Molecular basis of PS sensing by the enzyme unknown
    • Tissue-specific consequences of elevated PS not defined
  4. 2016 High

    Connected PSS1 dysregulation to phosphoinositide metabolism at contact sites, showing mutant PSS1 lowers PI4P via Sac1 and that PS synthesis is coupled to PI4KA-generated PI4P and ORP8-mediated transport.

    Evidence Mutant PSS1 expression with live-cell PI4P reporters, PI4KA inhibitors, and ORP8 membrane-association assays

    PMID:27044099

    Open questions at the time
    • Direct physical interaction between PSS1 and the transport machinery not shown
    • Quantitative stoichiometry of PS/PI4P counter-transport unresolved
  5. 2022 Medium

    Confirmed catalytic-residue requirements, identifying p.(Leu137Phe) as a loss-of-function substitution that abolishes enzyme activity.

    Evidence Overexpression of mutant PTDSS1 in HEK293 with [14C]-serine labeling and TLC

    PMID:35224839

    Open questions at the time
    • Single lab, single method
    • Structural role of the residue not mapped
  6. 2023 High

    Showed that gain-of-function PSS1 effects on cell physiology are catalysis-dependent, altering PS/PE acyl composition and lowering PI to disrupt osteoclast podosomes and resorption.

    Evidence PSS1-LMS overexpression in osteoclast precursors with lipidomics, actin imaging, and catalytic-dead rescue

    PMID:37714410

    Open questions at the time
    • Mechanism linking acyl-chain remodeling to podosome dynamics unresolved
    • Relationship to PI4P axis not directly tested
  7. 2022 High

    Placed PSS1 upstream of PS-dependent intercellular signaling in cancer, defining a PTDSS1→PS→MERTK axis that drives tumor-associated macrophage expansion.

    Evidence Ptdss1 knockdown in murine tumor cells with in vivo implantation, lipidomics, TAM flow cytometry, and macrophage Mertk knockout

    PMID:35425959

    Open questions at the time
    • Contribution of ether-PS versus diacyl-PS not separated
    • Direct PS-MERTK engagement not biochemically reconstituted
  8. 2025 High

    Extended PSS1's immunomodulatory role, showing its loss derepresses interferon-responsive genes and MHC-I, enhancing T cell killing and anti-PD-1 efficacy.

    Evidence In vivo CRISPR screen with genetic/pharmacological PTDSS1 inhibition, co-culture cytotoxicity, flow cytometry, and transcriptomics across tumor models

    PMID:40929270

    Open questions at the time
    • Mechanism linking PS depletion to interferon-gene derepression unknown
    • Whether effect is cell-intrinsic lipid signaling or surface PS-mediated not resolved
  9. 2025 Medium

    Linked mitochondrial PS supply to redox and death pathways, showing PTDSS1 knockdown promotes TRIM21-SLC3A2 interaction, depletes glutathione, and induces mitophagy, ferroptosis, and apoptosis.

    Evidence PTDSS1 knockdown in ESCC cells with Co-IP, GSH/mitophagy/ferroptosis assays, mitochondrial fractionation, and scRNA-seq

    PMID:42026035

    Open questions at the time
    • Single-lab Co-IP without reciprocal validation
    • Multi-step mechanistic chain involves inferred links between PS loss and TRIM21 activity

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PSS1 physically senses PS to mediate feedback inhibition, and how its catalytic output is mechanistically transduced into the diverse downstream programs (PI4P cycling, immune signaling, mitophagy), remain unresolved.
  • No structural/biophysical model of PS feedback sensing
  • Direct molecular link between PS levels and interferon/MHC-I regulation undefined
  • PSS1 enzymatic regulation in physiological tissues not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5
Localization
GO:0005739 mitochondrion 2 GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1430728 Metabolism 4

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Heterozygous missense mutations in PTDSS1 cause gain-of-function of PSS1 enzyme: phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced, demonstrating that PSS1 is subject to feedback inhibition by its own product phosphatidylserine. Whole-exome sequencing to identify variants; phosphatidylserine synthesis assay in patient fibroblasts; end-product inhibition assay in cells Nature genetics High 24241535
1999 PSS1 (PTDSS1) primarily uses phosphatidylcholine as a substrate for base-exchange with serine to produce phosphatidylserine, and its overexpression increases PtdSer and PtdSer-derived phosphatidylethanolamine synthesis while inhibiting the CDP-ethanolamine pathway for PE synthesis by ~50%. Unlike PSS2, PSS1 activity and PS synthesis are NOT subject to end-product inhibition by PS in this overexpression context. Stable cDNA expression in McArdle hepatoma cells and CHO mutant cells; radiolabeled substrate incorporation assays; comparison of PSS1 vs PSS2 transfectants The Biochemical journal High 10432300
1996 The pssA (PTDSS1 ortholog in CHO cells) gene product is phosphatidylserine synthase I, identified as a ~42 kDa membrane protein enriched in the mitochondria-associated membrane (MAM) fraction and microsome fraction, but not in mitochondria or cytosol; immunoprecipitation with anti-pssA antibodies co-precipitated PSS1 enzymatic activity. Immunoprecipitation with peptide antibodies; subcellular fractionation; activity assays in membrane fractions; immunoblot of overexpressing transfectant CDT-1 cells FEBS letters High 8898108
2016 LMS-causing PSS1 mutants (rendered insensitive to PS feedback inhibition) decrease phosphatidylinositol 4-phosphate (PI4P) levels at both Golgi and plasma membrane by activating Sac1 phosphatase, and alter PI4P cycling at the plasma membrane. Conversely, inhibitors of PI4KA (which generates PM PI4P) block PS synthesis and reduce PS levels by ~50% in normal cells, showing PS synthesis is tightly coupled to PI4P-dependent PS transport from ER. Mutant PSS1 also decreases PI4P-dependent membrane association of the PI4P-PS exchanger ORP8. Expression of mutant PSS1 in cells; PI4P reporter assays (live-cell imaging); PI4KA inhibitor treatment; ORP8 membrane association assay; pharmacological and genetic manipulation Proceedings of the National Academy of Sciences of the United States of America High 27044099
2022 A heterozygous loss-of-function variant p.(Leu137Phe) in PTDSS1, when overexpressed in HEK293 cells, displayed no catalytic activity as measured by C14-serine labeling and TLC analysis of lipids, establishing that this residue is required for PSS1 enzymatic activity. Overexpression of mutant PTDSS1 in HEK293 cells; radiolabeled [14C]-serine incorporation; thin-layer chromatography of lipids American journal of medical genetics. Part A Medium 35224839
2022 Depletion of Ptdss1 from murine mammary tumor cells reduced ether-phosphatidylserine (ePS) levels, stunted tumor growth, decreased tumor-associated macrophage (TAM) abundance, and reduced PS exposure during apoptosis recognized by the PS receptor MERTK on macrophages, defining a PTDSS1→PS→MERTK pathway that drives macrophage proliferation and tumor-promoting inflammation. Ptdss1 knockdown in murine tumor cells; in vivo tumor implantation; lipidomics; TAM flow cytometry; macrophage-specific Mertk knockout mice; transcriptomics Cancer research High 35425959
2023 LMS gain-of-function PSS1 mutants (PSS1LMS) inhibit osteoclast formation, multinucleation, and resorption activity, and cause abnormal actin podosome cluster patterns and dynamics. PSS1LMS does not change total PS levels but alters acyl chain compositions of PS and phosphatidylethanolamine and decreases phosphatidylinositol levels. Introduction of a catalytically inactive mutation into PSS1LMS abolished both lipid changes and osteoclast phenotypes, establishing catalytic activity as required for these effects. Overexpression of PSS1LMS in osteoclast precursor cells; osteoclast differentiation assays; actin staining and live imaging; lipidomics; catalytically inactive mutant rescue experiment Journal of lipid research High 37714410
2025 PTDSS1 knockdown in tumor cells increases expression of IFN-γ-regulated genes (B2m, Cxcl9, Cxcl10, Stat1) even without IFN-γ stimulation, upregulates MHC-I surface expression, enhances CD8+ T cell cytotoxicity, and increases iNOS+ myeloid subset frequency. Genetic and pharmacological PTDSS1 inhibition improved anti-PD-1 therapy efficacy in multiple tumor models. In vivo CRISPR screen; Ptdss1 genetic knockdown in tumor cells; in vitro co-culture cytotoxicity assay; flow cytometry; transcriptomics; pharmacological PTDSS1 inhibition; in vivo tumor models Science advances High 40929270
2025 PTDSS1 knockdown in esophageal squamous cell carcinoma cells promotes interaction between TRIM21 and SLC3A2, leading to decreased SLC3A2 protein expression, reduced glutathione (GSH) synthesis, elevated oxidative stress, activation of PINK1/Parkin mitophagy, and induction of ferroptosis and apoptosis. Additionally, PTDSS1 knockdown decreases phosphatidylserine at mitochondria and facilitates MFN2 translocation, providing substrates for mitophagy. PTDSS1 knockdown in ESCC cells; co-immunoprecipitation (TRIM21-SLC3A2 interaction); GSH measurement; mitophagy assays; ferroptosis assays; mitochondrial fractionation; single-cell RNA sequencing Cell death & disease Medium 42026035
2024 Knockout of PTDSS1 in HEK293T producer cells enriches extracellular vesicle-enclosed AAV (EV-AAV) 42.7-fold relative to free AAV in supernatant, and reduces free AAV by 300-fold, demonstrating that PTDSS1-dependent phosphatidylserine production in the plasma membrane influences the partitioning of AAV into extracellular vesicles. PTDSS1 knockout in HEK293T cells (ΔPTDSS1); AAV production and quantification; EV isolation; lipidomics of vesicle composition; transduction assays in cardiomyocytes and mouse brain bioRxivpreprint Medium

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome. Nature genetics 88 24241535
2016 Lenz-Majewski mutations in PTDSS1 affect phosphatidylinositol 4-phosphate metabolism at ER-PM and ER-Golgi junctions. Proceedings of the National Academy of Sciences of the United States of America 83 27044099
1999 Cloning and expression of murine liver phosphatidylserine synthase (PSS)-2: differential regulation of phospholipid metabolism by PSS1 and PSS2. The Biochemical journal 56 10432300
1996 Immunochemical identification of the pssA gene product as phosphatidylserine synthase I of Chinese hamster ovary cells. FEBS letters 36 8898108
2009 Multiple copies of rosR and pssA genes enhance exopolysaccharide production, symbiotic competitiveness and clover nodulation in Rhizobium leguminosarum bv. trifolii. Antonie van Leeuwenhoek 31 19588265
2009 PSSA-2, a membrane-spanning phosphoprotein of Trypanosoma brucei, is required for efficient maturation of infection. PloS one 29 19759911
2016 RYR2, PTDSS1 and AREG genes are implicated in a Lebanese population-based study of copy number variation in autism. Scientific reports 28 26742492
2022 Phosphatidylserine Synthase PTDSS1 Shapes the Tumor Lipidome to Maintain Tumor-Promoting Inflammation. Cancer research 27 35425959
2013 Mutation in the pssA gene involved in exopolysaccharide synthesis leads to several physiological and symbiotic defects in Rhizobium leguminosarum bv. trifolii. International journal of molecular sciences 19 24317432
2015 Lenz-Majewski hyperostotic dwarfism with hyperphosphoserinuria from a novel mutation in PTDSS1 encoding phosphatidylserine synthase 1. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 18 25363158
2013 Expression of the Rhizobium leguminosarum bv. trifolii pssA gene, involved in exopolysaccharide synthesis, is regulated by RosR, phosphate, and the carbon source. Journal of bacteriology 18 23708137
2000 Elevated levels of synthesis of over 20 proteins results after mutation of the Rhizobium leguminosarum exopolysaccharide synthesis gene pssA. Journal of bacteriology 17 10913086
2018 Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1. American journal of medical genetics. Part A 14 29341480
2015 Lenz-Majewski syndrome: Report of a case with novel mutation in PTDSS1 gene. European journal of medical genetics 14 26117586
1998 Isolation of a novel heat shock protein 70-like gene, pss1+ of Schizosaccharomyces pombe homologous to hsp110/SSE subfamily. Gene 14 9524252
2003 Dependency of sugar transport and phosphorylation by the phosphoenolpyruvate-dependent phosphotransferase system on membranous phosphatidylethanolamine in Escherichia coli: studies with a pssA mutant lacking phosphatidylserine synthase. Archives of microbiology 13 14634719
2023 Treatment outcomes with benzylpenicillin and non-benzylpenicillin antibiotics, and the performance of the penicillin zone-edge test versus molecular detection of blaZ in penicillin-susceptible Staphylococcus aureus (PSSA) bacteraemia. The Journal of antimicrobial chemotherapy 11 37596905
2019 Analysis of transgenic zebrafish expressing the Lenz-Majewski syndrome gene PTDSS1 in skeletal cell lineages. F1000Research 10 31231513
2023 A New Face of the Old Gene: Deletion of the PssA, Encoding Monotopic Inner Membrane Phosphoglycosyl Transferase in Rhizobium leguminosarum, Leads to Diverse Phenotypes That Could Be Attributable to Downstream Effects of the Lack of Exopolysaccharide. International journal of molecular sciences 8 36674551
2007 [The pssA gene encodes UDP-glucose: polyprenyl phosphate-glucosyl phosphotransferase initiating biosynthesis of Rhizobium leguminosarum exopolysaccharide]. Bioorganicheskaia khimiia 7 17375671
2022 De novo loss-of-function variant in PTDSS1 is associated with developmental delay. American journal of medical genetics. Part A 6 35224839
2010 The cortistatin gene PSS2 rather than the somatostatin gene PSS1 is strongly expressed in developing avian autonomic neurons. The Journal of comparative neurology 6 20058310
2009 PssA is required for alpha-amylase secretion in Antarctic Pseudoalteromonas haloplanktis. Microbiology (Reading, England) 5 19778966
2024 Kinesin-1-like protein PSS1 is essential for full-length homologous pairing and synapsis in rice meiosis. The Plant journal : for cell and molecular biology 4 39283979
2023 Disease-related PSS1 mutant impedes the formation and function of osteoclasts. Journal of lipid research 4 37714410
2025 Loss of PTDSS1 in tumor cells improves immunogenicity and response to anti-PD-1 therapy. Science advances 2 40929270
2025 A Japanese Case of Lenz-Majewski Syndrome With a Novel PTDSS1 Variant. Molecular genetics & genomic medicine 1 40524567
2025 PTDSS1 Drives Glycolysis and Malignant Progression of Lung Cancer Through Maintaining Nuclear-Mitochondrial Homeostatic Crosstalk. Frontiers in bioscience (Landmark edition) 1 41074449
2026 Cross-linked PVA/PSSA-CNTs based polyelectrolyte membranes with enhanced proton conductivity for fuel cell applications. Scientific reports 0 41896579
2026 Targeting PTDSS1 to modulate GSH synthesis triggers mitophagy and induces ferroptosis in esophageal squamous cell carcinoma cells. Cell death & disease 0 42026035
2025 Clinical and genetic characterization of Lenz-Majewski syndrome with a PTDSS1 variant: a case report and literature review. Frontiers in pediatrics 0 40837678

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