{"gene":"PTDSS1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2013,"finding":"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.","method":"Whole-exome sequencing to identify variants; phosphatidylserine synthesis assay in patient fibroblasts; end-product inhibition assay in cells","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional assays in patient fibroblasts with direct measurement of enzyme activity and feedback inhibition, replicated across multiple patients with distinct mutations","pmids":["24241535"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Stable cDNA expression in McArdle hepatoma cells and CHO mutant cells; radiolabeled substrate incorporation assays; comparison of PSS1 vs PSS2 transfectants","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct enzymatic assays with stable overexpression, multiple cell lines, orthogonal metabolic readouts; independently consistent with findings from PMID:24241535","pmids":["10432300"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Immunoprecipitation with peptide antibodies; subcellular fractionation; activity assays in membrane fractions; immunoblot of overexpressing transfectant CDT-1 cells","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal immunoprecipitation of enzyme activity, subcellular fractionation, and overexpression confirmation; multiple orthogonal methods in one study","pmids":["8898108"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Expression of mutant PSS1 in cells; PI4P reporter assays (live-cell imaging); PI4KA inhibitor treatment; ORP8 membrane association assay; pharmacological and genetic manipulation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (pharmacological, genetic, reporter imaging) in a single focused study with rigorous controls","pmids":["27044099"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Overexpression of mutant PTDSS1 in HEK293 cells; radiolabeled [14C]-serine incorporation; thin-layer chromatography of lipids","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct enzymatic activity assay with radiolabeling, single lab, single method","pmids":["35224839"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Ptdss1 knockdown in murine tumor cells; in vivo tumor implantation; lipidomics; TAM flow cytometry; macrophage-specific Mertk knockout mice; transcriptomics","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic knockdown combined with genetic epistasis (Mertk knockout), lipidomics, and transcriptomics; multiple orthogonal methods establishing pathway position","pmids":["35425959"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Overexpression of PSS1LMS in osteoclast precursor cells; osteoclast differentiation assays; actin staining and live imaging; lipidomics; catalytically inactive mutant rescue experiment","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — catalytic-dead mutagenesis rescue, lipidomics, and live cell imaging provide multiple orthogonal lines of evidence in a single study","pmids":["37714410"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo CRISPR screen followed by genetic and pharmacological validation, multiple tumor models, mechanistic readouts including transcriptomics and immune cell phenotyping","pmids":["40929270"],"is_preprint":false},{"year":2025,"finding":"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.","method":"PTDSS1 knockdown in ESCC cells; co-immunoprecipitation (TRIM21-SLC3A2 interaction); GSH measurement; mitophagy assays; ferroptosis assays; mitochondrial fractionation; single-cell RNA sequencing","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and functional assays in a single lab without independent replication; mechanistic chain involves multiple inferred steps","pmids":["42026035"],"is_preprint":false},{"year":2024,"finding":"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.","method":"PTDSS1 knockout in HEK293T cells (ΔPTDSS1); AAV production and quantification; EV isolation; lipidomics of vesicle composition; transduction assays in cardiomyocytes and mouse brain","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic knockout with direct quantitative readout of EV-AAV partitioning; preprint, single lab, not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"PTDSS1 encodes phosphatidylserine synthase 1 (PSS1), a ~42 kDa integral membrane enzyme localized to the mitochondria-associated membrane and microsomes that catalyzes base-exchange of phosphatidylcholine with serine to produce phosphatidylserine (PS); PSS1 activity is subject to end-product feedback inhibition by PS, gain-of-function mutations abolish this feedback and dysregulate PS and PI4P metabolism at ER-PM and ER-Golgi junctions, loss of PSS1 catalytic activity conversely impairs PS production and downstream PS-mediated signaling including MERTK-dependent macrophage recruitment, MHC-I regulation, and mitochondrial phospholipid homeostasis."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1996,"claim":"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","pmids":["8898108"],"confidence":"High","gaps":["No structural model of the membrane enzyme","Topology and active-site organization not defined"]},{"year":1999,"claim":"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","pmids":["10432300"],"confidence":"High","gaps":["Feedback regulation not detected in this overexpression context","Did not resolve physiological control of flux at endogenous levels"]},{"year":2013,"claim":"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","pmids":["24241535"],"confidence":"High","gaps":["Molecular basis of PS sensing by the enzyme unknown","Tissue-specific consequences of elevated PS not defined"]},{"year":2016,"claim":"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","pmids":["27044099"],"confidence":"High","gaps":["Direct physical interaction between PSS1 and the transport machinery not shown","Quantitative stoichiometry of PS/PI4P counter-transport unresolved"]},{"year":2022,"claim":"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","pmids":["35224839"],"confidence":"Medium","gaps":["Single lab, single method","Structural role of the residue not mapped"]},{"year":2023,"claim":"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","pmids":["37714410"],"confidence":"High","gaps":["Mechanism linking acyl-chain remodeling to podosome dynamics unresolved","Relationship to PI4P axis not directly tested"]},{"year":2022,"claim":"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","pmids":["35425959"],"confidence":"High","gaps":["Contribution of ether-PS versus diacyl-PS not separated","Direct PS-MERTK engagement not biochemically reconstituted"]},{"year":2025,"claim":"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","pmids":["40929270"],"confidence":"High","gaps":["Mechanism linking PS depletion to interferon-gene derepression unknown","Whether effect is cell-intrinsic lipid signaling or surface PS-mediated not resolved"]},{"year":2025,"claim":"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","pmids":["42026035"],"confidence":"Medium","gaps":["Single-lab Co-IP without reciprocal validation","Multi-step mechanistic chain involves inferred links between PS loss and TRIM21 activity"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,4,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,9]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,3,6]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48651","full_name":"Phosphatidylserine synthase 1","aliases":["Serine-exchange enzyme I"],"length_aa":473,"mass_kda":55.5,"function":"Catalyzes a base-exchange reaction in which the polar head group of phosphatidylethanolamine (PE) or phosphatidylcholine (PC) is replaced by L-serine (PubMed:19014349, PubMed:24241535). Catalyzes mainly the conversion of phosphatidylcholine (PubMed:19014349, PubMed:24241535). Also converts, in vitro and to a lesser extent, phosphatidylethanolamine (PubMed:19014349, PubMed:24241535)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P48651/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTDSS1","classification":"Not Classified","n_dependent_lines":332,"n_total_lines":1208,"dependency_fraction":0.27483443708609273},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000156471","cell_line_id":"CID000349","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"PDLIM7","stoichiometry":10.0},{"gene":"VCP","stoichiometry":10.0},{"gene":"SLC6A8","stoichiometry":0.2},{"gene":"NCLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000349","total_profiled":1310},"omim":[{"mim_id":"612793","title":"PHOSPHATIDYLSERINE SYNTHASE 2; PTDSS2","url":"https://www.omim.org/entry/612793"},{"mim_id":"612792","title":"PHOSPHATIDYLSERINE SYNTHASE 1; PTDSS1","url":"https://www.omim.org/entry/612792"},{"mim_id":"151050","title":"LENZ-MAJEWSKI HYPEROSTOTIC DWARFISM; LMHD","url":"https://www.omim.org/entry/151050"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTDSS1"},"hgnc":{"alias_symbol":["KIAA0024","PSSA","PSS1"],"prev_symbol":[]},"alphafold":{"accession":"P48651","domains":[{"cath_id":"-","chopping":"11-29_90-407","consensus_level":"high","plddt":88.4296,"start":11,"end":407}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48651","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48651-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48651-F1-predicted_aligned_error_v6.png","plddt_mean":81.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTDSS1","jax_strain_url":"https://www.jax.org/strain/search?query=PTDSS1"},"sequence":{"accession":"P48651","fasta_url":"https://rest.uniprot.org/uniprotkb/P48651.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48651/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48651"}},"corpus_meta":[{"pmid":"24241535","id":"PMC_24241535","title":"Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24241535","citation_count":88,"is_preprint":false},{"pmid":"27044099","id":"PMC_27044099","title":"Lenz-Majewski mutations in PTDSS1 affect phosphatidylinositol 4-phosphate metabolism at ER-PM and ER-Golgi junctions.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27044099","citation_count":83,"is_preprint":false},{"pmid":"10432300","id":"PMC_10432300","title":"Cloning and expression of murine liver phosphatidylserine synthase (PSS)-2: differential regulation of phospholipid metabolism by PSS1 and PSS2.","date":"1999","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10432300","citation_count":56,"is_preprint":false},{"pmid":"8898108","id":"PMC_8898108","title":"Immunochemical identification of the pssA gene product as phosphatidylserine synthase I of Chinese hamster ovary cells.","date":"1996","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8898108","citation_count":36,"is_preprint":false},{"pmid":"19588265","id":"PMC_19588265","title":"Multiple copies of rosR and pssA genes enhance exopolysaccharide production, symbiotic competitiveness and clover nodulation in Rhizobium leguminosarum bv. trifolii.","date":"2009","source":"Antonie van Leeuwenhoek","url":"https://pubmed.ncbi.nlm.nih.gov/19588265","citation_count":31,"is_preprint":false},{"pmid":"19759911","id":"PMC_19759911","title":"PSSA-2, a membrane-spanning phosphoprotein of Trypanosoma brucei, is required for efficient maturation of infection.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19759911","citation_count":29,"is_preprint":false},{"pmid":"26742492","id":"PMC_26742492","title":"RYR2, PTDSS1 and AREG genes are implicated in a Lebanese population-based study of copy number variation in autism.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26742492","citation_count":28,"is_preprint":false},{"pmid":"35425959","id":"PMC_35425959","title":"Phosphatidylserine Synthase PTDSS1 Shapes the Tumor Lipidome to Maintain Tumor-Promoting Inflammation.","date":"2022","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35425959","citation_count":27,"is_preprint":false},{"pmid":"24317432","id":"PMC_24317432","title":"Mutation in the pssA gene involved in exopolysaccharide synthesis leads to several physiological and symbiotic defects in Rhizobium leguminosarum bv. trifolii.","date":"2013","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24317432","citation_count":19,"is_preprint":false},{"pmid":"23708137","id":"PMC_23708137","title":"Expression of the Rhizobium leguminosarum bv. trifolii pssA gene, involved in exopolysaccharide synthesis, is regulated by RosR, phosphate, and the carbon source.","date":"2013","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/23708137","citation_count":18,"is_preprint":false},{"pmid":"25363158","id":"PMC_25363158","title":"Lenz-Majewski hyperostotic dwarfism with hyperphosphoserinuria from a novel mutation in PTDSS1 encoding phosphatidylserine synthase 1.","date":"2015","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/25363158","citation_count":18,"is_preprint":false},{"pmid":"10913086","id":"PMC_10913086","title":"Elevated levels of synthesis of over 20 proteins results after mutation of the Rhizobium leguminosarum exopolysaccharide synthesis gene pssA.","date":"2000","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/10913086","citation_count":17,"is_preprint":false},{"pmid":"29341480","id":"PMC_29341480","title":"Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1.","date":"2018","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/29341480","citation_count":14,"is_preprint":false},{"pmid":"9524252","id":"PMC_9524252","title":"Isolation of a novel heat shock protein 70-like gene, pss1+ of Schizosaccharomyces pombe homologous to hsp110/SSE subfamily.","date":"1998","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9524252","citation_count":14,"is_preprint":false},{"pmid":"26117586","id":"PMC_26117586","title":"Lenz-Majewski syndrome: Report of a case with novel mutation in PTDSS1 gene.","date":"2015","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26117586","citation_count":14,"is_preprint":false},{"pmid":"14634719","id":"PMC_14634719","title":"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.","date":"2003","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/14634719","citation_count":13,"is_preprint":false},{"pmid":"37596905","id":"PMC_37596905","title":"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.","date":"2023","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/37596905","citation_count":11,"is_preprint":false},{"pmid":"31231513","id":"PMC_31231513","title":"Analysis of transgenic zebrafish expressing the Lenz-Majewski syndrome gene PTDSS1 in skeletal cell lineages.","date":"2019","source":"F1000Research","url":"https://pubmed.ncbi.nlm.nih.gov/31231513","citation_count":10,"is_preprint":false},{"pmid":"36674551","id":"PMC_36674551","title":"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.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36674551","citation_count":8,"is_preprint":false},{"pmid":"17375671","id":"PMC_17375671","title":"[The pssA gene encodes UDP-glucose: polyprenyl phosphate-glucosyl phosphotransferase initiating biosynthesis of Rhizobium leguminosarum exopolysaccharide].","date":"2007","source":"Bioorganicheskaia khimiia","url":"https://pubmed.ncbi.nlm.nih.gov/17375671","citation_count":7,"is_preprint":false},{"pmid":"20058310","id":"PMC_20058310","title":"The cortistatin gene PSS2 rather than the somatostatin gene PSS1 is strongly expressed in developing avian autonomic neurons.","date":"2010","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/20058310","citation_count":6,"is_preprint":false},{"pmid":"35224839","id":"PMC_35224839","title":"De novo loss-of-function variant in PTDSS1 is associated with developmental delay.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/35224839","citation_count":6,"is_preprint":false},{"pmid":"19778966","id":"PMC_19778966","title":"PssA is required for alpha-amylase secretion in Antarctic Pseudoalteromonas haloplanktis.","date":"2009","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19778966","citation_count":5,"is_preprint":false},{"pmid":"39283979","id":"PMC_39283979","title":"Kinesin-1-like protein PSS1 is essential for full-length homologous pairing and synapsis in rice meiosis.","date":"2024","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/39283979","citation_count":4,"is_preprint":false},{"pmid":"37714410","id":"PMC_37714410","title":"Disease-related PSS1 mutant impedes the formation and function of osteoclasts.","date":"2023","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/37714410","citation_count":4,"is_preprint":false},{"pmid":"40929270","id":"PMC_40929270","title":"Loss of PTDSS1 in tumor cells improves immunogenicity and response to anti-PD-1 therapy.","date":"2025","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/40929270","citation_count":2,"is_preprint":false},{"pmid":"41074449","id":"PMC_41074449","title":"PTDSS1 Drives Glycolysis and Malignant Progression of Lung Cancer Through Maintaining Nuclear-Mitochondrial Homeostatic Crosstalk.","date":"2025","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/41074449","citation_count":1,"is_preprint":false},{"pmid":"40524567","id":"PMC_40524567","title":"A Japanese Case of Lenz-Majewski Syndrome With a Novel PTDSS1 Variant.","date":"2025","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40524567","citation_count":1,"is_preprint":false},{"pmid":"40837678","id":"PMC_40837678","title":"Clinical and genetic characterization of Lenz-Majewski syndrome with a PTDSS1 variant: a case report and literature review.","date":"2025","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/40837678","citation_count":0,"is_preprint":false},{"pmid":"42026035","id":"PMC_42026035","title":"Targeting PTDSS1 to modulate GSH synthesis triggers mitophagy and induces ferroptosis in esophageal squamous cell carcinoma cells.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/42026035","citation_count":0,"is_preprint":false},{"pmid":"41896579","id":"PMC_41896579","title":"Cross-linked PVA/PSSA-CNTs based polyelectrolyte membranes with enhanced proton conductivity for fuel cell applications.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41896579","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.28.672917","title":"Pre-Sensory Spontaneous Activity Accelerates Coordinated Maturation of Synaptic Partners and Drives Transition to the Mature Physiological Phenotype","date":"2025-08-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.28.672917","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.28.685134","title":"Comparing Kinetic versus Stoichiometric Priorities in Hybrid Models of CHO Metabolism","date":"2025-10-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.28.685134","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.14.632903","title":"The Lipocone Superfamily: A Unifying Theme In Metabolism Of Lipids, Peptidoglycan And Exopolysaccharides, Inter-Organismal Conflicts And Immunity","date":"2025-01-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.14.632903","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.16.608303","title":"Metabolic engineering improves transduction efficiency and downstream vector isolation by altering the lipid composition of extracellular vesicle-enclosed AAV.","date":"2024-08-19","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.16.608303","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19490,"output_tokens":2982,"usd":0.0516,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10444,"output_tokens":3255,"usd":0.066797,"stage2_stop_reason":"end_turn"},"total_usd":0.118397,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing to identify variants; phosphatidylserine synthesis assay in patient fibroblasts; end-product inhibition assay in cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional assays in patient fibroblasts with direct measurement of enzyme activity and feedback inhibition, replicated across multiple patients with distinct mutations\",\n      \"pmids\": [\"24241535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Stable cDNA expression in McArdle hepatoma cells and CHO mutant cells; radiolabeled substrate incorporation assays; comparison of PSS1 vs PSS2 transfectants\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct enzymatic assays with stable overexpression, multiple cell lines, orthogonal metabolic readouts; independently consistent with findings from PMID:24241535\",\n      \"pmids\": [\"10432300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation with peptide antibodies; subcellular fractionation; activity assays in membrane fractions; immunoblot of overexpressing transfectant CDT-1 cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal immunoprecipitation of enzyme activity, subcellular fractionation, and overexpression confirmation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"8898108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Expression of mutant PSS1 in cells; PI4P reporter assays (live-cell imaging); PI4KA inhibitor treatment; ORP8 membrane association assay; pharmacological and genetic manipulation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (pharmacological, genetic, reporter imaging) in a single focused study with rigorous controls\",\n      \"pmids\": [\"27044099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression of mutant PTDSS1 in HEK293 cells; radiolabeled [14C]-serine incorporation; thin-layer chromatography of lipids\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct enzymatic activity assay with radiolabeling, single lab, single method\",\n      \"pmids\": [\"35224839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Ptdss1 knockdown in murine tumor cells; in vivo tumor implantation; lipidomics; TAM flow cytometry; macrophage-specific Mertk knockout mice; transcriptomics\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic knockdown combined with genetic epistasis (Mertk knockout), lipidomics, and transcriptomics; multiple orthogonal methods establishing pathway position\",\n      \"pmids\": [\"35425959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression of PSS1LMS in osteoclast precursor cells; osteoclast differentiation assays; actin staining and live imaging; lipidomics; catalytically inactive mutant rescue experiment\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic-dead mutagenesis rescue, lipidomics, and live cell imaging provide multiple orthogonal lines of evidence in a single study\",\n      \"pmids\": [\"37714410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo CRISPR screen followed by genetic and pharmacological validation, multiple tumor models, mechanistic readouts including transcriptomics and immune cell phenotyping\",\n      \"pmids\": [\"40929270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"PTDSS1 knockdown in ESCC cells; co-immunoprecipitation (TRIM21-SLC3A2 interaction); GSH measurement; mitophagy assays; ferroptosis assays; mitochondrial fractionation; single-cell RNA sequencing\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and functional assays in a single lab without independent replication; mechanistic chain involves multiple inferred steps\",\n      \"pmids\": [\"42026035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"PTDSS1 knockout in HEK293T cells (ΔPTDSS1); AAV production and quantification; EV isolation; lipidomics of vesicle composition; transduction assays in cardiomyocytes and mouse brain\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic knockout with direct quantitative readout of EV-AAV partitioning; preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PTDSS1 encodes phosphatidylserine synthase 1 (PSS1), a ~42 kDa integral membrane enzyme localized to the mitochondria-associated membrane and microsomes that catalyzes base-exchange of phosphatidylcholine with serine to produce phosphatidylserine (PS); PSS1 activity is subject to end-product feedback inhibition by PS, gain-of-function mutations abolish this feedback and dysregulate PS and PI4P metabolism at ER-PM and ER-Golgi junctions, loss of PSS1 catalytic activity conversely impairs PS production and downstream PS-mediated signaling including MERTK-dependent macrophage recruitment, MHC-I regulation, and mitochondrial phospholipid homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#1, #2]. 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 [#0]. 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 [#3]. 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 [#4, #6]. 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 [#5], restrains interferon-responsive gene expression and MHC-I surface display to limit CD8+ T cell cytotoxicity [#7], and maintains mitochondrial PS that suppresses mitophagy-linked ferroptotic and oxidative-stress programs [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"Anti-pssA immunoprecipitation of enzyme activity plus subcellular fractionation in CHO/CDT-1 cells\",\n      \"pmids\": [\"8898108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the membrane enzyme\", \"Topology and active-site organization not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"Stable cDNA overexpression with radiolabeled substrate incorporation in McArdle and CHO cells, comparing PSS1 vs PSS2\",\n      \"pmids\": [\"10432300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Feedback regulation not detected in this overexpression context\", \"Did not resolve physiological control of flux at endogenous levels\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Whole-exome sequencing plus PS synthesis and end-product inhibition assays in patient fibroblasts\",\n      \"pmids\": [\"24241535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of PS sensing by the enzyme unknown\", \"Tissue-specific consequences of elevated PS not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mutant PSS1 expression with live-cell PI4P reporters, PI4KA inhibitors, and ORP8 membrane-association assays\",\n      \"pmids\": [\"27044099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between PSS1 and the transport machinery not shown\", \"Quantitative stoichiometry of PS/PI4P counter-transport unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed catalytic-residue requirements, identifying p.(Leu137Phe) as a loss-of-function substitution that abolishes enzyme activity.\",\n      \"evidence\": \"Overexpression of mutant PTDSS1 in HEK293 with [14C]-serine labeling and TLC\",\n      \"pmids\": [\"35224839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single method\", \"Structural role of the residue not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"PSS1-LMS overexpression in osteoclast precursors with lipidomics, actin imaging, and catalytic-dead rescue\",\n      \"pmids\": [\"37714410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking acyl-chain remodeling to podosome dynamics unresolved\", \"Relationship to PI4P axis not directly tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed PSS1 upstream of PS-dependent intercellular signaling in cancer, defining a PTDSS1\\u2192PS\\u2192MERTK axis that drives tumor-associated macrophage expansion.\",\n      \"evidence\": \"Ptdss1 knockdown in murine tumor cells with in vivo implantation, lipidomics, TAM flow cytometry, and macrophage Mertk knockout\",\n      \"pmids\": [\"35425959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of ether-PS versus diacyl-PS not separated\", \"Direct PS-MERTK engagement not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended PSS1's immunomodulatory role, showing its loss derepresses interferon-responsive genes and MHC-I, enhancing T cell killing and anti-PD-1 efficacy.\",\n      \"evidence\": \"In vivo CRISPR screen with genetic/pharmacological PTDSS1 inhibition, co-culture cytotoxicity, flow cytometry, and transcriptomics across tumor models\",\n      \"pmids\": [\"40929270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking PS depletion to interferon-gene derepression unknown\", \"Whether effect is cell-intrinsic lipid signaling or surface PS-mediated not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked mitochondrial PS supply to redox and death pathways, showing PTDSS1 knockdown promotes TRIM21-SLC3A2 interaction, depletes glutathione, and induces mitophagy, ferroptosis, and apoptosis.\",\n      \"evidence\": \"PTDSS1 knockdown in ESCC cells with Co-IP, GSH/mitophagy/ferroptosis assays, mitochondrial fractionation, and scRNA-seq\",\n      \"pmids\": [\"42026035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without reciprocal validation\", \"Multi-step mechanistic chain involves inferred links between PS loss and TRIM21 activity\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 3, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}