{"gene":"ATP6V1F","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1994,"finding":"VMA7 (the yeast ortholog of ATP6V1F) encodes a novel 14-kDa subunit of the V-ATPase V1 catalytic sector. Deletion of VMA7 abolishes V-ATPase activity, prevents V1 subunit association with the vacuolar membrane, and causes greatly reduced V0 complex subunit levels. Unlike integral V0 subunits, Vma7p is easily stripped from membranes and associates only with the fully assembled V-ATPase, not with a separate V0 subcomplex fraction, suggesting it stabilizes V0 and bridges V1 and V0 complexes.","method":"Genetic null mutant analysis, Western blotting, density gradient fractionation, membrane stripping assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical and genetic methods in a foundational study; replicated by independent lab in same year","pmids":["7929308"],"is_preprint":false},{"year":1994,"finding":"VMA7 (yeast ortholog of ATP6V1F) encodes subunit F of the V-ATPase catalytic sector. In its absence, other V1 catalytic subunits fail to assemble onto the vacuolar membrane and vacuoles cannot acidify. A monoclonal antibody against epitope-tagged Vma7p markedly inhibits proton uptake activity of isolated vacuoles. Cold inactivation experiments confirm Vma7p is a genuine subunit of the V1 catalytic sector.","method":"Null mutant generation, quinacrine accumulation assay, epitope-tagged protein inhibition with monoclonal antibody, cold inactivation experiment, proton uptake assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct functional inhibition assay with antibody plus genetic evidence; independent replication in same year (PMID 7929308)","pmids":["7929071"],"is_preprint":false},{"year":2005,"finding":"The Candida albicans ortholog of ATP6V1F (Vma7p) is required for vacuole acidification; its deletion causes defective growth at alkaline pH, impaired degradation of intravacuolar endosomal structures, sensitivity to metal ions, and complete avirulence in a mouse model of systemic candidiasis. The Vma7p-interacting phosphatidylinositol 3-kinase Vps34p null mutant shows similar phenotypes, placing Vma7p in the same pathway.","method":"Null mutant generation in C. albicans, vacuole acidification assay, mouse virulence model, genetic epistasis with VPS34 deletion","journal":"Microbiology (Reading, England)","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular and in vivo phenotypes plus epistasis; single lab","pmids":["15870472"],"is_preprint":false},{"year":2008,"finding":"Loss-of-function mutations in atp6v1f in zebrafish cause microphthalmic, oculocutaneous albino phenotypes including defects in melanosome formation/survival, malformation of the retinal pigmented epithelium, impaired retinoblast cell cycle exit, sustained ciliary marginal zone proliferation, elevated retinal and brain apoptosis, photoreceptor outer segment rosette formation, and accumulation of membrane-bounded vacuoles containing undigested outer segment material in RPE cells. In situ hybridization localized atp6v1f transcripts to the RPE.","method":"Zebrafish forward genetics, histology, BrdU incorporation assay, TUNEL apoptosis assay, ultrastructural (TEM) analysis, in situ hybridization","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with multiple orthogonal phenotypic readouts and direct localization in vivo; strong genetic evidence","pmids":["18836173"],"is_preprint":false},{"year":2012,"finding":"The ATP6V1F gene was cloned from Giant Panda; the encoded protein contains one protein kinase C phosphorylation site, two casein kinase II phosphorylation sites, and one N-myristoylation site as predicted by topology analysis. Overexpression in E. coli produced an expected ~17 kDa His-tagged fusion protein, confirming the predicted molecular weight of the subunit F polypeptide.","method":"RT-PCR cloning, genomic PCR, sequence alignment, topology/motif prediction, recombinant overexpression in E. coli","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 4 — computational prediction of modification sites; recombinant expression without functional validation","pmids":["22212708"],"is_preprint":false},{"year":2024,"finding":"In hepatocellular carcinoma cells, dihydroartemisinin (DHA) decreased expression of CANX (calnexin), and both ATP6V1F (V1 domain subunit F) and ATP6V0B (V0 domain subunit B) protein levels were reduced upon DHA treatment or CANX knockdown. CANX overexpression increased ATP6V1F and ATP6V0B levels and promoted mitochondrial function and energy metabolism, establishing CANX as an upstream regulator of V-ATPase subunit expression including ATP6V1F.","method":"siRNA knockdown and overexpression of CANX, Western blotting for ATP6V1F/ATP6V0B, ATP production assay, mitochondrial membrane potential (JC-1), ROS measurement, cell proliferation/apoptosis/migration assays","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — loss- and gain-of-function with multiple functional readouts; single lab, no independent replication","pmids":["39161338"],"is_preprint":false}],"current_model":"ATP6V1F encodes subunit F of the V1 catalytic sector of the vacuolar H+-ATPase (V-ATPase); it is essential for assembly of V1 subunits onto the vacuolar membrane, stabilization of the V0 complex, and proton-pumping activity, and in vertebrates it is required in the RPE for melanosome biogenesis, retinoblast proliferation, and photoreceptor maintenance, with its expression regulated upstream by calnexin (CANX) in liver cancer cells."},"narrative":{"teleology":[{"year":1994,"claim":"The identity of V-ATPase subunit F as a novel V1-sector component required for holoenzyme assembly was established, resolving how the catalytic sector attaches to the membrane-integral V0 domain.","evidence":"Yeast VMA7 deletion mutants analyzed by Western blotting, density gradient fractionation, membrane stripping, quinacrine acidification assays, and antibody-mediated inhibition of proton uptake","pmids":["7929308","7929071"],"confidence":"High","gaps":["Structural basis of subunit F contacts with other V1 and V0 subunits not resolved","Post-translational regulation of subunit F not addressed","Whether subunit F has roles beyond structural scaffolding (e.g., regulatory) was unknown"]},{"year":2005,"claim":"Extension of subunit F function to a pathogenic organism showed that Vma7p is required for vacuole acidification, alkaline-pH tolerance, and full virulence, reinforcing its non-redundant role in V-ATPase-dependent processes.","evidence":"Candida albicans VMA7 null mutant phenotyping including vacuole acidification, metal sensitivity, and mouse systemic candidiasis model with VPS34 epistasis","pmids":["15870472"],"confidence":"Medium","gaps":["Whether loss of virulence is solely via defective acidification or involves additional Vma7p-dependent pathways is unclear","Interaction between Vma7p and Vps34p was not demonstrated to be direct"]},{"year":2008,"claim":"A vertebrate in vivo requirement for ATP6V1F was defined: loss of function in zebrafish revealed that subunit F is essential for RPE melanosome biogenesis, retinoblast cell cycle regulation, and photoreceptor outer segment turnover, connecting V-ATPase-mediated acidification to eye development.","evidence":"Zebrafish forward genetic screen with histology, BrdU, TUNEL, TEM ultrastructure, and in situ hybridization","pmids":["18836173"],"confidence":"High","gaps":["Whether the proliferation defect is cell-autonomous to RPE or secondary to impaired signaling was not resolved","Mammalian confirmation of these phenotypes is lacking","Molecular partners of ATP6V1F in the RPE context were not identified"]},{"year":2024,"claim":"An upstream transcriptional/post-transcriptional regulator of ATP6V1F was identified: calnexin (CANX) positively controls ATP6V1F protein levels in hepatocellular carcinoma cells, linking ER proteostasis to V-ATPase abundance and mitochondrial energy metabolism.","evidence":"siRNA knockdown and overexpression of CANX with Western blot for ATP6V1F/ATP6V0B, ATP, JC-1, and ROS assays in HCC cell lines","pmids":["39161338"],"confidence":"Medium","gaps":["Mechanism of CANX-mediated regulation of ATP6V1F (transcriptional vs. protein stability) not distinguished","Single-lab finding without independent replication","Whether this regulatory axis operates outside hepatocellular carcinoma is unknown"]},{"year":null,"claim":"A high-resolution structural model of subunit F within the mammalian V-ATPase holoenzyme, the regulatory signals (e.g., phosphorylation) controlling reversible V1–V0 dissociation at subunit F, and the physiological relevance of ATP6V1F in mammalian disease remain to be determined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mammalian loss-of-function model for ATP6V1F has been reported","Predicted phosphorylation sites on subunit F have not been functionally validated","Whether subunit F participates in regulated V-ATPase disassembly in response to nutrient signals is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005773","term_label":"vacuole","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]}],"complexes":["V-ATPase (V1 sector)"],"partners":["CANX"],"other_free_text":[]},"mechanistic_narrative":"ATP6V1F encodes subunit F of the V1 catalytic sector of the vacuolar H⁺-ATPase (V-ATPase), a proton pump essential for organelle acidification, and is required for proper V1–V0 holoenzyme assembly and proton-pumping activity. Deletion of the yeast ortholog VMA7 abolishes V-ATPase activity, prevents V1 subunit association with the vacuolar membrane, and reduces V0 complex subunit levels, indicating that subunit F bridges the V1 and V0 sectors and stabilizes the assembled complex [PMID:7929308, PMID:7929071]. In zebrafish, loss-of-function mutations in atp6v1f cause oculocutaneous albinism with defective melanosome biogenesis, impaired retinal pigmented epithelium integrity, sustained retinoblast proliferation, photoreceptor degeneration, and accumulation of undigested outer segment material, demonstrating an essential in vivo role in RPE-mediated lysosomal degradation and eye development [PMID:18836173]. In hepatocellular carcinoma cells, ATP6V1F protein levels are positively regulated by the ER chaperone calnexin (CANX), linking V-ATPase expression to ER proteostasis and energy metabolism [PMID:39161338]."},"prefetch_data":{"uniprot":{"accession":"Q16864","full_name":"V-type proton ATPase subunit F","aliases":["V-ATPase 14 kDa subunit","Vacuolar proton pump subunit F"],"length_aa":119,"mass_kda":13.4,"function":"Subunit of the V1 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: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 (By similarity)","subcellular_location":"Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane; Cytoplasmic vesicle, clathrin-coated vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q16864/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP6V1F","classification":"Common Essential","n_dependent_lines":1193,"n_total_lines":1208,"dependency_fraction":0.9875827814569537},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000128524","cell_line_id":"CID001650","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"ATP6V0A2","stoichiometry":10.0},{"gene":"ATP6V1H","stoichiometry":10.0},{"gene":"C9ORF16","stoichiometry":10.0},{"gene":"ATP6V1G1","stoichiometry":10.0},{"gene":"ATP6V1A","stoichiometry":4.0},{"gene":"ATP6V1E1","stoichiometry":4.0},{"gene":"ATP6V1B2","stoichiometry":0.2},{"gene":"ATP6AP1","stoichiometry":0.2},{"gene":"VMA21","stoichiometry":0.2},{"gene":"DMXL1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001650","total_profiled":1310},"omim":[{"mim_id":"607160","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, 14-KD, V1 SUBUNIT F; ATP6V1F","url":"https://www.omim.org/entry/607160"}],"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/ATP6V1F"},"hgnc":{"alias_symbol":["ATP6S14","VATF","Vma7"],"prev_symbol":[]},"alphafold":{"accession":"Q16864","domains":[{"cath_id":"3.40.50.10580","chopping":"1-81","consensus_level":"medium","plddt":91.8225,"start":1,"end":81}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16864","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16864-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16864-F1-predicted_aligned_error_v6.png","plddt_mean":86.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP6V1F","jax_strain_url":"https://www.jax.org/strain/search?query=ATP6V1F"},"sequence":{"accession":"Q16864","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16864.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16864/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16864"}},"corpus_meta":[{"pmid":"14654946","id":"PMC_14654946","title":"Up-regulated 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research","url":"https://pubmed.ncbi.nlm.nih.gov/19199708","citation_count":237,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10440860","id":"PMC_10440860","title":"Animal plasma membrane energization by proton-motive V-ATPases.","date":"1999","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/10440860","citation_count":206,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29568061","id":"PMC_29568061","title":"An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29568061","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9210392","id":"PMC_9210392","title":"The vacuolar H+-ATPase: a universal proton pump of eukaryotes.","date":"1997","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/9210392","citation_count":199,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12448,"output_tokens":1683,"usd":0.031295},"stage2":{"model":"claude-opus-4-6","input_tokens":4919,"output_tokens":1391,"usd":0.089055},"total_usd":0.272859,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":23658,"output_tokens":1792,"usd":0.048927},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5271,"output_tokens":1708,"usd":0.103582}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"Vma7p (yeast ortholog of ATP6V1F) is a 14-kDa subunit of the vacuolar H+-ATPase V1 catalytic sector; deletion of VMA7 abolishes V-ATPase activity, prevents V1 subunit assembly onto vacuolar membranes, and greatly reduces V0 subunit levels, while Vma7p associates only with the fully assembled complex and not with a separate V0 subcomplex, suggesting it stabilizes V0 and bridges V1-V0 subcomplexes.\",\n      \"method\": \"Null mutant generation, vacuolar membrane isolation with ATPase activity assay, Western blot, density gradient fractionation, membrane stripping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro ATPase activity reconstitution and biochemical fractionation, replicated independently in two papers same year\",\n      \"pmids\": [\"7929308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Vma7p (yeast ortholog of ATP6V1F) is required for V-ATPase assembly; in its absence other V1 catalytic sector subunits fail to assemble onto the vacuolar membrane, vacuoles cannot acidify (quinacrine accumulation absent), and proton uptake is inhibited by antibody against epitope-tagged Vma7p. Cold-inactivation experiments confirmed it is a genuine subunit of the V1 catalytic sector, designated subunit F.\",\n      \"method\": \"Null mutant phenotypic analysis, quinacrine fluorescence assay, epitope-tagged protein + monoclonal antibody inhibition of proton uptake, cold inactivation experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro functional assay (antibody inhibition of proton uptake) plus mutagenesis, replicated\",\n      \"pmids\": [\"7929071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss-of-function of atp6v1f in zebrafish causes microphthalmic eyes, oculocutaneous albinism with melanosome formation/survival defects, impaired retinoblast cell-cycle exit and ciliary marginal zone proliferation, elevated retinal and brain apoptosis, abnormal photoreceptor outer segment morphology, and accumulation of undigested outer segment material in RPE vacuoles, establishing that the v-ATPase subunit F is required for acidification-dependent lysosomal digestion in the RPE and for normal retinal development.\",\n      \"method\": \"Zebrafish mutant characterization by histology, BrdU incorporation assay, TUNEL apoptosis assay, ultrastructural (electron microscopy) analysis, in situ hybridization\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function zebrafish mutant with multiple orthogonal phenotypic readouts including ultrastructural analysis\",\n      \"pmids\": [\"18836173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Vma7p (ortholog of ATP6V1F) in Candida albicans is required for vacuole acidification; vma7 null mutants show reduced vacuolar H+ gradient, defective intravacuolar degradation, sensitivity to metal ions (implicating V-ATPase-driven vacuolar ion sequestration), impaired alkaline-pH growth, defective hyphal induction, and complete avirulence in a mouse systemic candidiasis model.\",\n      \"method\": \"Null mutant generation, vacuole acidification assay, growth phenotyping, metal ion sensitivity assay, mouse virulence model\",\n      \"journal\": \"Microbiology (Reading, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular and in vivo phenotypes, single lab\",\n      \"pmids\": [\"15870472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Giant Panda ATP6V1F encodes a 119-amino acid protein with conserved predicted phosphorylation sites (protein kinase C, casein kinase II) and an N-myristoylation site; recombinant His-tagged ATP6V1F expressed in E. coli yields an ~17 kDa polypeptide consistent with its role as a v-ATPase subunit.\",\n      \"method\": \"cDNA cloning, RT-PCR, sequence/topology analysis, recombinant overexpression in E. coli\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — cloning and expression only, no functional assay\",\n      \"pmids\": [\"22212708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATP6V1F (V1 domain) and ATP6V0B (V0 domain) protein expression is reduced in hepatocellular carcinoma cells by dihydroartemisinin treatment acting through downregulation of CANX, linking CANX-mediated regulation of V-ATPase subunits to mitochondrial function and energy metabolism in HCC cells.\",\n      \"method\": \"Western blot of ATP6V1F and ATP6V0B protein levels after CANX siRNA knockdown and CANX overexpression; ATP/ROS/JC-1/NAD+/NADH assays; cell proliferation/apoptosis/migration assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method (Western blot) for ATP6V1F; mechanistic link to CANX is indirect\",\n      \"pmids\": [\"39161338\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V1F encodes the F subunit of the V1 catalytic sector of the vacuolar H+-ATPase; it is essential for assembly of V1 subunits onto the vacuolar membrane, stabilization of the V0 complex, and V-ATPase-driven proton translocation, with loss of function abolishing lysosomal/vacuolar acidification and causing defects in membrane trafficking, ion homeostasis, and organelle biogenesis across multiple eukaryotic models.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"VMA7 (the yeast ortholog of ATP6V1F) encodes a novel 14-kDa subunit of the V-ATPase V1 catalytic sector. Deletion of VMA7 abolishes V-ATPase activity, prevents V1 subunit association with the vacuolar membrane, and causes greatly reduced V0 complex subunit levels. Unlike integral V0 subunits, Vma7p is easily stripped from membranes and associates only with the fully assembled V-ATPase, not with a separate V0 subcomplex fraction, suggesting it stabilizes V0 and bridges V1 and V0 complexes.\",\n      \"method\": \"Genetic null mutant analysis, Western blotting, density gradient fractionation, membrane stripping assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical and genetic methods in a foundational study; replicated by independent lab in same year\",\n      \"pmids\": [\"7929308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"VMA7 (yeast ortholog of ATP6V1F) encodes subunit F of the V-ATPase catalytic sector. In its absence, other V1 catalytic subunits fail to assemble onto the vacuolar membrane and vacuoles cannot acidify. A monoclonal antibody against epitope-tagged Vma7p markedly inhibits proton uptake activity of isolated vacuoles. Cold inactivation experiments confirm Vma7p is a genuine subunit of the V1 catalytic sector.\",\n      \"method\": \"Null mutant generation, quinacrine accumulation assay, epitope-tagged protein inhibition with monoclonal antibody, cold inactivation experiment, proton uptake assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct functional inhibition assay with antibody plus genetic evidence; independent replication in same year (PMID 7929308)\",\n      \"pmids\": [\"7929071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The Candida albicans ortholog of ATP6V1F (Vma7p) is required for vacuole acidification; its deletion causes defective growth at alkaline pH, impaired degradation of intravacuolar endosomal structures, sensitivity to metal ions, and complete avirulence in a mouse model of systemic candidiasis. The Vma7p-interacting phosphatidylinositol 3-kinase Vps34p null mutant shows similar phenotypes, placing Vma7p in the same pathway.\",\n      \"method\": \"Null mutant generation in C. albicans, vacuole acidification assay, mouse virulence model, genetic epistasis with VPS34 deletion\",\n      \"journal\": \"Microbiology (Reading, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular and in vivo phenotypes plus epistasis; single lab\",\n      \"pmids\": [\"15870472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss-of-function mutations in atp6v1f in zebrafish cause microphthalmic, oculocutaneous albino phenotypes including defects in melanosome formation/survival, malformation of the retinal pigmented epithelium, impaired retinoblast cell cycle exit, sustained ciliary marginal zone proliferation, elevated retinal and brain apoptosis, photoreceptor outer segment rosette formation, and accumulation of membrane-bounded vacuoles containing undigested outer segment material in RPE cells. In situ hybridization localized atp6v1f transcripts to the RPE.\",\n      \"method\": \"Zebrafish forward genetics, histology, BrdU incorporation assay, TUNEL apoptosis assay, ultrastructural (TEM) analysis, in situ hybridization\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple orthogonal phenotypic readouts and direct localization in vivo; strong genetic evidence\",\n      \"pmids\": [\"18836173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The ATP6V1F gene was cloned from Giant Panda; the encoded protein contains one protein kinase C phosphorylation site, two casein kinase II phosphorylation sites, and one N-myristoylation site as predicted by topology analysis. Overexpression in E. coli produced an expected ~17 kDa His-tagged fusion protein, confirming the predicted molecular weight of the subunit F polypeptide.\",\n      \"method\": \"RT-PCR cloning, genomic PCR, sequence alignment, topology/motif prediction, recombinant overexpression in E. coli\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction of modification sites; recombinant expression without functional validation\",\n      \"pmids\": [\"22212708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In hepatocellular carcinoma cells, dihydroartemisinin (DHA) decreased expression of CANX (calnexin), and both ATP6V1F (V1 domain subunit F) and ATP6V0B (V0 domain subunit B) protein levels were reduced upon DHA treatment or CANX knockdown. CANX overexpression increased ATP6V1F and ATP6V0B levels and promoted mitochondrial function and energy metabolism, establishing CANX as an upstream regulator of V-ATPase subunit expression including ATP6V1F.\",\n      \"method\": \"siRNA knockdown and overexpression of CANX, Western blotting for ATP6V1F/ATP6V0B, ATP production assay, mitochondrial membrane potential (JC-1), ROS measurement, cell proliferation/apoptosis/migration assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss- and gain-of-function with multiple functional readouts; single lab, no independent replication\",\n      \"pmids\": [\"39161338\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V1F encodes subunit F of the V1 catalytic sector of the vacuolar H+-ATPase (V-ATPase); it is essential for assembly of V1 subunits onto the vacuolar membrane, stabilization of the V0 complex, and proton-pumping activity, and in vertebrates it is required in the RPE for melanosome biogenesis, retinoblast proliferation, and photoreceptor maintenance, with its expression regulated upstream by calnexin (CANX) in liver cancer cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATP6V1F encodes subunit F of the V1 catalytic sector of the vacuolar H+-ATPase (V-ATPase), a proton pump essential for acidification of lysosomes, vacuoles, and other endomembrane compartments. Deletion of the yeast ortholog VMA7 abolishes V-ATPase activity by preventing assembly of V1 subunits onto the vacuolar membrane and destabilizing the V0 integral membrane subcomplex, and antibody-mediated inhibition of the tagged subunit directly blocks proton translocation, establishing subunit F as an essential structural and functional component of the holoenzyme [PMID:7929308, PMID:7929071]. In zebrafish, loss of atp6v1f causes defective lysosomal acidification in the retinal pigment epithelium, leading to accumulation of undigested photoreceptor outer segments, oculocutaneous albinism, retinal apoptosis, and abnormal eye development [PMID:18836173]. In Candida albicans, vma7 null mutants lose vacuolar proton gradient-dependent ion sequestration and intravacuolar degradation, are sensitive to metal ions, fail to undergo hyphal morphogenesis at alkaline pH, and are completely avirulent in a systemic infection model [PMID:15870472].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"The identity and essentiality of subunit F were established: Vma7p was shown to be a bona fide V1-sector subunit whose deletion abolishes V-ATPase activity, prevents V1 assembly on vacuolar membranes, and destabilizes V0, answering how the holoenzyme is assembled and maintained.\",\n      \"evidence\": \"Yeast null mutant generation, vacuolar membrane fractionation, ATPase activity assays, antibody inhibition of proton uptake, cold-inactivation experiments across two independent studies\",\n      \"pmids\": [\"7929308\", \"7929071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding interfaces between subunit F and other V1/V0 subunits were not mapped\",\n        \"No structural model of how subunit F bridges V1 and V0 subcomplexes\",\n        \"Post-translational regulation of subunit F was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The requirement for subunit F was extended to a pathogenic fungus, showing that loss of vacuolar acidification through Vma7p deletion impairs ion homeostasis, alkaline-pH adaptation, morphogenetic switching, and virulence in Candida albicans.\",\n      \"evidence\": \"Candida albicans vma7 null mutant with vacuole acidification assays, metal sensitivity tests, and mouse systemic candidiasis model\",\n      \"pmids\": [\"15870472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication in other pathogenic fungi was not reported\",\n        \"Molecular mechanism linking vacuolar acidification to hyphal induction was not dissected\",\n        \"Contribution of subunit F versus other V-ATPase subunits to virulence was not compared\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"A vertebrate loss-of-function model revealed that ATP6V1F is required for lysosomal digestion in the retinal pigment epithelium and for normal retinal and pigment cell development, connecting V-ATPase function to organelle-level processes in a complex tissue.\",\n      \"evidence\": \"Zebrafish atp6v1f mutant characterized by histology, BrdU incorporation, TUNEL assay, electron microscopy, and in situ hybridization\",\n      \"pmids\": [\"18836173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether phenotypes are cell-autonomous to RPE versus secondary to systemic acidification defects was not resolved\",\n        \"No rescue experiment was performed to confirm gene specificity\",\n        \"Mammalian in vivo loss-of-function data are absent\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of subunit F's bridging role between V1 and V0, the regulation of ATP6V1F expression and post-translational modification in mammalian tissues, and whether ATP6V1F mutations cause human disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of subunit F within the mammalian V-ATPase holoenzyme\",\n        \"No mammalian knockout or conditional deletion phenotype reported\",\n        \"No human Mendelian disease association established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"complexes\": [\n      \"V-ATPase (V1 sector)\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ATP6V1F encodes subunit F of the V1 catalytic sector of the vacuolar H⁺-ATPase (V-ATPase), a proton pump essential for organelle acidification, and is required for proper V1–V0 holoenzyme assembly and proton-pumping activity. Deletion of the yeast ortholog VMA7 abolishes V-ATPase activity, prevents V1 subunit association with the vacuolar membrane, and reduces V0 complex subunit levels, indicating that subunit F bridges the V1 and V0 sectors and stabilizes the assembled complex [PMID:7929308, PMID:7929071]. In zebrafish, loss-of-function mutations in atp6v1f cause oculocutaneous albinism with defective melanosome biogenesis, impaired retinal pigmented epithelium integrity, sustained retinoblast proliferation, photoreceptor degeneration, and accumulation of undigested outer segment material, demonstrating an essential in vivo role in RPE-mediated lysosomal degradation and eye development [PMID:18836173]. In hepatocellular carcinoma cells, ATP6V1F protein levels are positively regulated by the ER chaperone calnexin (CANX), linking V-ATPase expression to ER proteostasis and energy metabolism [PMID:39161338].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"The identity of V-ATPase subunit F as a novel V1-sector component required for holoenzyme assembly was established, resolving how the catalytic sector attaches to the membrane-integral V0 domain.\",\n      \"evidence\": \"Yeast VMA7 deletion mutants analyzed by Western blotting, density gradient fractionation, membrane stripping, quinacrine acidification assays, and antibody-mediated inhibition of proton uptake\",\n      \"pmids\": [\"7929308\", \"7929071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of subunit F contacts with other V1 and V0 subunits not resolved\",\n        \"Post-translational regulation of subunit F not addressed\",\n        \"Whether subunit F has roles beyond structural scaffolding (e.g., regulatory) was unknown\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extension of subunit F function to a pathogenic organism showed that Vma7p is required for vacuole acidification, alkaline-pH tolerance, and full virulence, reinforcing its non-redundant role in V-ATPase-dependent processes.\",\n      \"evidence\": \"Candida albicans VMA7 null mutant phenotyping including vacuole acidification, metal sensitivity, and mouse systemic candidiasis model with VPS34 epistasis\",\n      \"pmids\": [\"15870472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether loss of virulence is solely via defective acidification or involves additional Vma7p-dependent pathways is unclear\",\n        \"Interaction between Vma7p and Vps34p was not demonstrated to be direct\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"A vertebrate in vivo requirement for ATP6V1F was defined: loss of function in zebrafish revealed that subunit F is essential for RPE melanosome biogenesis, retinoblast cell cycle regulation, and photoreceptor outer segment turnover, connecting V-ATPase-mediated acidification to eye development.\",\n      \"evidence\": \"Zebrafish forward genetic screen with histology, BrdU, TUNEL, TEM ultrastructure, and in situ hybridization\",\n      \"pmids\": [\"18836173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the proliferation defect is cell-autonomous to RPE or secondary to impaired signaling was not resolved\",\n        \"Mammalian confirmation of these phenotypes is lacking\",\n        \"Molecular partners of ATP6V1F in the RPE context were not identified\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"An upstream transcriptional/post-transcriptional regulator of ATP6V1F was identified: calnexin (CANX) positively controls ATP6V1F protein levels in hepatocellular carcinoma cells, linking ER proteostasis to V-ATPase abundance and mitochondrial energy metabolism.\",\n      \"evidence\": \"siRNA knockdown and overexpression of CANX with Western blot for ATP6V1F/ATP6V0B, ATP, JC-1, and ROS assays in HCC cell lines\",\n      \"pmids\": [\"39161338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of CANX-mediated regulation of ATP6V1F (transcriptional vs. protein stability) not distinguished\",\n        \"Single-lab finding without independent replication\",\n        \"Whether this regulatory axis operates outside hepatocellular carcinoma is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structural model of subunit F within the mammalian V-ATPase holoenzyme, the regulatory signals (e.g., phosphorylation) controlling reversible V1–V0 dissociation at subunit F, and the physiological relevance of ATP6V1F in mammalian disease remain to be determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No mammalian loss-of-function model for ATP6V1F has been reported\",\n        \"Predicted phosphorylation sites on subunit F have not been functionally validated\",\n        \"Whether subunit F participates in regulated V-ATPase disassembly in response to nutrient signals is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"V-ATPase (V1 sector)\"\n    ],\n    \"partners\": [\n      \"CANX\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}