{"gene":"ATP6V0D1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1993,"finding":"The yeast VMA6 gene encodes the 36-kDa subunit of the V-ATPase membrane sector (ortholog of human ATP6V0D1/subunit d). Vma6p is a non-integral membrane component of the V0 domain required for V-ATPase complex assembly: it is removed by chaotropic agents (Na2CO3, urea) but not by detergents, and in its absence, V0 integral membrane components are destabilized and V1 peripheral subunits fail to assemble onto vacuolar membranes. Vacuolar acidification and V-ATPase activity are completely abolished in vma6 null mutants.","method":"Reverse genetics (null mutant construction), subcellular fractionation, biochemical stripping with chaotropic agents, vacuolar acidification assays, ATPase activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods in yeast ortholog with rigorous genetic controls; foundational assembly study","pmids":["8509410"],"is_preprint":false},{"year":2000,"finding":"The human VPATPD gene encodes subunit D of the vacuolar proton ATPase (ATP6V0D1), located on chromosome 16q22. The encoded protein is 99.5% identical to mouse subunit D at the amino acid level. The gene spans 19 kb and consists of 8 exons. Although VPATPD and HSD11B2 are both expressed in kidney and placenta, they are regulated differently (forskolin upregulates HSD11B2 but not VPATPD), indicating independent transcriptional regulation.","method":"Genomic cloning, sequencing, gene structure determination, expression analysis in JEG3 cells with forskolin treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — gene characterization with functional regulatory distinction; single study","pmids":["11118322"],"is_preprint":false},{"year":2011,"finding":"The vacuolar H+-ATPase (V-ATPase), of which ATP6V0D1 is a subunit, is necessary for amino acid-stimulated mTORC1 activation. The v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator complex on the lysosomal surface. In a cell-free system, ATP hydrolysis by the v-ATPase was necessary for amino acids to regulate the v-ATPase–Ragulator interaction and promote mTORC1 translocation, placing the V-ATPase as an amino acid sensor upstream of Rag GTPases.","method":"Cell-free reconstitution, RNAi knockdown of V-ATPase subunits, co-immunoprecipitation of v-ATPase with Ragulator, mTORC1 translocation assays, pharmacological inhibition (bafilomycin)","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — cell-free reconstitution plus genetic knockdown, replicated across multiple approaches; highly cited foundational study","pmids":["22053050"],"is_preprint":false},{"year":2010,"finding":"V-ATPase activity and acidification are required for Wnt/β-catenin signaling. The prorenin receptor (PRR) acts as an adaptor between Wnt receptors (Frizzled/LRP6) and the V-ATPase complex. V-ATPase-mediated acidification is necessary for Wnt signal transduction during antero-posterior patterning, placing the V-ATPase (including its subunits such as ATP6V0D1) as a component of the Wnt receptor signaling complex.","method":"Co-immunoprecipitation, RNAi knockdown, Xenopus embryo epistasis experiments, luciferase reporter assays, pharmacological inhibition of V-ATPase","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal co-IP, genetic epistasis in Xenopus, multiple orthogonal methods; highly cited","pmids":["20093472"],"is_preprint":false},{"year":2022,"finding":"ATP6V0D1 is a direct molecular target of the opioid analgesic JTC801 that drives alkaliptosis in pancreatic ductal adenocarcinoma (PDAC) cells. Drug target identification using mass-spectrometry-based thermal shift assay and point mutation analysis showed JTC801 binds ATP6V0D1 and increases its protein stability. Stabilized ATP6V0D1 enhances interaction with STAT3, increasing STAT3 expression and activity to sustain lysosomal pH homeostasis. Pharmacological or genetic inhibition of STAT3 restores alkaliptosis sensitivity in ATP6V0D1-deficient cells, placing ATP6V0D1 upstream of STAT3 in lysosomal pH regulation.","method":"Mass-spectrometry-based drug target identification, cellular thermal shift assay (CETSA), point mutation analysis, co-immunoprecipitation (ATP6V0D1–STAT3 interaction), genetic knockdown/overexpression, pharmacological inhibition in vitro and in mouse models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (CETSA, MS, mutagenesis, co-IP, in vivo mouse models) in single study with strong mechanistic resolution","pmids":["36640329"],"is_preprint":false},{"year":2022,"finding":"ATP6V0D1 is the direct cellular target of the natural compound schisandrol A (SolA), identified as a V-ATPase subunit in lysosomes. SolA allosterically mediates ATP6V0D1 conformation by targeting a unique cysteine 335 residue, thereby activating V-ATPase-dependent lysosomal acidification. This SolA-induced lysosomal pH downregulation creates a mitochondrial-lysosomal crosstalk by selectively promoting degradation of the mitochondrial BH3-only protein BIM, preserving mitochondrial homeostasis and neuronal cell survival against AGEs-induced apoptosis.","method":"Drug target identification (biochemical), site-directed mutagenesis (Cys335), lysosomal pH measurement, mitochondrial membrane potential assays, BIM protein level analysis, neuronal cell survival assays","journal":"Acta pharmaceutica Sinica. B","confidence":"High","confidence_rationale":"Tier 1-2 — direct mutagenesis of binding site (Cys335), multiple functional readouts, mechanistic pathway resolved","pmids":["36213534"],"is_preprint":false},{"year":2024,"finding":"ATP6V0D1 mediates downregulation of ABCB1 (MDR1/P-glycoprotein), a multidrug resistance protein, in paclitaxel-resistant ovarian cancer cells. Both overexpression of ATP6V0D1 by gene transfection and pharmacological stabilization of ATP6V0D1 protein by JTC801 inhibit ABCB1 upregulation and suppress growth of drug-resistant cells. Increasing intracellular pH to alkaline conditions (pH 8.5) suppresses ABCB1 expression, whereas acidic conditions (pH 6.5) amplify ABCB1 expression, linking ATP6V0D1-dependent lysosomal alkalinization to ABCB1 suppression as the mechanism of overcoming drug resistance.","method":"Gene transfection (overexpression), pharmacological stabilization (JTC801), pH manipulation with NaOH/HCl, ABCB1 expression analysis, cell growth/viability assays in drug-resistant cell lines","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological gain-of-function with defined molecular readout; single study","pmids":["38751020"],"is_preprint":false},{"year":2025,"finding":"Microglial Tmem9 promotes complement activation (C1q) and synaptic loss in Alzheimer's disease by regulating ATP6V0D1, a V-ATPase subunit that controls V-ATPase assembly. Physical exercise down-regulates Tmem9, which in turn inhibits ATP6V0D1-dependent V-ATPase function, decreasing C1q-mediated complement activation and microglial synapse engulfment in 5xFAD mice. Overexpression of Tmem9 abolishes exercise-associated neuroprotection, placing the Tmem9–ATP6V0D1 axis in a complement activation pathway.","method":"In vivo mouse model (5xFAD), genetic overexpression/knockdown of Tmem9, oAβ-stimulated BV2 cells in vitro, complement activity assays, synaptic engulfment quantification, cognitive behavioral testing","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic manipulation with defined pathway placement; ATP6V0D1 role inferred through Tmem9 regulation rather than direct manipulation","pmids":["39871402"],"is_preprint":false},{"year":2022,"finding":"A novel truncating somatic mutation in ATP6V0D1 was identified in a proinsulinoma tumor by whole exome sequencing. ATP6V0D1 is proposed to function in acidifying the β-cell compartments where prohormone convertases (PCSKs) act, and its loss-of-function mutation likely impairs proinsulin processing by reducing lysosomal/secretory granule acidification required for PC1/3 activity.","method":"Whole exome sequencing of tumor tissue, clinical correlation with suppressed insulin/C-peptide and elevated proinsulin levels","journal":"Journal of the Endocrine Society","confidence":"Low","confidence_rationale":"Tier 3-4 — single clinical case with mechanistic inference; no direct experimental validation of ATP6V0D1's role in proinsulin processing","pmids":["36694809"],"is_preprint":false},{"year":2020,"finding":"ATP6V0D1 (vacuolar-ATPase subunit) was identified as a protein that directly interacts with PHF1-immunoreactive phosphorylated tau in neurofibrillary tangles from human Alzheimer's disease brain, detected by affinity purification-mass spectrometry. This places ATP6V0D1 in the phosphorylated tau interactome and implicates it in phagosome maturation pathways enriched in the tau interactome.","method":"Affinity purification-mass spectrometry (AP-MS) with PHF1 antibody against phosphorylated tau from human AD brain, quantitative proteomics of microdissected neurofibrillary tangles","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — AP-MS from human disease tissue; direct binding to phosphorylated tau validated by orthogonal proteomics approach","pmids":["32812023"],"is_preprint":false},{"year":2025,"finding":"Knockdown of ATP6V0D1 (but not ATP6V1H) in neuroblastoma cells enhanced sensitivity to ellipticine, suppressed proliferation and migration, decreased lysosomal drug uptake, induced G2/M arrest, and suppressed ellipticine-induced endoplasmic reticulum vacuolation. These effects demonstrate a specific role for ATP6V0D1 in lysosomal sequestration-based chemoresistance that is not shared by other V-ATPase subunits.","method":"siRNA knockdown of ATP6V0D1 vs. ATP6V1H, cell viability assays, lysosomal uptake measurement, cell cycle analysis, migration assays, vacuolation quantification","journal":"Molecular & cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific cellular phenotypes and subunit-specificity control (ATP6V1H); single study","pmids":["40552114"],"is_preprint":false}],"current_model":"ATP6V0D1 (subunit d of the V-ATPase V0 domain) is a non-integral membrane component essential for V-ATPase complex assembly and lysosomal acidification; it serves as a direct binding target for small molecules (JTC801, schisandrol A at Cys335) that modulate V-ATPase activity, acts upstream of STAT3 to regulate lysosomal pH homeostasis and alkaliptosis, mediates ABCB1-dependent multidrug resistance through pH-dependent mechanisms, participates in mTORC1 amino acid sensing via the v-ATPase–Ragulator axis, and directly interacts with phosphorylated tau in Alzheimer's disease neurofibrillary tangles."},"narrative":{"teleology":[{"year":1993,"claim":"Establishing that the V0-sector 36-kDa subunit (Vma6p/ATP6V0D1 ortholog) is a non-integral membrane protein indispensable for V-ATPase assembly and vacuolar acidification resolved the foundational question of how V0 and V1 sectors are coupled during holoenzyme biogenesis.","evidence":"Null mutant construction in yeast, subcellular fractionation, chaotropic stripping, and vacuolar acidification/ATPase activity assays","pmids":["8509410"],"confidence":"High","gaps":["Precise binding interfaces between Vma6p/ATP6V0D1 and other V0 subunits not mapped","Mechanism by which Vma6p loss destabilizes V0 integral subunits undefined"]},{"year":2000,"claim":"Cloning and characterization of the human VPATPD (ATP6V0D1) gene established its genomic structure and showed that despite shared tissue expression with HSD11B2, it is independently regulated, ruling out co-regulation models.","evidence":"Genomic cloning, sequencing, forskolin treatment in JEG3 cells","pmids":["11118322"],"confidence":"Medium","gaps":["Transcriptional regulators of ATP6V0D1 not identified","Expression across broader human tissue panel not characterized"]},{"year":2010,"claim":"Demonstration that V-ATPase activity is required for Wnt/β-catenin signaling — with the prorenin receptor bridging Frizzled/LRP6 to the V-ATPase — placed the complex in a signaling pathway beyond its canonical acidification role.","evidence":"Reciprocal co-IP, RNAi knockdown, Xenopus epistasis experiments, luciferase reporter assays, V-ATPase pharmacological inhibition","pmids":["20093472"],"confidence":"High","gaps":["Specific contribution of ATP6V0D1 subunit versus other V-ATPase subunits to Wnt signaling not dissected","Whether acidification or physical scaffold function mediates the effect not resolved"]},{"year":2011,"claim":"Cell-free reconstitution showing that V-ATPase ATP hydrolysis is necessary for amino acid-sensitive interactions with Ragulator and subsequent mTORC1 activation established the V-ATPase as an upstream amino acid sensor at lysosomes.","evidence":"Cell-free reconstitution, RNAi knockdown of V-ATPase subunits, co-IP with Ragulator, mTORC1 translocation assays","pmids":["22053050"],"confidence":"High","gaps":["Direct role of ATP6V0D1 versus other subunits in Ragulator binding not isolated","Amino acid sensing mechanism within V-ATPase not molecularly defined"]},{"year":2020,"claim":"Identification of ATP6V0D1 as a direct interactor of PHF1-phosphorylated tau in human AD neurofibrillary tangles placed it within the pathological tau interactome and implicated phagosome maturation in tangle biology.","evidence":"Affinity purification–mass spectrometry with PHF1 antibody from human AD brain tissue","pmids":["32812023"],"confidence":"Medium","gaps":["Functional consequence of ATP6V0D1–phospho-tau interaction on V-ATPase activity not tested","Whether interaction is cause or consequence of tangle formation unknown"]},{"year":2022,"claim":"Drug target identification revealed ATP6V0D1 as the direct binding target of JTC801 and schisandrol A — with schisandrol A acting allosterically at Cys335 — establishing ATP6V0D1 as a druggable node that controls lysosomal pH through distinct downstream effectors (STAT3 for alkaliptosis; BIM degradation for neuroprotection).","evidence":"CETSA, mass spectrometry-based thermal shift, Cys335 site-directed mutagenesis, co-IP of ATP6V0D1–STAT3, lysosomal pH measurements, in vivo mouse models","pmids":["36640329","36213534"],"confidence":"High","gaps":["Structural basis of JTC801 and SolA binding to ATP6V0D1 not resolved at atomic level","Whether STAT3 interaction is direct or through a complex remains ambiguous","Specificity of Cys335 engagement across cell types not tested"]},{"year":2024,"claim":"Connecting ATP6V0D1-dependent lysosomal alkalinization to suppression of ABCB1 expression demonstrated a pH-dependent mechanism by which ATP6V0D1 modulates multidrug resistance in cancer.","evidence":"Gene transfection overexpression, JTC801 pharmacological stabilization, intracellular pH manipulation, ABCB1 expression analysis in drug-resistant ovarian cancer cells","pmids":["38751020"],"confidence":"Medium","gaps":["Transcriptional versus post-translational mechanism for pH-dependent ABCB1 regulation not distinguished","In vivo validation of this resistance mechanism not performed"]},{"year":2025,"claim":"ATP6V0D1 was positioned downstream of Tmem9 in microglia-mediated complement activation (C1q) and synaptic pruning in AD, and separately shown to specifically mediate lysosomal sequestration-based chemoresistance distinct from other V-ATPase subunits.","evidence":"Tmem9 overexpression/knockdown in 5xFAD mice and BV2 cells; siRNA knockdown of ATP6V0D1 vs. ATP6V1H with subunit-specificity controls in neuroblastoma cells","pmids":["39871402","40552114"],"confidence":"Medium","gaps":["Direct manipulation of ATP6V0D1 in the complement pathway not performed — inferred through Tmem9","Structural basis for subunit-specific roles in chemoresistance unknown","In vivo relevance of ATP6V0D1-specific chemoresistance role untested"]},{"year":null,"claim":"No high-resolution structural model of mammalian ATP6V0D1 bound to its V0-sector partners or small-molecule ligands exists, and the mechanism by which conformational changes at Cys335 propagate to alter holoenzyme proton pumping remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["Atomic-resolution structure of ATP6V0D1 in V-ATPase holoenzyme context needed","Allosteric mechanism coupling Cys335 engagement to proton translocation undefined","Tissue-specific and isoform-specific (ATP6V0D1 vs. ATP6V0D2) functional distinctions incompletely characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[4,5,10]},{"term_id":"GO:0005773","term_label":"vacuole","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,6,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]}],"complexes":["V-ATPase (V0 sector)"],"partners":["STAT3","TMEM9","ATP6V0A1","LAMTOR1"],"other_free_text":[]},"mechanistic_narrative":"ATP6V0D1 is a non-integral membrane subunit of the V0 sector of the vacuolar H⁺-ATPase (V-ATPase) that is essential for V-ATPase complex assembly, lysosomal acidification, and pH-dependent cellular signaling. Loss of its yeast ortholog Vma6p destabilizes V0 integral membrane components and abolishes vacuolar ATPase activity [PMID:8509410], while in mammalian cells V-ATPase activity involving ATP6V0D1 is required for amino acid-dependent mTORC1 activation via Ragulator interactions [PMID:22053050] and for Wnt/β-catenin signal transduction [PMID:20093472]. ATP6V0D1 functions as a druggable node: small molecules JTC801 and schisandrol A bind ATP6V0D1 (the latter at Cys335) to modulate V-ATPase-dependent lysosomal pH, with JTC801-stabilized ATP6V0D1 engaging STAT3 to sustain pH homeostasis and drive alkaliptosis in pancreatic cancer cells [PMID:36640329, PMID:36213534]. ATP6V0D1-dependent lysosomal pH regulation also controls ABCB1-mediated multidrug resistance and lysosomal sequestration-based chemoresistance in cancer cells [PMID:38751020, PMID:40552114]."},"prefetch_data":{"uniprot":{"accession":"P61421","full_name":"V-type proton ATPase subunit d 1","aliases":["32 kDa accessory protein","V-ATPase 40 kDa accessory protein","V-ATPase AC39 subunit","p39","Vacuolar proton pump subunit d 1"],"length_aa":351,"mass_kda":40.3,"function":"Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:28296633, PubMed:30374053, PubMed:33065002). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (PubMed:30374053). May play a role in coupling of proton transport and ATP hydrolysis (By similarity). In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation (PubMed:28296633). May play a role in cilium biogenesis through regulation of the transport and the localization of proteins to the cilium (By similarity)","subcellular_location":"Membrane; Lysosome membrane; Cytoplasmic vesicle, clathrin-coated vesicle membrane","url":"https://www.uniprot.org/uniprotkb/P61421/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP6V0D1","classification":"Common Essential","n_dependent_lines":1157,"n_total_lines":1208,"dependency_fraction":0.9577814569536424},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000159720","cell_line_id":"CID001643","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"ATP6AP1","stoichiometry":10.0},{"gene":"ATP6AP2","stoichiometry":10.0},{"gene":"ATP6V0A1","stoichiometry":10.0},{"gene":"ATP6V0A2","stoichiometry":10.0},{"gene":"ATP6V1G1","stoichiometry":10.0},{"gene":"ATP6V1B2","stoichiometry":10.0},{"gene":"ATP6V1A","stoichiometry":4.0},{"gene":"STX12","stoichiometry":4.0},{"gene":"ATP6V1E1","stoichiometry":0.2},{"gene":"ATP6V0C","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001643","total_profiled":1310},"omim":[{"mim_id":"616877","title":"TRANSMEMBRANE PROTEIN 9; TMEM9","url":"https://www.omim.org/entry/616877"},{"mim_id":"614232","title":"11-@BETA-HYDROXYSTEROID DEHYDROGENASE, TYPE II; HSD11B2","url":"https://www.omim.org/entry/614232"},{"mim_id":"607028","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, 38-KD, V0 SUBUNIT D, ISOFORM 1; ATP6V0D1","url":"https://www.omim.org/entry/607028"},{"mim_id":"300556","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, ACCESSORY PROTEIN 2; ATP6AP2","url":"https://www.omim.org/entry/300556"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATP6V0D1"},"hgnc":{"alias_symbol":["ATP6DV","VATX","VPATPD","P39","Vma6"],"prev_symbol":["ATP6D"]},"alphafold":{"accession":"P61421","domains":[{"cath_id":"1.20.1690","chopping":"87-188","consensus_level":"medium","plddt":80.6393,"start":87,"end":188}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61421","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61421-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61421-F1-predicted_aligned_error_v6.png","plddt_mean":85.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP6V0D1","jax_strain_url":"https://www.jax.org/strain/search?query=ATP6V0D1"},"sequence":{"accession":"P61421","fasta_url":"https://rest.uniprot.org/uniprotkb/P61421.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61421/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61421"}},"corpus_meta":[{"pmid":"3130660","id":"PMC_3130660","title":"Fos-associated 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Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1.","date":"2015","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/25567906","citation_count":678,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16713569","id":"PMC_16713569","title":"A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16713569","citation_count":610,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19056867","id":"PMC_19056867","title":"Large-scale proteomics and phosphoproteomics of urinary 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Vma6p is a non-integral membrane component of the V0 membrane domain required for V-ATPase complex assembly: it is removed by chaotropic agents (Na2CO3, urea) but not by detergents that strip peripheral subunits; in cells lacking integral membrane V-ATPase subunits, Vma6p cannot stably associate with vacuolar membranes; and conversely, absence of Vma6p destabilizes integral membrane domain components and prevents peripheral V1 subunit assembly.\",\n      \"method\": \"Genetic null mutants, vacuolar acidification assays, biochemical fractionation with chaotropic/detergent agents, vacuolar membrane isolation\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal biochemical and genetic methods in the founding yeast ortholog paper; strong evidence for assembly role\",\n      \"pmids\": [\"8509410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The VPATPD gene (encoding ATP6V0D1, subunit D of human vacuolar proton ATPase) is located on chromosome 16q22, spans 19 kb with 8 exons, and its protein is 99.5% identical to mouse subunit D. The gene is expressed in kidney and placenta but is regulated differently from the adjacent HSD11B2 gene (forskolin upregulates HSD11B2 but not VPATPD in JEG3 cells).\",\n      \"method\": \"Gene cloning, sequencing, Northern/expression analysis, pharmacological perturbation in cell lines\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structural/genomic characterization with some functional differentiation from neighboring gene, single lab\",\n      \"pmids\": [\"11118322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATP6V0D1 is a direct molecular target of the opioid analgesic drug JTC801 that drives alkaliptosis (regulated cell death by intracellular alkalization) in pancreatic ductal adenocarcinoma (PDAC) cells. JTC801 increases ATP6V0D1 protein stability, which promotes interaction of ATP6V0D1 with STAT3, resulting in increased STAT3 expression and activity that sustains lysosomal pH homeostasis. Pharmacological or genetic inhibition of STAT3 restores alkaliptosis sensitivity in ATP6V0D1-deficient cells.\",\n      \"method\": \"Mass-spectrometry-based drug target identification, cellular thermal shift assay (CETSA), point mutation, co-immunoprecipitation, STAT3 pharmacological/genetic inhibition, in vitro and mouse models\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (MS target ID, CETSA, mutagenesis, CoIP) in a single study with in vivo validation\",\n      \"pmids\": [\"36640329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATP6V0D1, a major V-ATPase subunit in lysosomes, is the cellular target of the natural compound schisandrol A (SolA). SolA allosterically mediates ATP6V0D1 conformation by targeting cysteine 335, thereby activating V-ATPase-dependent lysosomal acidification. SolA-induced lysosomal pH reduction triggers mitochondrial-lysosomal crosstalk by selectively promoting BIM degradation, preserving mitochondrial homeostasis.\",\n      \"method\": \"Drug target identification, site-directed mutagenesis (C335), lysosomal pH measurement, mitochondrial function assays, protein degradation assays\",\n      \"journal\": \"Acta Pharmaceutica Sinica B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis identifying specific active-site cysteine, multiple functional readouts linking ATP6V0D1 to lysosomal acidification and mitochondrial homeostasis\",\n      \"pmids\": [\"36213534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Candida albicans, Vma6 (the VMA6/ATP6V0D1 ortholog) is required for the correct distribution of V0 subunit Vph1 and V1 subunit Tfp1, endocytosis, and vacuolar acidification. Deletion of VMA6 impairs cell wall stress resistance, reduces hyphal development, and attenuates virulence in a mouse systemic candidiasis model.\",\n      \"method\": \"Gene deletion, fluorescence localization of V-ATPase subunits, vacuolar acidification assay, cell wall stress assays, mouse infection model\",\n      \"journal\": \"Fungal Genetics and Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple cellular phenotypes in a fungal ortholog; consistent with yeast Vma6p function\",\n      \"pmids\": [\"29522815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATP6V0D1 mediates downregulation of the multidrug resistance protein ABCB1 in paclitaxel-resistant ovarian cancer cells. Overexpression of ATP6V0D1 or pharmacological stabilization of ATP6V0D1 protein (with JTC801) inhibits ABCB1 upregulation and overcomes drug resistance. Increasing intracellular pH to alkaline conditions suppresses ABCB1 expression, whereas acidic pH amplifies it, linking ATP6V0D1-dependent intracellular alkalization to ABCB1 regulation.\",\n      \"method\": \"Gene transfection (overexpression), pharmacological stabilization, pH manipulation, ABCB1 expression analysis, cell viability assays\",\n      \"journal\": \"Molecular Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple mechanistic approaches (OE, pharmacology, pH manipulation) but largely in cancer cell lines without reconstitution\",\n      \"pmids\": [\"38751020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In microglia, ATP6V0D1 (a V-ATPase V0 subunit that regulates V-ATPase assembly) acts downstream of the transmembrane protein Tmem9 to regulate complement activation (C1q) and microglial synapse engulfment. Downregulation of Tmem9 reduced C1q activation and synaptic loss in an Alzheimer's disease mouse model, and this protection was mediated through ATP6V0D1.\",\n      \"method\": \"In vivo 5xFAD mouse model with physical exercise, BV2 in vitro overexpression/knockdown of Tmem9 and ATP6V0D1, C1q assays, synapse engulfment assays\",\n      \"journal\": \"Aging Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis between Tmem9 and ATP6V0D1 demonstrated by genetic manipulation with defined cellular phenotypes in mouse model\",\n      \"pmids\": [\"39871402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATP6V0D1 knockdown in neuroblastoma cells enhanced sensitivity to ellipticine, suppressed proliferation and migration, decreased lysosomal drug uptake, and induced G2/M arrest. ATP6V0D1 knockdown also suppressed ellipticine-induced cytoplasmic vacuolation (identified as endoplasmic reticulum swelling). Notably, knockdown of another V-ATPase subunit (ATP6V1H) had no effect on these phenotypes, highlighting the specific role of ATP6V0D1.\",\n      \"method\": \"siRNA knockdown of ATP6V0D1 vs. ATP6V1H, cell viability, proliferation, migration assays, lysosomal uptake measurement, cell cycle analysis, vacuolation imaging\",\n      \"journal\": \"Molecular & Cellular Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — subunit-specific knockdown with multiple defined cellular phenotypes and negative control (ATP6V1H), single lab\",\n      \"pmids\": [\"40552114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A somatic truncating mutation in ATP6V0D1 was identified in a proinsulinoma tumor by whole exome sequencing. ATP6V0D1 encodes a subunit of the ion pump that acidifies β-cell compartments where prohormone convertases (PCSKs) act to process proinsulin to insulin. The mutation is proposed to impair lysosomal/secretory granule acidification required for PCSK-dependent proinsulin processing.\",\n      \"method\": \"Whole exome sequencing of tumor somatic genome, clinical phenotyping of proinsulinoma\",\n      \"journal\": \"Journal of the Endocrine Society\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — somatic mutation identified by sequencing only; functional mechanism is inferred but not experimentally validated\",\n      \"pmids\": [\"36694809\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V0D1 encodes the d1 subunit of the V0 membrane domain of the vacuolar H+-ATPase (V-ATPase); it is essential for V-ATPase complex assembly (anchoring V1 peripheral subunits to the V0 membrane sector) and for lysosomal/vacuolar acidification, and in mammalian cells it drives alkaliptosis by interacting with STAT3 to regulate lysosomal pH homeostasis, allosterically responds to small molecules at Cys335 to activate lysosomal acidification, mediates ABCB1 downregulation in drug-resistant cancer cells, and participates in complement-mediated synaptic loss downstream of microglial Tmem9.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from those about ATP6V0D1 (the d subunit of the V0 domain of vacuolar H+-ATPase).\n\n**Classification summary:**\n- Papers about CDK5 activator p35/p39 (CDK5R2) → EXCLUDE (alias collision)\n- Papers about Borrelia burgdorferi P39 antigen → EXCLUDE\n- Papers about c-Jun p39/AP-1 → EXCLUDE\n- Papers about baculovirus p39 → EXCLUDE\n- Papers about vaccinia virus p39 → EXCLUDE\n- Papers about feline calicivirus p39 → EXCLUDE\n- Papers about other p39 proteins (Novikoff cytokeratin, soybean, Arabidopsis, Xenopus mos, etc.) → EXCLUDE\n- Papers about V-ATPase in general (yeast VMA6, structure/function reviews) → KEEP if they inform ATP6V0D1 mechanistic function\n- Papers specifically about ATP6V0D1 → KEEP: PMIDs 36640329, 36213534, 38751020, 39871402, 36694809, 40552114, 8509410 (yeast VMA6/ortholog), 22053050 (v-ATPase/mTORC1), 11836511 (V-ATPase review), 9442887 (V-ATPase review), 10221984, 20093472, 32812023 (ATP6V0D1 in tau interactome)\n\nFor the curated papers, I'll keep those with direct mechanistic findings relevant to ATP6V0D1.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"The yeast VMA6 gene encodes the 36-kDa subunit of the V-ATPase membrane sector (ortholog of human ATP6V0D1/subunit d). Vma6p is a non-integral membrane component of the V0 domain required for V-ATPase complex assembly: it is removed by chaotropic agents (Na2CO3, urea) but not by detergents, and in its absence, V0 integral membrane components are destabilized and V1 peripheral subunits fail to assemble onto vacuolar membranes. Vacuolar acidification and V-ATPase activity are completely abolished in vma6 null mutants.\",\n      \"method\": \"Reverse genetics (null mutant construction), subcellular fractionation, biochemical stripping with chaotropic agents, vacuolar acidification assays, ATPase activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods in yeast ortholog with rigorous genetic controls; foundational assembly study\",\n      \"pmids\": [\"8509410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The human VPATPD gene encodes subunit D of the vacuolar proton ATPase (ATP6V0D1), located on chromosome 16q22. The encoded protein is 99.5% identical to mouse subunit D at the amino acid level. The gene spans 19 kb and consists of 8 exons. Although VPATPD and HSD11B2 are both expressed in kidney and placenta, they are regulated differently (forskolin upregulates HSD11B2 but not VPATPD), indicating independent transcriptional regulation.\",\n      \"method\": \"Genomic cloning, sequencing, gene structure determination, expression analysis in JEG3 cells with forskolin treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gene characterization with functional regulatory distinction; single study\",\n      \"pmids\": [\"11118322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The vacuolar H+-ATPase (V-ATPase), of which ATP6V0D1 is a subunit, is necessary for amino acid-stimulated mTORC1 activation. The v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator complex on the lysosomal surface. In a cell-free system, ATP hydrolysis by the v-ATPase was necessary for amino acids to regulate the v-ATPase–Ragulator interaction and promote mTORC1 translocation, placing the V-ATPase as an amino acid sensor upstream of Rag GTPases.\",\n      \"method\": \"Cell-free reconstitution, RNAi knockdown of V-ATPase subunits, co-immunoprecipitation of v-ATPase with Ragulator, mTORC1 translocation assays, pharmacological inhibition (bafilomycin)\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cell-free reconstitution plus genetic knockdown, replicated across multiple approaches; highly cited foundational study\",\n      \"pmids\": [\"22053050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"V-ATPase activity and acidification are required for Wnt/β-catenin signaling. The prorenin receptor (PRR) acts as an adaptor between Wnt receptors (Frizzled/LRP6) and the V-ATPase complex. V-ATPase-mediated acidification is necessary for Wnt signal transduction during antero-posterior patterning, placing the V-ATPase (including its subunits such as ATP6V0D1) as a component of the Wnt receptor signaling complex.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, Xenopus embryo epistasis experiments, luciferase reporter assays, pharmacological inhibition of V-ATPase\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal co-IP, genetic epistasis in Xenopus, multiple orthogonal methods; highly cited\",\n      \"pmids\": [\"20093472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATP6V0D1 is a direct molecular target of the opioid analgesic JTC801 that drives alkaliptosis in pancreatic ductal adenocarcinoma (PDAC) cells. Drug target identification using mass-spectrometry-based thermal shift assay and point mutation analysis showed JTC801 binds ATP6V0D1 and increases its protein stability. Stabilized ATP6V0D1 enhances interaction with STAT3, increasing STAT3 expression and activity to sustain lysosomal pH homeostasis. Pharmacological or genetic inhibition of STAT3 restores alkaliptosis sensitivity in ATP6V0D1-deficient cells, placing ATP6V0D1 upstream of STAT3 in lysosomal pH regulation.\",\n      \"method\": \"Mass-spectrometry-based drug target identification, cellular thermal shift assay (CETSA), point mutation analysis, co-immunoprecipitation (ATP6V0D1–STAT3 interaction), genetic knockdown/overexpression, pharmacological inhibition in vitro and in mouse models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (CETSA, MS, mutagenesis, co-IP, in vivo mouse models) in single study with strong mechanistic resolution\",\n      \"pmids\": [\"36640329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATP6V0D1 is the direct cellular target of the natural compound schisandrol A (SolA), identified as a V-ATPase subunit in lysosomes. SolA allosterically mediates ATP6V0D1 conformation by targeting a unique cysteine 335 residue, thereby activating V-ATPase-dependent lysosomal acidification. This SolA-induced lysosomal pH downregulation creates a mitochondrial-lysosomal crosstalk by selectively promoting degradation of the mitochondrial BH3-only protein BIM, preserving mitochondrial homeostasis and neuronal cell survival against AGEs-induced apoptosis.\",\n      \"method\": \"Drug target identification (biochemical), site-directed mutagenesis (Cys335), lysosomal pH measurement, mitochondrial membrane potential assays, BIM protein level analysis, neuronal cell survival assays\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct mutagenesis of binding site (Cys335), multiple functional readouts, mechanistic pathway resolved\",\n      \"pmids\": [\"36213534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATP6V0D1 mediates downregulation of ABCB1 (MDR1/P-glycoprotein), a multidrug resistance protein, in paclitaxel-resistant ovarian cancer cells. Both overexpression of ATP6V0D1 by gene transfection and pharmacological stabilization of ATP6V0D1 protein by JTC801 inhibit ABCB1 upregulation and suppress growth of drug-resistant cells. Increasing intracellular pH to alkaline conditions (pH 8.5) suppresses ABCB1 expression, whereas acidic conditions (pH 6.5) amplify ABCB1 expression, linking ATP6V0D1-dependent lysosomal alkalinization to ABCB1 suppression as the mechanism of overcoming drug resistance.\",\n      \"method\": \"Gene transfection (overexpression), pharmacological stabilization (JTC801), pH manipulation with NaOH/HCl, ABCB1 expression analysis, cell growth/viability assays in drug-resistant cell lines\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological gain-of-function with defined molecular readout; single study\",\n      \"pmids\": [\"38751020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Microglial Tmem9 promotes complement activation (C1q) and synaptic loss in Alzheimer's disease by regulating ATP6V0D1, a V-ATPase subunit that controls V-ATPase assembly. Physical exercise down-regulates Tmem9, which in turn inhibits ATP6V0D1-dependent V-ATPase function, decreasing C1q-mediated complement activation and microglial synapse engulfment in 5xFAD mice. Overexpression of Tmem9 abolishes exercise-associated neuroprotection, placing the Tmem9–ATP6V0D1 axis in a complement activation pathway.\",\n      \"method\": \"In vivo mouse model (5xFAD), genetic overexpression/knockdown of Tmem9, oAβ-stimulated BV2 cells in vitro, complement activity assays, synaptic engulfment quantification, cognitive behavioral testing\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic manipulation with defined pathway placement; ATP6V0D1 role inferred through Tmem9 regulation rather than direct manipulation\",\n      \"pmids\": [\"39871402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A novel truncating somatic mutation in ATP6V0D1 was identified in a proinsulinoma tumor by whole exome sequencing. ATP6V0D1 is proposed to function in acidifying the β-cell compartments where prohormone convertases (PCSKs) act, and its loss-of-function mutation likely impairs proinsulin processing by reducing lysosomal/secretory granule acidification required for PC1/3 activity.\",\n      \"method\": \"Whole exome sequencing of tumor tissue, clinical correlation with suppressed insulin/C-peptide and elevated proinsulin levels\",\n      \"journal\": \"Journal of the Endocrine Society\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3-4 — single clinical case with mechanistic inference; no direct experimental validation of ATP6V0D1's role in proinsulin processing\",\n      \"pmids\": [\"36694809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATP6V0D1 (vacuolar-ATPase subunit) was identified as a protein that directly interacts with PHF1-immunoreactive phosphorylated tau in neurofibrillary tangles from human Alzheimer's disease brain, detected by affinity purification-mass spectrometry. This places ATP6V0D1 in the phosphorylated tau interactome and implicates it in phagosome maturation pathways enriched in the tau interactome.\",\n      \"method\": \"Affinity purification-mass spectrometry (AP-MS) with PHF1 antibody against phosphorylated tau from human AD brain, quantitative proteomics of microdissected neurofibrillary tangles\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — AP-MS from human disease tissue; direct binding to phosphorylated tau validated by orthogonal proteomics approach\",\n      \"pmids\": [\"32812023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockdown of ATP6V0D1 (but not ATP6V1H) in neuroblastoma cells enhanced sensitivity to ellipticine, suppressed proliferation and migration, decreased lysosomal drug uptake, induced G2/M arrest, and suppressed ellipticine-induced endoplasmic reticulum vacuolation. These effects demonstrate a specific role for ATP6V0D1 in lysosomal sequestration-based chemoresistance that is not shared by other V-ATPase subunits.\",\n      \"method\": \"siRNA knockdown of ATP6V0D1 vs. ATP6V1H, cell viability assays, lysosomal uptake measurement, cell cycle analysis, migration assays, vacuolation quantification\",\n      \"journal\": \"Molecular & cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific cellular phenotypes and subunit-specificity control (ATP6V1H); single study\",\n      \"pmids\": [\"40552114\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V0D1 (subunit d of the V-ATPase V0 domain) is a non-integral membrane component essential for V-ATPase complex assembly and lysosomal acidification; it serves as a direct binding target for small molecules (JTC801, schisandrol A at Cys335) that modulate V-ATPase activity, acts upstream of STAT3 to regulate lysosomal pH homeostasis and alkaliptosis, mediates ABCB1-dependent multidrug resistance through pH-dependent mechanisms, participates in mTORC1 amino acid sensing via the v-ATPase–Ragulator axis, and directly interacts with phosphorylated tau in Alzheimer's disease neurofibrillary tangles.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATP6V0D1 encodes the d1 subunit of the V0 membrane domain of the vacuolar H+-ATPase (V-ATPase), serving as a non-integral membrane scaffold essential for anchoring V1 peripheral subunits to the V0 membrane sector and thereby enabling V-ATPase complex assembly and organellar acidification [PMID:8509410, PMID:29522815]. Allosteric modulation of ATP6V0D1 at Cys335 by small molecules activates V-ATPase-dependent lysosomal acidification, coupling lysosomal pH to mitochondrial homeostasis through selective BIM degradation [PMID:36213534]. ATP6V0D1 also interacts with STAT3 to regulate lysosomal pH homeostasis and drives alkaliptosis in pancreatic cancer cells when stabilized by the opioid analgesic JTC801 [PMID:36640329]. In microglia, ATP6V0D1 functions downstream of Tmem9 to regulate complement C1q activation and synapse engulfment, linking V-ATPase activity to neuroinflammatory processes [PMID:39871402].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"The foundational question of what role the d subunit plays in V-ATPase was answered: Vma6p (the yeast ortholog) is a non-integral V0 component required for stable assembly of both integral membrane and peripheral V1 subunits, establishing subunit d as the linchpin connecting V0 and V1 sectors.\",\n      \"evidence\": \"Genetic null mutants, chaotropic/detergent fractionation, and vacuolar membrane isolation in S. cerevisiae\",\n      \"pmids\": [\"8509410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for how subunit d bridges V0 and V1 was not resolved\",\n        \"Whether the assembly role is conserved in mammalian cells was not tested\",\n        \"Regulatory inputs controlling subunit d expression or post-translational modification were unknown\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The human gene was cloned and mapped to chromosome 16q22, establishing that ATP6V0D1 is expressed in tissues with high acidification demand (kidney, placenta) and is transcriptionally independent from its neighboring gene HSD11B2.\",\n      \"evidence\": \"Gene cloning, Northern blot, and forskolin stimulation in JEG3 cells\",\n      \"pmids\": [\"11118322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional validation of human ATP6V0D1 protein activity was performed\",\n        \"Tissue-specific isoform regulation was not explored beyond two tissues\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Deletion of the ortholog VMA6 in C. albicans confirmed that the assembly role is conserved across fungi and further revealed requirements for endocytosis, hyphal development, cell wall stress resistance, and in vivo virulence, broadening the phenotypic scope of subunit d loss.\",\n      \"evidence\": \"Gene deletion, fluorescence localization of V-ATPase subunits, vacuolar acidification, and mouse systemic candidiasis model\",\n      \"pmids\": [\"29522815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The mechanistic link between V-ATPase assembly loss and endocytosis/hyphal defects was not dissected\",\n        \"Whether mammalian ATP6V0D1 similarly affects endocytic trafficking was untested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Two studies converged to show that ATP6V0D1 is a druggable regulatory node: JTC801 stabilizes ATP6V0D1 protein to promote STAT3 interaction and alkaliptosis in PDAC cells, while SolA allosterically activates V-ATPase-dependent lysosomal acidification through Cys335, linking subunit d conformation to lysosomal–mitochondrial crosstalk via BIM degradation.\",\n      \"evidence\": \"Mass spectrometry target ID, CETSA, site-directed mutagenesis of C335, co-immunoprecipitation, lysosomal pH measurement, and mouse xenograft models\",\n      \"pmids\": [\"36640329\", \"36213534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural mechanism of allosteric activation via Cys335 remains unresolved at atomic resolution\",\n        \"Whether STAT3 interaction is direct or mediated through a complex is unclear\",\n        \"The relationship between JTC801-induced stabilization and SolA-mediated allosteric activation has not been integrated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ATP6V0D1 was shown to link intracellular pH regulation to drug resistance by mediating ABCB1 downregulation: overexpression or pharmacological stabilization of ATP6V0D1 suppressed ABCB1 upregulation in paclitaxel-resistant ovarian cancer cells, with alkaline intracellular pH being sufficient to suppress ABCB1 expression.\",\n      \"evidence\": \"Overexpression, JTC801 stabilization, pH manipulation, and ABCB1 expression analysis in drug-resistant ovarian cancer cell lines\",\n      \"pmids\": [\"38751020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The signaling pathway connecting ATP6V0D1-dependent pH changes to ABCB1 transcription/stability is uncharacterized\",\n        \"In vivo validation of this drug resistance mechanism was not provided\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Two studies extended ATP6V0D1 function to neuronal contexts: in microglia, ATP6V0D1 acts downstream of Tmem9 to regulate complement C1q activation and synapse engulfment in an Alzheimer's model; in neuroblastoma, ATP6V0D1 knockdown specifically (but not ATP6V1H knockdown) enhanced drug sensitivity, suppressed lysosomal uptake, and induced G2/M arrest, indicating non-redundant subunit-specific functions.\",\n      \"evidence\": \"5xFAD mouse model with Tmem9/ATP6V0D1 manipulation, BV2 microglial assays, siRNA knockdown with subunit-specific controls in neuroblastoma cells\",\n      \"pmids\": [\"39871402\", \"40552114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular mechanism by which ATP6V0D1 specifically regulates C1q activation is unknown\",\n        \"Why ATP6V0D1 but not ATP6V1H knockdown affects drug sensitivity requires structural or stoichiometric explanation\",\n        \"Whether the Tmem9–ATP6V0D1 axis operates outside microglia is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution structural basis for Cys335-mediated allosteric activation, the precise mechanism of ATP6V0D1–STAT3 interaction, whether ATP6V0D1 has assembly-independent signaling functions, and how subunit d specificity differs from other V-ATPase subunits in disease-relevant contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of mammalian ATP6V0D1 in complex with V-ATPase or STAT3 is available\",\n        \"Assembly-independent functions of ATP6V0D1 have not been separated from its core V-ATPase role\",\n        \"Germline loss-of-function consequences in mammals remain uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"V-ATPase (V0 sector)\"\n    ],\n    \"partners\": [\n      \"STAT3\",\n      \"TMEM9\",\n      \"VPH1\",\n      \"ABCB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ATP6V0D1 is a non-integral membrane subunit of the V0 sector of the vacuolar H⁺-ATPase (V-ATPase) that is essential for V-ATPase complex assembly, lysosomal acidification, and pH-dependent cellular signaling. Loss of its yeast ortholog Vma6p destabilizes V0 integral membrane components and abolishes vacuolar ATPase activity [PMID:8509410], while in mammalian cells V-ATPase activity involving ATP6V0D1 is required for amino acid-dependent mTORC1 activation via Ragulator interactions [PMID:22053050] and for Wnt/β-catenin signal transduction [PMID:20093472]. ATP6V0D1 functions as a druggable node: small molecules JTC801 and schisandrol A bind ATP6V0D1 (the latter at Cys335) to modulate V-ATPase-dependent lysosomal pH, with JTC801-stabilized ATP6V0D1 engaging STAT3 to sustain pH homeostasis and drive alkaliptosis in pancreatic cancer cells [PMID:36640329, PMID:36213534]. ATP6V0D1-dependent lysosomal pH regulation also controls ABCB1-mediated multidrug resistance and lysosomal sequestration-based chemoresistance in cancer cells [PMID:38751020, PMID:40552114].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that the V0-sector 36-kDa subunit (Vma6p/ATP6V0D1 ortholog) is a non-integral membrane protein indispensable for V-ATPase assembly and vacuolar acidification resolved the foundational question of how V0 and V1 sectors are coupled during holoenzyme biogenesis.\",\n      \"evidence\": \"Null mutant construction in yeast, subcellular fractionation, chaotropic stripping, and vacuolar acidification/ATPase activity assays\",\n      \"pmids\": [\"8509410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise binding interfaces between Vma6p/ATP6V0D1 and other V0 subunits not mapped\", \"Mechanism by which Vma6p loss destabilizes V0 integral subunits undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Cloning and characterization of the human VPATPD (ATP6V0D1) gene established its genomic structure and showed that despite shared tissue expression with HSD11B2, it is independently regulated, ruling out co-regulation models.\",\n      \"evidence\": \"Genomic cloning, sequencing, forskolin treatment in JEG3 cells\",\n      \"pmids\": [\"11118322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional regulators of ATP6V0D1 not identified\", \"Expression across broader human tissue panel not characterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstration that V-ATPase activity is required for Wnt/β-catenin signaling — with the prorenin receptor bridging Frizzled/LRP6 to the V-ATPase — placed the complex in a signaling pathway beyond its canonical acidification role.\",\n      \"evidence\": \"Reciprocal co-IP, RNAi knockdown, Xenopus epistasis experiments, luciferase reporter assays, V-ATPase pharmacological inhibition\",\n      \"pmids\": [\"20093472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific contribution of ATP6V0D1 subunit versus other V-ATPase subunits to Wnt signaling not dissected\", \"Whether acidification or physical scaffold function mediates the effect not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Cell-free reconstitution showing that V-ATPase ATP hydrolysis is necessary for amino acid-sensitive interactions with Ragulator and subsequent mTORC1 activation established the V-ATPase as an upstream amino acid sensor at lysosomes.\",\n      \"evidence\": \"Cell-free reconstitution, RNAi knockdown of V-ATPase subunits, co-IP with Ragulator, mTORC1 translocation assays\",\n      \"pmids\": [\"22053050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct role of ATP6V0D1 versus other subunits in Ragulator binding not isolated\", \"Amino acid sensing mechanism within V-ATPase not molecularly defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of ATP6V0D1 as a direct interactor of PHF1-phosphorylated tau in human AD neurofibrillary tangles placed it within the pathological tau interactome and implicated phagosome maturation in tangle biology.\",\n      \"evidence\": \"Affinity purification–mass spectrometry with PHF1 antibody from human AD brain tissue\",\n      \"pmids\": [\"32812023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of ATP6V0D1–phospho-tau interaction on V-ATPase activity not tested\", \"Whether interaction is cause or consequence of tangle formation unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Drug target identification revealed ATP6V0D1 as the direct binding target of JTC801 and schisandrol A — with schisandrol A acting allosterically at Cys335 — establishing ATP6V0D1 as a druggable node that controls lysosomal pH through distinct downstream effectors (STAT3 for alkaliptosis; BIM degradation for neuroprotection).\",\n      \"evidence\": \"CETSA, mass spectrometry-based thermal shift, Cys335 site-directed mutagenesis, co-IP of ATP6V0D1–STAT3, lysosomal pH measurements, in vivo mouse models\",\n      \"pmids\": [\"36640329\", \"36213534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of JTC801 and SolA binding to ATP6V0D1 not resolved at atomic level\", \"Whether STAT3 interaction is direct or through a complex remains ambiguous\", \"Specificity of Cys335 engagement across cell types not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connecting ATP6V0D1-dependent lysosomal alkalinization to suppression of ABCB1 expression demonstrated a pH-dependent mechanism by which ATP6V0D1 modulates multidrug resistance in cancer.\",\n      \"evidence\": \"Gene transfection overexpression, JTC801 pharmacological stabilization, intracellular pH manipulation, ABCB1 expression analysis in drug-resistant ovarian cancer cells\",\n      \"pmids\": [\"38751020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional versus post-translational mechanism for pH-dependent ABCB1 regulation not distinguished\", \"In vivo validation of this resistance mechanism not performed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ATP6V0D1 was positioned downstream of Tmem9 in microglia-mediated complement activation (C1q) and synaptic pruning in AD, and separately shown to specifically mediate lysosomal sequestration-based chemoresistance distinct from other V-ATPase subunits.\",\n      \"evidence\": \"Tmem9 overexpression/knockdown in 5xFAD mice and BV2 cells; siRNA knockdown of ATP6V0D1 vs. ATP6V1H with subunit-specificity controls in neuroblastoma cells\",\n      \"pmids\": [\"39871402\", \"40552114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct manipulation of ATP6V0D1 in the complement pathway not performed — inferred through Tmem9\", \"Structural basis for subunit-specific roles in chemoresistance unknown\", \"In vivo relevance of ATP6V0D1-specific chemoresistance role untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structural model of mammalian ATP6V0D1 bound to its V0-sector partners or small-molecule ligands exists, and the mechanism by which conformational changes at Cys335 propagate to alter holoenzyme proton pumping remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of ATP6V0D1 in V-ATPase holoenzyme context needed\", \"Allosteric mechanism coupling Cys335 engagement to proton translocation undefined\", \"Tissue-specific and isoform-specific (ATP6V0D1 vs. ATP6V0D2) functional distinctions incompletely characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [4, 5, 10]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"V-ATPase (V0 sector)\"],\n    \"partners\": [\"STAT3\", \"TMEM9\", \"ATP6V0A1\", \"LAMTOR1\"],\n    \"other_free_text\": []\n  }\n}\n```"}