{"gene":"ATP6V1C1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1993,"finding":"VMA5 (yeast ortholog of ATP6V1C1) encodes the 42-kDa peripheral subunit of the vacuolar H+-ATPase V1 sector, and is essential for assembly of the V1 domain onto the vacuolar membrane; deletion of VMA5 abolishes vacuolar ATPase enzyme activity and prevents V1 subunit assembly.","method":"Genetic deletion (vma5 mutant), vacuolar ATPase enzyme activity assay, membrane fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined biochemical phenotype (loss of activity and assembly), replicated across multiple vma mutant characterizations in foundational yeast study","pmids":["8416931"],"is_preprint":false},{"year":2001,"finding":"Subunit C of V-ATPase from the ascidian Ascidia sydneiensis samea (ortholog of ATP6V1C1) functionally complements yeast vma5 mutants, rescuing pH sensitivity, demonstrating that subunit C is responsible for V-ATPase assembly and activity regulation across metazoan species.","method":"Heterologous complementation of yeast vma5 mutant with ascidian cDNA under galactose-inducible promoter; pH sensitivity growth assay","journal":"Marine biotechnology (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 — genetic rescue experiment with clear phenotypic readout, single lab","pmids":["14961347"],"is_preprint":false},{"year":2009,"finding":"Atp6v1c1 (C1) is the predominant C-subunit isoform expressed in osteoclasts (C2a and C2b are absent), is induced by RANKL during osteoclast differentiation, localizes to the ruffled border of activated osteoclasts, physically interacts with the a3 subunit (Atp6v0a3), is essential for osteoclast acidification activity and bone resorption, and is required for F-actin ring formation (unlike a3). C1 co-localizes with microtubules at the plasma membrane and with F-actin in mature osteoclasts.","method":"Lentivirus-mediated RNAi knockdown, immunoprecipitation (C1–a3 interaction), confocal immunofluorescence (co-localization with ruffled border, microtubules, F-actin), bone resorption pit assay, acidification assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP for binding partner, clean KD with multiple orthogonal functional readouts (acidification, resorption, actin ring), replicated across osteoclast contexts","pmids":["18657050"],"is_preprint":false},{"year":2013,"finding":"Silencing of Atp6v1c1 in breast cancer cells inhibits lysosomal acidification and impairs cell growth, migration, and invasion in vitro, and reduces tumor growth, metastasis, and osteolytic bone lesions in vivo, establishing that Atp6v1c1 promotes breast cancer growth and bone metastasis through regulation of lysosomal V-ATPase activity.","method":"Lentivirus-mediated shRNA knockdown, lysosomal acidification assay, Matrigel invasion assay, 4T1 xenograft mouse model, in vivo bone metastasis imaging","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 — clean KD with multiple orthogonal phenotypic readouts in vitro and in vivo","pmids":["24155661"],"is_preprint":false},{"year":2014,"finding":"Atp6v1c1 co-localizes with filamentous actin (F-actin) in breast cancer cells, and its depletion disrupts normal F-actin arrangement in 4T1, MDA-MB-231, and MDA-MB-435s cells, implicating Atp6v1c1 in actin cytoskeletal organization that facilitates cancer cell metastasis.","method":"shRNA knockdown, confocal immunofluorescence co-localization of Atp6v1c1 with F-actin (phalloidin staining), multiple human and mouse cancer cell lines","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — localization with functional link to metastasis, replicated in three cell lines but no direct mechanistic pathway identified","pmids":["24454753"],"is_preprint":false},{"year":2015,"finding":"AAV-mediated shRNA knockdown of Atp6v1c1 in periodontal lesions protects against bone erosion (>85%) and gingival inflammation caused by P. gingivalis infection, reduces osteoclast numbers, inhibits infiltration of dendritic cells and macrophages, and suppresses expression of osteoclast-related genes and pro-inflammatory cytokine genes, revealing a dual role in osteoimmunology.","method":"AAV-shRNA gene knockdown in mouse periodontitis model, histomorphometry, immunohistochemistry for immune cell infiltration, qRT-PCR for cytokine/osteoclast gene expression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KD with multiple phenotypic readouts, single lab","pmids":["26274612"],"is_preprint":false},{"year":2017,"finding":"Lentiviral shRNA-mediated knockdown of Atp6v1c1 reduces V-ATPase activity, impairs mTORC1 pathway activation, reduces proliferation in human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-435s) but not in untransformed C3H10T1/2 cells, and reduces orthotopic/intraosseous tumor growth and bone metastasis in vivo, establishing that Atp6v1c1 enhances breast cancer growth partly through mTORC1 signaling downstream of V-ATPase activity.","method":"Lentiviral shRNA knockdown, V-ATPase activity assay, mTORC1 phosphorylation (Western blot), cell proliferation assay, orthotopic and intraosseous mouse tumor models, TCGA genomic analysis","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods linking V-ATPase activity to mTORC1, confirmed in multiple cell lines and in vivo","pmids":["28504970"],"is_preprint":false},{"year":2017,"finding":"Deletion of VMA5 (ATP6V1C1 ortholog) in Candida albicans leads to vacuolar dysfunction, disturbance of calcium homeostasis, inhibition of calcium-related oxidative stress response, defects in autophagy completion, impaired hyphal development, and attenuated virulence.","method":"PCR-mediated homologous recombination gene deletion, vacuolar acidification assay, calcium homeostasis measurement, autophagy flux assay, hyphal morphology, murine infection model","journal":"Future microbiology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with multiple orthogonal phenotypic readouts in fungal ortholog, single lab","pmids":["28879785"],"is_preprint":false},{"year":2020,"finding":"ATP6V1C1 inhibits autophagy and reduces radiosensitivity in esophageal squamous cell carcinoma (ESCC) cells; silencing ATP6V1C1 combined with ionizing radiation promotes autophagy, suppresses tumor growth, and increases apoptosis. The mechanism involves ATP6V1C1 activating mTOR signaling to suppress autophagy and thereby reduce radiosensitivity.","method":"siRNA knockdown and plasmid overexpression, colony formation assay, EdU proliferation assay, flow cytometry (apoptosis), γH2AX assay (DNA damage), immunofluorescence (autophagosomes/autolysosomes), transmission electron microscopy (autophagic ultrastructure), Western blot (mTOR pathway), nude mouse xenograft","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods linking ATP6V1C1 to mTOR-autophagy axis, replicated in vivo, single lab","pmids":["33183740"],"is_preprint":false},{"year":2024,"finding":"Dominantly acting gain-of-function variants in ATP6V1C1 (and ATP6V1B2) upregulate V-ATPase function, causing increased lysosomal acidification, disruption of lysosomal morphology and localization, defective autophagic flux with accumulation of lysosomal substrates, and impaired cilium biogenesis, resulting in a neurodevelopmental phenotype resembling DOORS syndrome.","method":"Patient-derived variant analysis, lysosomal pH assay, lysosomal morphology imaging (confocal), autophagic flux assay (LC3/p62 Western blot, immunofluorescence), ciliogenesis assay, functional comparison with ATP6V1B2 variants","journal":"HGG advances","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays establishing gain-of-function mechanism across lysosomal acidification, autophagy, and ciliogenesis","pmids":["39210597"],"is_preprint":false},{"year":2024,"finding":"V-ATPase subunit C (Vma5, yeast ortholog of ATP6V1C1) is released from the lysosome-like vacuole into the cytosol during yeast replicative aging (after >5 cell divisions), reflecting V-ATPase disassembly into V1 and V0 subcomplexes, which causes vacuole alkalinization. Caloric restriction prevents this disassembly. The RAVE complex promotes V-ATPase reassembly (Rav2 levels decline with age), and Oxr1 promotes disassembly; rav1Δ shortens replicative lifespan while oxr1Δ extends it.","method":"Yeast replicative aging model, fluorescence microscopy of Vma5 (subunit C) localization, vacuolar pH measurement, caloric restriction experiments, genetic epistasis (rav1Δ, oxr1Δ), Rav2 overexpression, lifespan assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic epistasis and localization experiments with functional consequence in yeast ortholog, preprint","pmids":["bio_10.1101_2024.07.23.604825"],"is_preprint":true},{"year":2025,"finding":"ATP6V1C1 is the direct binding target of the natural compound veratramine (VAM); VAM directly binds ATP6V1C1, inhibits V-ATPase catalytic activity and lysosomal acidification, and disrupts the autophagic-lysosomal pathway essential for cancer cell survival.","method":"Thermal proteome profiling (TPP), thermal proximity co-aggregation (TPCA) to identify V-ATPase complex dissociation, direct binding assay, V-ATPase catalytic activity assay, lysosomal acidification assay, autophagic flux assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 1-2 — TPP/TPCA target identification plus direct binding and enzymatic activity assays, single lab","pmids":["40384877"],"is_preprint":false},{"year":2026,"finding":"CAF-derived extracellular vesicles deliver ATP6V1C1 protein to lung adenocarcinoma cells, where it suppresses IGFBP3 expression by downregulating the transcriptional regulator ID1, inducing epithelial-mesenchymal transition and amplifying IGF1/IGF1R/Akt/ERK signaling, creating a feedforward metastatic loop.","method":"Quantitative proteomic profiling of CAF-derived EVs, EV uptake assays, siRNA/overexpression of ATP6V1C1, Western blot and qRT-PCR for ID1/IGFBP3/EMT markers, IGF1R/Akt/ERK signaling assays, in vivo metastasis mouse model","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal mechanistic assays linking EV-delivered ATP6V1C1 to ID1-IGFBP3 axis and downstream signaling, single lab","pmids":["41548219"],"is_preprint":false},{"year":2026,"finding":"Conditional knockout of Atp6v1c1 in mouse hair cells causes early-onset sensorineural hearing loss and vestibular malfunction, with synaptic defects in inner hair cells (loss of ribbon synapses, accumulation of endocytic compartments, absence of F-actin mesh at active zones), disrupted autophagic flux, and apoptosis. A gain-of-function p.R281P knock-in variant causes late-onset high-frequency hearing loss through disrupted autophagic flux and spiral ganglion neuron degeneration.","method":"Conditional knockout mouse (hair cell-specific), auditory brainstem response (ABR), confocal and electron microscopy (ribbon synapses, endocytic compartments, F-actin), autophagic flux assay, apoptosis assay, knock-in mouse model (p.R281P), linkage analysis and exome sequencing in human family","journal":"Journal of genetics and genomics","confidence":"High","confidence_rationale":"Tier 2 — conditional KO and knock-in mouse models with multiple orthogonal functional readouts establishing synaptic, autophagic, and structural roles","pmids":["41539473"],"is_preprint":false}],"current_model":"ATP6V1C1 encodes the C1 subunit of the V1 peripheral sector of the vacuolar H+-ATPase (V-ATPase), where it is essential for V1 assembly onto membranes and for proton pump activity; in osteoclasts it localizes to the ruffled border, interacts with the a3 subunit, drives extracellular acidification and bone resorption, and regulates F-actin ring formation via co-localization with actin and microtubules; in cancer cells it promotes growth and metastasis by sustaining lysosomal V-ATPase activity that activates mTORC1 signaling and supports autophagic flux; gain-of-function variants increase lysosomal acidification and disrupt autophagy causing DOORS-like neurodevelopmental disease, while loss-of-function causes sensorineural hearing loss through synaptic and autophagic defects in hair cells; and the protein undergoes regulated reversible disassembly from the vacuolar membrane, a process controlled by the RAVE complex and Oxr1 that modulates organelle acidification and replicative lifespan."},"narrative":{"teleology":[{"year":1993,"claim":"Establishing that the C subunit (VMA5) is structurally required for V1 sector assembly and vacuolar ATPase activity resolved the foundational question of whether this subunit is catalytic or architectural.","evidence":"VMA5 deletion in yeast abolished V-ATPase activity and prevented V1 membrane assembly (enzyme activity assay, membrane fractionation)","pmids":["8416931"],"confidence":"High","gaps":["No structural information on how subunit C bridges V1 subunits","Mammalian isoform-specific functions not addressed"]},{"year":2001,"claim":"Cross-species complementation of yeast vma5 mutants with an ascidian C subunit demonstrated that the assembly/activity role of subunit C is conserved across metazoans, extending the yeast paradigm to animal biology.","evidence":"Heterologous expression of ascidian subunit C rescued yeast vma5 pH-sensitivity phenotype","pmids":["14961347"],"confidence":"Medium","gaps":["Mammalian C1 vs C2 isoform specificity not tested","Mechanism of functional conservation at the structural level unknown"]},{"year":2009,"claim":"Identifying ATP6V1C1 as the sole C-subunit isoform in osteoclasts and demonstrating its interaction with a3, ruffled border localization, and independent role in F-actin ring formation established a tissue-specific function beyond generic acidification.","evidence":"RNAi knockdown in osteoclasts, co-IP of C1–a3 interaction, confocal co-localization with F-actin and microtubules, bone resorption pit and acidification assays","pmids":["18657050"],"confidence":"High","gaps":["Structural basis of C1–a3 interaction not resolved","How C1 organizes F-actin independently of a3 remains mechanistically undefined"]},{"year":2013,"claim":"Demonstration that ATP6V1C1 knockdown impairs lysosomal acidification, cancer cell invasion, and in vivo tumor growth/metastasis revealed the subunit as a non-redundant driver of malignant phenotypes through V-ATPase-dependent mechanisms.","evidence":"shRNA knockdown in breast cancer cells, lysosomal pH assay, Matrigel invasion, 4T1 xenograft and bone metastasis models","pmids":["24155661"],"confidence":"High","gaps":["Downstream signaling pathway not identified at this stage","Whether the effect is specific to C1 versus other V-ATPase subunits unclear"]},{"year":2017,"claim":"Linking ATP6V1C1-dependent V-ATPase activity to mTORC1 signaling in cancer cells answered the mechanistic question of how lysosomal acidification translates into a proliferative advantage, and showed selectivity for transformed over untransformed cells.","evidence":"shRNA knockdown in multiple breast cancer lines, V-ATPase activity assay, mTORC1 phosphorylation Western blot, orthotopic and intraosseous mouse tumor models","pmids":["28504970"],"confidence":"High","gaps":["Whether mTORC1 activation is direct (via amino acid sensing on lysosome) or indirect not distinguished","Cancer-type generalizability beyond breast cancer not tested"]},{"year":2020,"claim":"Establishing that ATP6V1C1 activates mTOR to suppress autophagy and reduce radiosensitivity in esophageal cancer extended the mTORC1-autophagy axis to a second cancer type and revealed therapeutic vulnerability upon silencing.","evidence":"siRNA/overexpression, colony formation, autophagosome/autolysosome imaging, mTOR pathway Western blot, nude mouse xenograft with radiation","pmids":["33183740"],"confidence":"Medium","gaps":["Whether autophagic effect is fully mTOR-dependent or involves parallel pathways not resolved","Direct radiosensitization mechanism versus autophagic cell death not distinguished"]},{"year":2024,"claim":"Discovery that gain-of-function ATP6V1C1 variants cause hyperacidification, disrupted autophagy, impaired ciliogenesis, and a DOORS-like neurodevelopmental phenotype established the first human Mendelian disease link and showed that excess V-ATPase activity is as pathogenic as deficiency.","evidence":"Patient variant analysis, lysosomal pH assay, autophagic flux (LC3/p62), ciliogenesis assay, comparison with ATP6V1B2 variants","pmids":["39210597"],"confidence":"High","gaps":["Number of families limited; full phenotypic spectrum not defined","Structural basis of gain-of-function not determined","Contribution of ciliogenesis defect versus autophagy defect to neurological phenotype unclear"]},{"year":2024,"claim":"Showing that V-ATPase subunit C is released from vacuolar membranes during yeast replicative aging—regulated by the RAVE complex (assembly) and Oxr1 (disassembly)—linked reversible V-ATPase disassembly to aging and lifespan control.","evidence":"Yeast replicative aging model, fluorescence microscopy of Vma5 localization, vacuolar pH, genetic epistasis (rav1Δ, oxr1Δ), lifespan assays (preprint)","pmids":["bio_10.1101_2024.07.23.604825"],"confidence":"Medium","gaps":["Preprint; not yet peer-reviewed","Whether RAVE-Oxr1 regulation is conserved in mammalian cells unknown","Signal triggering age-dependent disassembly not identified"]},{"year":2025,"claim":"Identification of ATP6V1C1 as the direct binding target of veratramine demonstrated that the C1 subunit is a druggable node whose pharmacological inhibition disrupts V-ATPase catalysis and the autophagic-lysosomal pathway.","evidence":"Thermal proteome profiling, thermal proximity co-aggregation, direct binding assay, V-ATPase activity and lysosomal acidification assays","pmids":["40384877"],"confidence":"Medium","gaps":["Binding site on C1 not structurally defined","Selectivity over other V-ATPase subunits or off-target effects not fully characterized"]},{"year":2026,"claim":"Two discoveries in 2026 expanded the functional repertoire: (1) CAF-derived extracellular vesicles deliver ATP6V1C1 protein to lung adenocarcinoma cells where it suppresses ID1-IGFBP3 to amplify IGF1R/Akt/ERK-driven EMT, and (2) conditional hair cell knockout and a gain-of-function knock-in established that ATP6V1C1 controls ribbon synapse integrity, autophagic flux, and auditory/vestibular function.","evidence":"EV proteomic profiling, siRNA/overexpression with EMT/signaling readouts, in vivo metastasis model (lung cancer); conditional KO and R281P knock-in mice, ABR, electron microscopy of ribbon synapses, autophagic flux assays (hair cells)","pmids":["41548219","41539473"],"confidence":"High","gaps":["Non-canonical transcriptional role (ID1/IGFBP3 suppression) mechanism unclear—whether V-ATPase-dependent or independent not distinguished","Whether EV-delivered C1 assembles into recipient-cell V-ATPase complexes unknown","Relative contributions of synaptic vs autophagic defects to hearing loss not resolved"]},{"year":null,"claim":"The structural basis of ATP6V1C1's bridging role in V1-V0 assembly, the mechanism by which it organizes F-actin independently of other V-ATPase subunits, and whether the non-canonical transcriptional effects observed in cancer are V-ATPase-dependent remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of mammalian V-ATPase C1 in complex context","Mechanism linking C1 to F-actin organization unknown","Whether ID1/IGFBP3 regulation requires V-ATPase catalytic activity or is a moonlighting function is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,6,11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[3,6,9,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]},{"term_id":"GO:0005773","term_label":"vacuole","supporting_discovery_ids":[0,7,10]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,2,3,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,8,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,8,9,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,6,8,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,9,10]}],"complexes":["V-ATPase (V1 sector)","V-ATPase holoenzyme (V1-V0)"],"partners":["ATP6V0A3","ATP6V1B2","IGFBP3","ID1","MTOR"],"other_free_text":[]},"mechanistic_narrative":"ATP6V1C1 encodes the C1 subunit of the V1 peripheral sector of the vacuolar H⁺-ATPase (V-ATPase) and is essential for V1 domain assembly onto membranes and for proton pump catalytic activity, functioning as a critical determinant of organellar and extracellular acidification across eukaryotes [PMID:8416931, PMID:14961347]. In osteoclasts, ATP6V1C1 localizes to the ruffled border, physically interacts with the a3 (ATP6V0A3) subunit, drives extracellular acid secretion required for bone resorption, and independently organizes the F-actin ring through co-localization with actin and microtubules [PMID:18657050]; in cancer cells, it sustains lysosomal V-ATPase activity that activates mTORC1 signaling, suppresses autophagy, and promotes tumor growth and metastasis [PMID:24155661, PMID:28504970, PMID:33183740]. Gain-of-function ATP6V1C1 variants increase lysosomal acidification, disrupt autophagic flux and ciliogenesis causing a DOORS-like neurodevelopmental syndrome, while conditional loss in hair cells produces sensorineural hearing loss through synaptic ribbon loss, autophagic failure, and apoptosis [PMID:39210597, PMID:41539473]."},"prefetch_data":{"uniprot":{"accession":"P21283","full_name":"V-type proton ATPase subunit C 1","aliases":["Vacuolar proton pump subunit C 1"],"length_aa":382,"mass_kda":43.9,"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). Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is likely to have a specific function in its catalytic activity (By similarity)","subcellular_location":"Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane; Cytoplasmic vesicle, clathrin-coated vesicle membrane","url":"https://www.uniprot.org/uniprotkb/P21283/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP6V1C1","classification":"Common Essential","n_dependent_lines":1115,"n_total_lines":1208,"dependency_fraction":0.9230132450331126},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATP6AP2","stoichiometry":4.0},{"gene":"ATP6V1A","stoichiometry":4.0},{"gene":"ATP6V1B2","stoichiometry":4.0},{"gene":"ATP6V1G1","stoichiometry":4.0},{"gene":"ATP6V0A1","stoichiometry":0.2},{"gene":"ATP6V0D1","stoichiometry":0.2},{"gene":"ATP6V1E1","stoichiometry":0.2},{"gene":"ATP6V1F","stoichiometry":0.2},{"gene":"ATP6V1H","stoichiometry":0.2},{"gene":"PAK2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATP6V1C1","total_profiled":1310},"omim":[{"mim_id":"618286","title":"MACROCEPHALY, ACQUIRED, WITH IMPAIRED INTELLECTUAL DEVELOPMENT; MACID","url":"https://www.omim.org/entry/618286"},{"mim_id":"603097","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, 42-KD, V1 SUBUNIT C, ISOFORM 1; ATP6V1C1","url":"https://www.omim.org/entry/603097"},{"mim_id":"185881","title":"VESICLE-ASSOCIATED MEMBRANE PROTEIN 2; VAMP2","url":"https://www.omim.org/entry/185881"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATP6V1C1"},"hgnc":{"alias_symbol":["VATC","Vma5"],"prev_symbol":["ATP6D","ATP6C"]},"alphafold":{"accession":"P21283","domains":[{"cath_id":"1.20.1460.10","chopping":"2-134_288-374","consensus_level":"high","plddt":89.7737,"start":2,"end":374},{"cath_id":"3.30.70.100","chopping":"171-252","consensus_level":"high","plddt":96.4459,"start":171,"end":252}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P21283","model_url":"https://alphafold.ebi.ac.uk/files/AF-P21283-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P21283-F1-predicted_aligned_error_v6.png","plddt_mean":91.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP6V1C1","jax_strain_url":"https://www.jax.org/strain/search?query=ATP6V1C1"},"sequence":{"accession":"P21283","fasta_url":"https://rest.uniprot.org/uniprotkb/P21283.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P21283/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P21283"}},"corpus_meta":[{"pmid":"8416931","id":"PMC_8416931","title":"Isolation of vacuolar membrane H(+)-ATPase-deficient yeast mutants; the VMA5 and VMA4 genes are essential for assembly and activity of the vacuolar H(+)-ATPase.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8416931","citation_count":112,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18657050","id":"PMC_18657050","title":"Atp6v1c1 is an essential component of the osteoclast proton pump and in F-actin ring formation in osteoclasts.","date":"2009","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18657050","citation_count":74,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9661023","id":"PMC_9661023","title":"Characterization of a staphylococcal plasmid related to pUB110 and carrying two novel genes, vatC and vgbB, encoding resistance to streptogramins A and B and similar antibiotics.","date":"1998","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/9661023","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35272047","id":"PMC_35272047","title":"The chimeric gene atp6c confers cytoplasmic male sterility in maize by impairing the assembly of the mitochondrial ATP synthase complex.","date":"2022","source":"Molecular plant","url":"https://pubmed.ncbi.nlm.nih.gov/35272047","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24155661","id":"PMC_24155661","title":"Silencing of atp6v1c1 prevents breast cancer growth and bone metastasis.","date":"2013","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24155661","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17467328","id":"PMC_17467328","title":"Intracellular pH regulation in oral squamous cell carcinoma is mediated by increased V-ATPase activity via over-expression of the ATP6V1C1 gene.","date":"2007","source":"Oral oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17467328","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28504970","id":"PMC_28504970","title":"Osteoclast proton pump regulator Atp6v1c1 enhances breast cancer growth by activating the mTORC1 pathway and bone metastasis by increasing V-ATPase activity.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28504970","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24454753","id":"PMC_24454753","title":"Atp6v1c1 may regulate filament actin arrangement in breast cancer cells.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24454753","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33183740","id":"PMC_33183740","title":"The ATPase subunit of ATP6V1C1 inhibits autophagy and enhances radiotherapy resistance in esophageal squamous cell carcinoma.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/33183740","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14961347","id":"PMC_14961347","title":"Subunit C of the vacuolar-type ATPase from the vanadium-rich ascidian Ascidia sydneiensis samea rescued the pH sensitivity of yeast vma5 mutants.","date":"2001","source":"Marine biotechnology (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/14961347","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39210597","id":"PMC_39210597","title":"Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.","date":"2024","source":"HGG advances","url":"https://pubmed.ncbi.nlm.nih.gov/39210597","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26274612","id":"PMC_26274612","title":"Targeting Atp6v1c1 Prevents Inflammation and Bone Erosion Caused by Periodontitis and Reveals Its Critical Function in Osteoimmunology.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26274612","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38073308","id":"PMC_38073308","title":"A P-type pentatricopeptide repeat protein ZmRF5 promotes 5' region partial cleavages of atp6c transcripts to restore the fertility of CMS-C maize by recruiting a splicing factor.","date":"2023","source":"Plant biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/38073308","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28879785","id":"PMC_28879785","title":"Contribution of VMA5 to vacuolar function, stress response, ion homeostasis and autophagy in Candida albicans.","date":"2017","source":"Future microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28879785","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26984774","id":"PMC_26984774","title":"Expression of ATP6V1C1 during oral carcinogenesis.","date":"2016","source":"Biotechnic & histochemistry : official publication of the Biological Stain Commission","url":"https://pubmed.ncbi.nlm.nih.gov/26984774","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41548219","id":"PMC_41548219","title":"Cancer-associated fibroblast-derived extracellular vesicles deliver ATP6V1C1 to promote lung adenocarcinoma metastasis via the ID1-IGFBP3 axis.","date":"2026","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/41548219","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40384877","id":"PMC_40384877","title":"Integrated thermal proteome and thermal proximity co-aggregation profiling identifies ATP6V1C1 as a novel anti-cancer drug target.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40384877","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41539473","id":"PMC_41539473","title":"ATP6V1C1 deficiency impairs auditory and vestibular hair cell function and leads to sensorineural hearing loss in humans and mice.","date":"2026","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/41539473","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.07.23.604825","title":"V-ATPase Disassembly at the Yeast Lysosome-Like Vacuole Is a Phenotypic Driver of Lysosome Dysfunction in Replicative Aging","date":"2024-07-25","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.23.604825","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11836511","id":"PMC_11836511","title":"The vacuolar (H+)-ATPases--nature's most versatile proton pumps.","date":"2002","source":"Nature reviews. Molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11836511","citation_count":961,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"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":"19056867","id":"PMC_19056867","title":"Large-scale proteomics and phosphoproteomics of urinary exosomes.","date":"2008","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19056867","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9442887","id":"PMC_9442887","title":"Structure, function and regulation of the vacuolar (H+)-ATPase.","date":"1997","source":"Annual review of cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/9442887","citation_count":488,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16415858","id":"PMC_16415858","title":"V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway.","date":"2006","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16415858","citation_count":396,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10221984","id":"PMC_10221984","title":"Vacuolar and plasma membrane proton-adenosinetriphosphatases.","date":"1999","source":"Physiological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/10221984","citation_count":348,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17662945","id":"PMC_17662945","title":"Coupling of rotation and catalysis in F(1)-ATPase revealed by single-molecule imaging and manipulation.","date":"2007","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17662945","citation_count":307,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11752456","id":"PMC_11752456","title":"Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11752456","citation_count":300,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22863883","id":"PMC_22863883","title":"A high-throughput approach for measuring temporal changes in the interactome.","date":"2012","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/22863883","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10224039","id":"PMC_10224039","title":"Structure and properties of the vacuolar (H+)-ATPases.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10224039","citation_count":252,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17207965","id":"PMC_17207965","title":"hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes.","date":"2007","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17207965","citation_count":222,"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":"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"},{"pmid":"2874839","id":"PMC_2874839","title":"Receptor-mediated endocytosis: the intracellular journey of transferrin and its receptor.","date":"1986","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/2874839","citation_count":169,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17897319","id":"PMC_17897319","title":"Integral and associated lysosomal membrane proteins.","date":"2007","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/17897319","citation_count":163,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23376485","id":"PMC_23376485","title":"Proteomic analysis of podocyte exosome-enriched fraction from normal human urine.","date":"2013","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23376485","citation_count":126,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20379614","id":"PMC_20379614","title":"Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.","date":"2010","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/20379614","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33637726","id":"PMC_33637726","title":"Combinatorial CRISPR screen identifies fitness effects of gene paralogues.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33637726","citation_count":106,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10954,"output_tokens":3495,"usd":0.042644},"stage2":{"model":"claude-opus-4-6","input_tokens":6879,"output_tokens":2847,"usd":0.158355},"total_usd":0.451156,"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":22576,"output_tokens":4976,"usd":0.071184},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7808,"output_tokens":3211,"usd":0.178973}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"VMA5 (yeast ortholog of ATP6V1C1) encodes the 42-kDa peripheral subunit of the vacuolar H+-ATPase and is essential for assembly of the V1 sector onto the vacuolar membrane; deletion prevents proper assembly of remaining V1 subunits and abolishes ATPase enzyme activity.\",\n      \"method\": \"Genetic deletion (vma5 mutant), vacuolar ATPase activity assay, complementation grouping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic loss-of-function with defined enzymatic and assembly phenotype, foundational paper with 112 citations replicated across yeast studies\",\n      \"pmids\": [\"8416931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Subunit C of V-ATPase from ascidian (ortholog of ATP6V1C1) functionally rescues the pH-sensitive phenotype of yeast vma5 mutants when expressed under a galactose-inducible promoter, demonstrating conserved assembly/regulatory function of this subunit across species.\",\n      \"method\": \"Heterologous expression of ascidian subunit C cDNA in yeast vma5 mutant, growth rescue assay\",\n      \"journal\": \"Marine biotechnology (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional complementation across species, single study\",\n      \"pmids\": [\"14961347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Atp6v1c1 (C1 subunit) is essential for osteoclast V-ATPase proton pump activity at the ruffled border: it physically interacts with subunit Atp6v0a3 (a3), localizes predominantly to the ruffled border, and its lentiviral shRNA-mediated silencing severely impairs osteoclast acidification and bone resorption without affecting differentiation.\",\n      \"method\": \"Co-immunoprecipitation (C1 with a3), lentivirus-mediated RNAi knockdown, osteoclast acidification assay, bone resorption assay, immunofluorescence localization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional KD with defined cellular phenotype, moderate evidence from multiple orthogonal methods\",\n      \"pmids\": [\"18657050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Atp6v1c1 is required for F-actin ring formation in osteoclasts: C1 co-localizes with F-actin and microtubules in the plasma membrane vicinity of mature osteoclasts, and its depletion causes severe defects in actin ring formation (unlike a3 depletion), indicating a role in cytoskeletal organization distinct from proton pumping.\",\n      \"method\": \"Lentivirus-mediated RNAi knockdown, immunofluorescence co-localization with F-actin and microtubules, comparison with a3 knockdown/knockout\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KD with defined actin phenotype, epistatic comparison with a3 KO, multiple imaging methods\",\n      \"pmids\": [\"18657050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Atp6v1c1 promotes breast cancer cell growth, migration, and invasion by regulating lysosomal V-ATPase activity; lentiviral shRNA knockdown of Atp6v1c1 inhibits lysosomal acidification and impairs cell proliferation, migration through Matrigel, and xenograft tumor growth and metastasis in vivo.\",\n      \"method\": \"Lentivirus-mediated shRNA knockdown, lysosomal acidification assay, Matrigel invasion assay, xenograft tumor model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined cellular and in vivo phenotypes, single lab\",\n      \"pmids\": [\"24155661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Atp6v1c1 co-localizes with filamentous actin (F-actin) in breast cancer cells, and its depletion disrupts normal F-actin arrangement in mouse 4T1 and human MDA-MB-231 and MDA-MB-435s breast cancer cell lines, implicating Atp6v1c1 in actin cytoskeletal regulation in cancer cells.\",\n      \"method\": \"shRNA knockdown, immunofluorescence co-localization with F-actin, multiple cell lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization with functional link via KD, replicated across multiple cell lines but single lab\",\n      \"pmids\": [\"24454753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AAV-mediated shRNA knockdown of Atp6v1c1 in a mouse periodontitis model reduces osteoclast numbers, inhibits infiltration of dendritic cells and macrophages, suppresses osteoclast-related gene expression, and prevents pro-inflammatory cytokine gene expression, revealing a dual role in osteoclast-mediated bone erosion and innate immune inflammation.\",\n      \"method\": \"AAV-shRNA knockdown in vivo, histology, gene expression analysis, infection model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KD with multiple defined cellular phenotypes, single lab\",\n      \"pmids\": [\"26274612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Atp6v1c1 enhances breast cancer cell proliferation through activation of the mTORC1 signaling pathway; lentiviral shRNA knockdown of ATP6v1c1 reduces V-ATPase activity and impairs mTORC1 pathway activation in multiple human cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-435s) but not in untransformed C3H10T1/2 cells.\",\n      \"method\": \"Lentiviral shRNA knockdown, V-ATPase activity assay, mTORC1 pathway activation (western blot), multiple cell lines including untransformed control\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined signaling pathway readout in multiple cell lines with appropriate controls\",\n      \"pmids\": [\"28504970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATP6V1C1 inhibits autophagy and promotes radiotherapy resistance in esophageal squamous cell carcinoma cells by activating mTOR signaling; siRNA-mediated silencing of ATP6V1C1 combined with ionizing radiation promotes autophagy and apoptosis and suppresses tumor growth in vivo.\",\n      \"method\": \"siRNA/plasmid transfection, colony formation assay, flow cytometry, immunofluorescence autophagosome quantification, transmission electron microscopy, western blot, xenograft mouse model\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods including in vivo, defines mTOR pathway link, single lab\",\n      \"pmids\": [\"33183740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dominantly acting gain-of-function variants in ATP6V1C1 upregulate V-ATPase proton-pumping activity, resulting in increased lysosomal acidification, disrupted lysosomal morphology and localization, defective autophagic flux with accumulation of lysosomal substrates, and impaired cilium biogenesis, causing a neurodevelopmental DOORS-like syndrome.\",\n      \"method\": \"Functional variant analysis in patient cells, lysosomal acidification assays, lysosomal morphology/localization imaging, autophagic flux assays, ciliogenesis assay\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal cellular assays in patient-derived material, single study\",\n      \"pmids\": [\"39210597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Natural compound veratramine (VAM) directly binds to ATP6V1C1 and inhibits V-ATPase catalytic activity and lysosomal acidification, thereby disrupting the autophagic-lysosomal pathway in cancer cells; this was identified by thermal proteome profiling (TPP) and thermal proximity co-aggregation (TPCA) showing VAM causes V-ATPase complex dissociation.\",\n      \"method\": \"Thermal proteome profiling (TPP), thermal proximity co-aggregation (TPCA), direct binding assay, V-ATPase activity assay, lysosomal acidification assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding demonstrated by TPP plus enzymatic activity assay, single study\",\n      \"pmids\": [\"40384877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Conditional knockout of Atp6v1c1 in mouse hair cells causes early-onset sensorineural hearing loss and vestibular malfunction through synaptic defects in inner hair cells (loss of ribbon synapses, accumulation of endocytic compartments, absence of F-actin mesh around active zones), disrupted autophagic flux, and apoptosis; a p.R281P knock-in causes late-onset high-frequency hearing loss with spiral ganglion neuron degeneration.\",\n      \"method\": \"Conditional knockout mouse, knock-in mouse model, auditory brainstem response, confocal imaging of ribbon synapses and F-actin, autophagic flux assays, linkage analysis and exome sequencing in human family\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — conditional KO and knock-in mouse models with multiple orthogonal readouts including structural, electrophysiological, and biochemical assays\",\n      \"pmids\": [\"41539473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAF-derived extracellular vesicle-delivered ATP6V1C1 suppresses IGFBP3 expression by downregulating transcriptional regulator ID1, induces EMT in lung adenocarcinoma cells, and amplifies IGF1/IGF1R/Akt/ERK oncogenic signaling to promote metastasis.\",\n      \"method\": \"Quantitative proteomic profiling of CAF-derived EVs, EV transfer assays, ID1/IGFBP3 expression analysis, IGF1R/Akt/ERK signaling readouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway defined with multiple signaling readouts, single study\",\n      \"pmids\": [\"41548219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In replicatively aging yeast, V-ATPase disassembles into V1 and V0 subcomplexes with release of V1 subunit C (Vma5/ATP6V1C1 ortholog) from the vacuole into cytosol, causing vacuole alkalinization; caloric restriction prevents this disassembly; the RAVE complex promotes reassembly while Oxr1 promotes disassembly, and Rav2 levels decline with age.\",\n      \"method\": \"Replicative aging model in yeast, subcellular fractionation, vacuolar pH measurement, genetic epistasis (rav1Δ, oxr1Δ mutants), Rav2 overexpression\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and biochemical approaches in yeast aging model, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.07.23.604825\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ATP6V1C1 encodes the C1 subunit of the V1 sector of the vacuolar H+-ATPase (V-ATPase), where it is essential for V1 assembly onto the membrane and for proton pump activity; it physically interacts with the V0 subunit a3 at the osteoclast ruffled border, regulates lysosomal acidification and autophagic flux, activates mTORC1 signaling to promote cell proliferation, and additionally controls F-actin cytoskeletal organization and inner hair cell synaptic integrity in a V-ATPase-dependent manner, while gain-of-function variants cause hyperactive lysosomal acidification linked to neurodevelopmental disease.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries from KEPT papers only.\n\n**Classification:**\n\nRetrieved papers:\n1. PMID:8416931 - Yeast VMA5/VMA4 (ortholog of ATP6V1C1 subunit C) - KEEP (yeast ortholog)\n2. PMID:18657050 - Atp6v1c1 in osteoclasts - KEEP\n3. PMID:9661023 - vatC in Staphylococcus (streptogramin resistance gene) - EXCLUDE (alias collision, bacterial resistance gene)\n4. PMID:35272047 - atp6c in maize CMS (plant mitochondrial ATP synthase) - EXCLUDE (symbol collision, plant)\n5. PMID:24155661 - Atp6v1c1 in breast cancer - KEEP\n6. PMID:17467328 - ATP6V1C1 in oral cancer pH regulation - KEEP (mechanistic angle)\n7. PMID:28504970 - Atp6v1c1 in breast cancer/mTORC1 - KEEP\n8. PMID:24454753 - Atp6v1c1 and F-actin in breast cancer - KEEP\n9. PMID:33183740 - ATP6V1C1 in ESCC radiotherapy - KEEP\n10. PMID:14961347 - Ascidian subunit C rescuing yeast vma5 - KEEP (ortholog functional rescue)\n11. PMID:39210597 - ATP6V1C1 gain-of-function variants in DOORS syndrome - KEEP\n12. PMID:26274612 - Atp6v1c1 in periodontitis - KEEP\n13. PMID:38073308 - ZmRF5/atp6c in maize CMS restoration - EXCLUDE (plant gene)\n14. PMID:28879785 - VMA5 in Candida albicans - KEEP (fungal ortholog)\n15. PMID:26984774 - ATP6V1C1 expression in oral cancer - EXCLUDE (expression/IHC only)\n16. PMID:41548219 - ATP6V1C1 in CAF-EVs/LUAD metastasis - KEEP\n17. PMID:40384877 - ATP6V1C1 as drug target via veratramine - KEEP\n18. PMID:41539473 - ATP6V1C1 in hearing loss/hair cells - KEEP\n19. bio_10.1101_2024.07.23.604825 - Yeast V-ATPase disassembly in aging - KEEP (ortholog)\n\ngene2pubmed papers:\n- PMID:11836511 - V-ATPases review - KEEP for context but mostly review\n- PMID:9442887 - V-ATPase structure/function review - KEEP for context\n- PMID:16415858 - V-ATPase/ARNO/Arf6 interaction - KEEP (mechanistic, involves V-ATPase complex including subunit C context)\n- Others are large genomics/proteomics/interactome datasets or unrelated - mostly EXCLUDE from discovery extraction unless they provide specific mechanistic data about ATP6V1C1\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"VMA5 (yeast ortholog of ATP6V1C1) encodes the 42-kDa peripheral subunit of the vacuolar H+-ATPase V1 sector, and is essential for assembly of the V1 domain onto the vacuolar membrane; deletion of VMA5 abolishes vacuolar ATPase enzyme activity and prevents V1 subunit assembly.\",\n      \"method\": \"Genetic deletion (vma5 mutant), vacuolar ATPase enzyme activity assay, membrane fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined biochemical phenotype (loss of activity and assembly), replicated across multiple vma mutant characterizations in foundational yeast study\",\n      \"pmids\": [\"8416931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Subunit C of V-ATPase from the ascidian Ascidia sydneiensis samea (ortholog of ATP6V1C1) functionally complements yeast vma5 mutants, rescuing pH sensitivity, demonstrating that subunit C is responsible for V-ATPase assembly and activity regulation across metazoan species.\",\n      \"method\": \"Heterologous complementation of yeast vma5 mutant with ascidian cDNA under galactose-inducible promoter; pH sensitivity growth assay\",\n      \"journal\": \"Marine biotechnology (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic rescue experiment with clear phenotypic readout, single lab\",\n      \"pmids\": [\"14961347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Atp6v1c1 (C1) is the predominant C-subunit isoform expressed in osteoclasts (C2a and C2b are absent), is induced by RANKL during osteoclast differentiation, localizes to the ruffled border of activated osteoclasts, physically interacts with the a3 subunit (Atp6v0a3), is essential for osteoclast acidification activity and bone resorption, and is required for F-actin ring formation (unlike a3). C1 co-localizes with microtubules at the plasma membrane and with F-actin in mature osteoclasts.\",\n      \"method\": \"Lentivirus-mediated RNAi knockdown, immunoprecipitation (C1–a3 interaction), confocal immunofluorescence (co-localization with ruffled border, microtubules, F-actin), bone resorption pit assay, acidification assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP for binding partner, clean KD with multiple orthogonal functional readouts (acidification, resorption, actin ring), replicated across osteoclast contexts\",\n      \"pmids\": [\"18657050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Silencing of Atp6v1c1 in breast cancer cells inhibits lysosomal acidification and impairs cell growth, migration, and invasion in vitro, and reduces tumor growth, metastasis, and osteolytic bone lesions in vivo, establishing that Atp6v1c1 promotes breast cancer growth and bone metastasis through regulation of lysosomal V-ATPase activity.\",\n      \"method\": \"Lentivirus-mediated shRNA knockdown, lysosomal acidification assay, Matrigel invasion assay, 4T1 xenograft mouse model, in vivo bone metastasis imaging\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with multiple orthogonal phenotypic readouts in vitro and in vivo\",\n      \"pmids\": [\"24155661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Atp6v1c1 co-localizes with filamentous actin (F-actin) in breast cancer cells, and its depletion disrupts normal F-actin arrangement in 4T1, MDA-MB-231, and MDA-MB-435s cells, implicating Atp6v1c1 in actin cytoskeletal organization that facilitates cancer cell metastasis.\",\n      \"method\": \"shRNA knockdown, confocal immunofluorescence co-localization of Atp6v1c1 with F-actin (phalloidin staining), multiple human and mouse cancer cell lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization with functional link to metastasis, replicated in three cell lines but no direct mechanistic pathway identified\",\n      \"pmids\": [\"24454753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AAV-mediated shRNA knockdown of Atp6v1c1 in periodontal lesions protects against bone erosion (>85%) and gingival inflammation caused by P. gingivalis infection, reduces osteoclast numbers, inhibits infiltration of dendritic cells and macrophages, and suppresses expression of osteoclast-related genes and pro-inflammatory cytokine genes, revealing a dual role in osteoimmunology.\",\n      \"method\": \"AAV-shRNA gene knockdown in mouse periodontitis model, histomorphometry, immunohistochemistry for immune cell infiltration, qRT-PCR for cytokine/osteoclast gene expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KD with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"26274612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lentiviral shRNA-mediated knockdown of Atp6v1c1 reduces V-ATPase activity, impairs mTORC1 pathway activation, reduces proliferation in human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-435s) but not in untransformed C3H10T1/2 cells, and reduces orthotopic/intraosseous tumor growth and bone metastasis in vivo, establishing that Atp6v1c1 enhances breast cancer growth partly through mTORC1 signaling downstream of V-ATPase activity.\",\n      \"method\": \"Lentiviral shRNA knockdown, V-ATPase activity assay, mTORC1 phosphorylation (Western blot), cell proliferation assay, orthotopic and intraosseous mouse tumor models, TCGA genomic analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking V-ATPase activity to mTORC1, confirmed in multiple cell lines and in vivo\",\n      \"pmids\": [\"28504970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Deletion of VMA5 (ATP6V1C1 ortholog) in Candida albicans leads to vacuolar dysfunction, disturbance of calcium homeostasis, inhibition of calcium-related oxidative stress response, defects in autophagy completion, impaired hyphal development, and attenuated virulence.\",\n      \"method\": \"PCR-mediated homologous recombination gene deletion, vacuolar acidification assay, calcium homeostasis measurement, autophagy flux assay, hyphal morphology, murine infection model\",\n      \"journal\": \"Future microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple orthogonal phenotypic readouts in fungal ortholog, single lab\",\n      \"pmids\": [\"28879785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATP6V1C1 inhibits autophagy and reduces radiosensitivity in esophageal squamous cell carcinoma (ESCC) cells; silencing ATP6V1C1 combined with ionizing radiation promotes autophagy, suppresses tumor growth, and increases apoptosis. The mechanism involves ATP6V1C1 activating mTOR signaling to suppress autophagy and thereby reduce radiosensitivity.\",\n      \"method\": \"siRNA knockdown and plasmid overexpression, colony formation assay, EdU proliferation assay, flow cytometry (apoptosis), γH2AX assay (DNA damage), immunofluorescence (autophagosomes/autolysosomes), transmission electron microscopy (autophagic ultrastructure), Western blot (mTOR pathway), nude mouse xenograft\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking ATP6V1C1 to mTOR-autophagy axis, replicated in vivo, single lab\",\n      \"pmids\": [\"33183740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dominantly acting gain-of-function variants in ATP6V1C1 (and ATP6V1B2) upregulate V-ATPase function, causing increased lysosomal acidification, disruption of lysosomal morphology and localization, defective autophagic flux with accumulation of lysosomal substrates, and impaired cilium biogenesis, resulting in a neurodevelopmental phenotype resembling DOORS syndrome.\",\n      \"method\": \"Patient-derived variant analysis, lysosomal pH assay, lysosomal morphology imaging (confocal), autophagic flux assay (LC3/p62 Western blot, immunofluorescence), ciliogenesis assay, functional comparison with ATP6V1B2 variants\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays establishing gain-of-function mechanism across lysosomal acidification, autophagy, and ciliogenesis\",\n      \"pmids\": [\"39210597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"V-ATPase subunit C (Vma5, yeast ortholog of ATP6V1C1) is released from the lysosome-like vacuole into the cytosol during yeast replicative aging (after >5 cell divisions), reflecting V-ATPase disassembly into V1 and V0 subcomplexes, which causes vacuole alkalinization. Caloric restriction prevents this disassembly. The RAVE complex promotes V-ATPase reassembly (Rav2 levels decline with age), and Oxr1 promotes disassembly; rav1Δ shortens replicative lifespan while oxr1Δ extends it.\",\n      \"method\": \"Yeast replicative aging model, fluorescence microscopy of Vma5 (subunit C) localization, vacuolar pH measurement, caloric restriction experiments, genetic epistasis (rav1Δ, oxr1Δ), Rav2 overexpression, lifespan assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis and localization experiments with functional consequence in yeast ortholog, preprint\",\n      \"pmids\": [\"bio_10.1101_2024.07.23.604825\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATP6V1C1 is the direct binding target of the natural compound veratramine (VAM); VAM directly binds ATP6V1C1, inhibits V-ATPase catalytic activity and lysosomal acidification, and disrupts the autophagic-lysosomal pathway essential for cancer cell survival.\",\n      \"method\": \"Thermal proteome profiling (TPP), thermal proximity co-aggregation (TPCA) to identify V-ATPase complex dissociation, direct binding assay, V-ATPase catalytic activity assay, lysosomal acidification assay, autophagic flux assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — TPP/TPCA target identification plus direct binding and enzymatic activity assays, single lab\",\n      \"pmids\": [\"40384877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAF-derived extracellular vesicles deliver ATP6V1C1 protein to lung adenocarcinoma cells, where it suppresses IGFBP3 expression by downregulating the transcriptional regulator ID1, inducing epithelial-mesenchymal transition and amplifying IGF1/IGF1R/Akt/ERK signaling, creating a feedforward metastatic loop.\",\n      \"method\": \"Quantitative proteomic profiling of CAF-derived EVs, EV uptake assays, siRNA/overexpression of ATP6V1C1, Western blot and qRT-PCR for ID1/IGFBP3/EMT markers, IGF1R/Akt/ERK signaling assays, in vivo metastasis mouse model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal mechanistic assays linking EV-delivered ATP6V1C1 to ID1-IGFBP3 axis and downstream signaling, single lab\",\n      \"pmids\": [\"41548219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Conditional knockout of Atp6v1c1 in mouse hair cells causes early-onset sensorineural hearing loss and vestibular malfunction, with synaptic defects in inner hair cells (loss of ribbon synapses, accumulation of endocytic compartments, absence of F-actin mesh at active zones), disrupted autophagic flux, and apoptosis. A gain-of-function p.R281P knock-in variant causes late-onset high-frequency hearing loss through disrupted autophagic flux and spiral ganglion neuron degeneration.\",\n      \"method\": \"Conditional knockout mouse (hair cell-specific), auditory brainstem response (ABR), confocal and electron microscopy (ribbon synapses, endocytic compartments, F-actin), autophagic flux assay, apoptosis assay, knock-in mouse model (p.R281P), linkage analysis and exome sequencing in human family\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO and knock-in mouse models with multiple orthogonal functional readouts establishing synaptic, autophagic, and structural roles\",\n      \"pmids\": [\"41539473\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V1C1 encodes the C1 subunit of the V1 peripheral sector of the vacuolar H+-ATPase (V-ATPase), where it is essential for V1 assembly onto membranes and for proton pump activity; in osteoclasts it localizes to the ruffled border, interacts with the a3 subunit, drives extracellular acidification and bone resorption, and regulates F-actin ring formation via co-localization with actin and microtubules; in cancer cells it promotes growth and metastasis by sustaining lysosomal V-ATPase activity that activates mTORC1 signaling and supports autophagic flux; gain-of-function variants increase lysosomal acidification and disrupt autophagy causing DOORS-like neurodevelopmental disease, while loss-of-function causes sensorineural hearing loss through synaptic and autophagic defects in hair cells; and the protein undergoes regulated reversible disassembly from the vacuolar membrane, a process controlled by the RAVE complex and Oxr1 that modulates organelle acidification and replicative lifespan.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATP6V1C1 encodes the C1 subunit of the V1 peripheral sector of the vacuolar H+-ATPase (V-ATPase), serving as an essential structural linker required for V1 assembly onto the vacuolar membrane and for proton pump activity, with conserved function from yeast to mammals [PMID:8416931, PMID:14961347]. In osteoclasts, ATP6V1C1 physically interacts with the V0 a3 subunit at the ruffled border to drive acidification-dependent bone resorption and independently organizes the F-actin ring required for osteoclast sealing zone formation [PMID:18657050]; in hair cells, conditional knockout disrupts ribbon synapses, F-actin organization at active zones, and autophagic flux, causing sensorineural hearing loss [PMID:41539473]. ATP6V1C1 regulates lysosomal acidification and autophagic-lysosomal pathway integrity, and its activity feeds into mTORC1 signaling to promote cancer cell proliferation and suppress autophagy [PMID:24155661, PMID:28504970, PMID:33183740, PMID:40384877]. Dominantly acting gain-of-function variants in ATP6V1C1 cause hyperactive lysosomal acidification, disrupted autophagic flux, and impaired ciliogenesis, resulting in a neurodevelopmental DOORS-like syndrome [PMID:39210597].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that the C subunit (VMA5) is a core V-ATPase component resolved whether this peripheral subunit was essential for enzyme assembly and activity: its deletion prevented V1 sector assembly onto the vacuolar membrane and abolished ATPase activity, defining it as indispensable rather than regulatory.\",\n      \"evidence\": \"Genetic deletion of VMA5 in yeast with vacuolar ATPase activity assays and complementation grouping\",\n      \"pmids\": [\"8416931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which subunit C bridges V1 and V0 sectors was not resolved\", \"No mammalian data at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Cross-species rescue of yeast vma5 mutants by an ascidian subunit C ortholog demonstrated that the assembly/regulatory function of this subunit is conserved across metazoa, supporting extrapolation of yeast findings to mammalian systems.\",\n      \"evidence\": \"Heterologous expression of ascidian subunit C cDNA in yeast vma5 mutant with growth rescue assay\",\n      \"pmids\": [\"14961347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian-specific functions not yet tested\", \"Structural basis for cross-species compatibility unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Two previously unlinked questions — how V-ATPase assembles at the osteoclast ruffled border and how osteoclasts organize their actin cytoskeleton — were both answered by showing that Atp6v1c1 physically interacts with the a3 subunit to enable proton pumping and independently controls F-actin ring formation, establishing it as a bifunctional hub in bone-resorbing osteoclasts.\",\n      \"evidence\": \"Co-immunoprecipitation of C1 with a3, lentiviral shRNA knockdown, acidification and bone resorption assays, immunofluorescence co-localization with F-actin and microtubules, epistatic comparison with a3 knockout\",\n      \"pmids\": [\"18657050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between C1 and actin regulatory machinery not identified\", \"Whether the actin-organizing function requires V-ATPase catalytic activity was not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extending the biological role of ATP6V1C1 beyond specialized cell types, its knockdown in breast cancer cells revealed that V-ATPase-dependent lysosomal acidification driven by C1 is required for cancer cell proliferation, migration, invasion, and in vivo tumor growth, establishing a cancer-relevant function.\",\n      \"evidence\": \"Lentiviral shRNA knockdown in breast cancer cell lines, Matrigel invasion assay, xenograft tumor model, lysosomal acidification assay\",\n      \"pmids\": [\"24155661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway downstream of acidification not yet defined\", \"Contribution of C1 versus other V-ATPase subunits to cancer phenotype unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The downstream signaling mechanism was clarified: ATP6V1C1 knockdown reduced V-ATPase activity and impaired mTORC1 pathway activation specifically in cancer cells but not in untransformed cells, linking V-ATPase-mediated acidification to nutrient-sensing mTORC1 signaling in a cancer-selective manner.\",\n      \"evidence\": \"Lentiviral shRNA knockdown, V-ATPase activity assay, mTORC1 pathway western blots in multiple cancer cell lines and untransformed controls\",\n      \"pmids\": [\"28504970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which V-ATPase activity is sensed by mTORC1 not identified\", \"Cancer selectivity mechanism unexplained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The mTOR–autophagy axis was further resolved: ATP6V1C1 silencing combined with ionizing radiation promoted autophagy and apoptosis in esophageal cancer cells, demonstrating that ATP6V1C1-driven mTOR activation suppresses autophagy and thereby confers radiotherapy resistance.\",\n      \"evidence\": \"siRNA knockdown and overexpression, colony formation, flow cytometry, autophagosome quantification by immunofluorescence and TEM, xenograft model\",\n      \"pmids\": [\"33183740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ATP6V1C1 regulation of autophagy is entirely mTOR-dependent or has mTOR-independent components\", \"No structural data on how C1 levels modulate V-ATPase assembly dynamics in cancer\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The first human disease link was established: dominant gain-of-function ATP6V1C1 variants caused hyperactive V-ATPase proton pumping, excessive lysosomal acidification, disrupted lysosomal morphology, defective autophagic flux, and impaired ciliogenesis, resulting in a neurodevelopmental DOORS-like syndrome — revealing that too much, not just too little, V-ATPase activity is pathogenic.\",\n      \"evidence\": \"Patient-derived cell analysis with lysosomal acidification assays, lysosomal morphology imaging, autophagic flux assays, ciliogenesis assay\",\n      \"pmids\": [\"39210597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for gain-of-function not determined\", \"Whether cilium defect is a direct consequence of lysosomal dysfunction or an independent C1 function\", \"Replication in animal models needed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Direct pharmacological targeting of ATP6V1C1 was demonstrated: the natural compound veratramine binds ATP6V1C1, causes V-ATPase complex dissociation, inhibits catalytic activity and lysosomal acidification, and disrupts the autophagic-lysosomal pathway in cancer cells, validating C1 as a druggable node.\",\n      \"evidence\": \"Thermal proteome profiling, thermal proximity co-aggregation, direct binding assay, V-ATPase activity and lysosomal acidification assays\",\n      \"pmids\": [\"40384877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity for C1 versus other V-ATPase subunits not fully established\", \"In vivo pharmacological validation incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Two studies resolved tissue-specific roles: conditional knockout in mouse hair cells showed that ATP6V1C1 maintains inner hair cell ribbon synapses and F-actin organization at active zones and is required for autophagic flux, with loss causing hearing loss; separately, CAF-derived extracellular vesicle delivery of ATP6V1C1 was shown to suppress IGFBP3 via ID1 downregulation and activate IGF1R/Akt/ERK signaling to drive lung cancer metastasis.\",\n      \"evidence\": \"Conditional KO and knock-in mouse models with ABR, confocal imaging, autophagic flux assays (hearing); proteomic profiling of CAF-derived EVs, EV transfer assays, signaling readouts (cancer)\",\n      \"pmids\": [\"41539473\", \"41548219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether hair cell F-actin defect is V-ATPase-dependent or reflects the cytoskeletal function seen in osteoclasts\", \"Mechanism of EV-mediated ATP6V1C1 transfer and its stoichiometric significance in recipient cells unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for how C1 bridges V1–V0 assembly and how gain-of-function mutations alter this; whether the F-actin organizing activity is catalytically dependent or represents a moonlighting function; and how V-ATPase activity is sensed by mTORC1 through ATP6V1C1.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of mammalian V-ATPase with C1 in assembled and disassembled states\", \"Molecular partners mediating C1-dependent actin organization unknown\", \"Mechanism coupling V-ATPase luminal acidification to mTORC1 activation via C1 not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 5, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [4, 9, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0009612973\", \"supporting_discovery_ids\": [8, 9, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 12]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 2, 10]}\n    ],\n    \"complexes\": [\"V-ATPase (V1 sector)\"],\n    \"partners\": [\"ATP6V0A3\", \"ID1\", \"IGFBP3\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ATP6V1C1 encodes the C1 subunit of the V1 peripheral sector of the vacuolar H⁺-ATPase (V-ATPase) and is essential for V1 domain assembly onto membranes and for proton pump catalytic activity, functioning as a critical determinant of organellar and extracellular acidification across eukaryotes [PMID:8416931, PMID:14961347]. In osteoclasts, ATP6V1C1 localizes to the ruffled border, physically interacts with the a3 (ATP6V0A3) subunit, drives extracellular acid secretion required for bone resorption, and independently organizes the F-actin ring through co-localization with actin and microtubules [PMID:18657050]; in cancer cells, it sustains lysosomal V-ATPase activity that activates mTORC1 signaling, suppresses autophagy, and promotes tumor growth and metastasis [PMID:24155661, PMID:28504970, PMID:33183740]. Gain-of-function ATP6V1C1 variants increase lysosomal acidification, disrupt autophagic flux and ciliogenesis causing a DOORS-like neurodevelopmental syndrome, while conditional loss in hair cells produces sensorineural hearing loss through synaptic ribbon loss, autophagic failure, and apoptosis [PMID:39210597, PMID:41539473].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that the C subunit (VMA5) is structurally required for V1 sector assembly and vacuolar ATPase activity resolved the foundational question of whether this subunit is catalytic or architectural.\",\n      \"evidence\": \"VMA5 deletion in yeast abolished V-ATPase activity and prevented V1 membrane assembly (enzyme activity assay, membrane fractionation)\",\n      \"pmids\": [\"8416931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural information on how subunit C bridges V1 subunits\", \"Mammalian isoform-specific functions not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Cross-species complementation of yeast vma5 mutants with an ascidian C subunit demonstrated that the assembly/activity role of subunit C is conserved across metazoans, extending the yeast paradigm to animal biology.\",\n      \"evidence\": \"Heterologous expression of ascidian subunit C rescued yeast vma5 pH-sensitivity phenotype\",\n      \"pmids\": [\"14961347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian C1 vs C2 isoform specificity not tested\", \"Mechanism of functional conservation at the structural level unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying ATP6V1C1 as the sole C-subunit isoform in osteoclasts and demonstrating its interaction with a3, ruffled border localization, and independent role in F-actin ring formation established a tissue-specific function beyond generic acidification.\",\n      \"evidence\": \"RNAi knockdown in osteoclasts, co-IP of C1–a3 interaction, confocal co-localization with F-actin and microtubules, bone resorption pit and acidification assays\",\n      \"pmids\": [\"18657050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of C1–a3 interaction not resolved\", \"How C1 organizes F-actin independently of a3 remains mechanistically undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that ATP6V1C1 knockdown impairs lysosomal acidification, cancer cell invasion, and in vivo tumor growth/metastasis revealed the subunit as a non-redundant driver of malignant phenotypes through V-ATPase-dependent mechanisms.\",\n      \"evidence\": \"shRNA knockdown in breast cancer cells, lysosomal pH assay, Matrigel invasion, 4T1 xenograft and bone metastasis models\",\n      \"pmids\": [\"24155661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathway not identified at this stage\", \"Whether the effect is specific to C1 versus other V-ATPase subunits unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking ATP6V1C1-dependent V-ATPase activity to mTORC1 signaling in cancer cells answered the mechanistic question of how lysosomal acidification translates into a proliferative advantage, and showed selectivity for transformed over untransformed cells.\",\n      \"evidence\": \"shRNA knockdown in multiple breast cancer lines, V-ATPase activity assay, mTORC1 phosphorylation Western blot, orthotopic and intraosseous mouse tumor models\",\n      \"pmids\": [\"28504970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mTORC1 activation is direct (via amino acid sensing on lysosome) or indirect not distinguished\", \"Cancer-type generalizability beyond breast cancer not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing that ATP6V1C1 activates mTOR to suppress autophagy and reduce radiosensitivity in esophageal cancer extended the mTORC1-autophagy axis to a second cancer type and revealed therapeutic vulnerability upon silencing.\",\n      \"evidence\": \"siRNA/overexpression, colony formation, autophagosome/autolysosome imaging, mTOR pathway Western blot, nude mouse xenograft with radiation\",\n      \"pmids\": [\"33183740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether autophagic effect is fully mTOR-dependent or involves parallel pathways not resolved\", \"Direct radiosensitization mechanism versus autophagic cell death not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that gain-of-function ATP6V1C1 variants cause hyperacidification, disrupted autophagy, impaired ciliogenesis, and a DOORS-like neurodevelopmental phenotype established the first human Mendelian disease link and showed that excess V-ATPase activity is as pathogenic as deficiency.\",\n      \"evidence\": \"Patient variant analysis, lysosomal pH assay, autophagic flux (LC3/p62), ciliogenesis assay, comparison with ATP6V1B2 variants\",\n      \"pmids\": [\"39210597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Number of families limited; full phenotypic spectrum not defined\", \"Structural basis of gain-of-function not determined\", \"Contribution of ciliogenesis defect versus autophagy defect to neurological phenotype unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that V-ATPase subunit C is released from vacuolar membranes during yeast replicative aging—regulated by the RAVE complex (assembly) and Oxr1 (disassembly)—linked reversible V-ATPase disassembly to aging and lifespan control.\",\n      \"evidence\": \"Yeast replicative aging model, fluorescence microscopy of Vma5 localization, vacuolar pH, genetic epistasis (rav1Δ, oxr1Δ), lifespan assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.23.604825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; not yet peer-reviewed\", \"Whether RAVE-Oxr1 regulation is conserved in mammalian cells unknown\", \"Signal triggering age-dependent disassembly not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of ATP6V1C1 as the direct binding target of veratramine demonstrated that the C1 subunit is a druggable node whose pharmacological inhibition disrupts V-ATPase catalysis and the autophagic-lysosomal pathway.\",\n      \"evidence\": \"Thermal proteome profiling, thermal proximity co-aggregation, direct binding assay, V-ATPase activity and lysosomal acidification assays\",\n      \"pmids\": [\"40384877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site on C1 not structurally defined\", \"Selectivity over other V-ATPase subunits or off-target effects not fully characterized\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Two discoveries in 2026 expanded the functional repertoire: (1) CAF-derived extracellular vesicles deliver ATP6V1C1 protein to lung adenocarcinoma cells where it suppresses ID1-IGFBP3 to amplify IGF1R/Akt/ERK-driven EMT, and (2) conditional hair cell knockout and a gain-of-function knock-in established that ATP6V1C1 controls ribbon synapse integrity, autophagic flux, and auditory/vestibular function.\",\n      \"evidence\": \"EV proteomic profiling, siRNA/overexpression with EMT/signaling readouts, in vivo metastasis model (lung cancer); conditional KO and R281P knock-in mice, ABR, electron microscopy of ribbon synapses, autophagic flux assays (hair cells)\",\n      \"pmids\": [\"41548219\", \"41539473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Non-canonical transcriptional role (ID1/IGFBP3 suppression) mechanism unclear—whether V-ATPase-dependent or independent not distinguished\", \"Whether EV-delivered C1 assembles into recipient-cell V-ATPase complexes unknown\", \"Relative contributions of synaptic vs autophagic defects to hearing loss not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of ATP6V1C1's bridging role in V1-V0 assembly, the mechanism by which it organizes F-actin independently of other V-ATPase subunits, and whether the non-canonical transcriptional effects observed in cancer are V-ATPase-dependent remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of mammalian V-ATPase C1 in complex context\", \"Mechanism linking C1 to F-actin organization unknown\", \"Whether ID1/IGFBP3 regulation requires V-ATPase catalytic activity or is a moonlighting function is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 6, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [3, 6, 9, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0, 7, 10]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 2, 3, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 8, 9, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 6, 8, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 9, 10]}\n    ],\n    \"complexes\": [\n      \"V-ATPase (V1 sector)\",\n      \"V-ATPase holoenzyme (V1-V0)\"\n    ],\n    \"partners\": [\n      \"ATP6V0A3\",\n      \"ATP6V1B2\",\n      \"IGFBP3\",\n      \"ID1\",\n      \"MTOR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}