{"gene":"ATP6V0C","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1990,"finding":"The VMA3 gene product (yeast ortholog of ATP6V0C), subunit c of vacuolar H+-ATPase, is indispensable for assembly of subunits a and b of the H+-ATPase complex, vacuolar acidification, protein transport to the vacuole, and endocytosis; disruption of VMA3 completely abolishes vacuolar H+-ATPase activity.","method":"VMA3 gene disruption in Saccharomyces cerevisiae, biochemical subunit assembly analysis, in vivo vacuolar acidification assay, lucifer yellow endocytosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO with multiple orthogonal readouts (ATPase activity, vacuolar acidification, protein transport, endocytosis), foundational study replicated across fungi","pmids":["2145283"],"is_preprint":false},{"year":2002,"finding":"The human ATP6V0C (ATP6L) promoter is GC-rich, lacks TATA/CCAAT boxes, and is regulated by cooperative binding of transcription factors Sp1 and Oct1; anticancer agent TAS-103 increases nuclear Sp1/Sp3 and Oct1 levels and induces promoter activity via the Oct1-binding site, while cisplatin stabilizes ATP6L mRNA rather than activating the promoter.","method":"In vivo footprint analysis, promoter-reporter luciferase assay, site-directed mutagenesis of Oct1-binding site, nuclear extract gel-shift (EMSA), qRT-PCR","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (footprint, mutagenesis, EMSA, luciferase) in a single rigorous study","pmids":["12133827"],"is_preprint":false},{"year":2005,"finding":"Knockdown of ATP6V0C (ATP6L) in hepatocellular carcinoma cells inhibits proton secretion, impairs intracellular pH recovery from acidification, reduces MMP-2 expression and gelatinase activity, and suppresses tumor growth and metastasis in vivo.","method":"DNA vector-based siRNA knockdown, intracellular pH measurement, Matrigel invasion assay, gelatin zymography, xenograft mouse model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vitro and in vivo readouts; highly cited foundational study","pmids":["16061667"],"is_preprint":false},{"year":2006,"finding":"ATP6V0C directly binds to HIF-1α at its N-terminal amino acids 1-16, competes with VHL protein for HIF-1α binding, stabilizes HIF-1α in a pH-independent manner, and translocates together with HIF-1α to the nucleus upon bafilomycin A1 treatment; ATP6V0C overexpression increases HIF-1α levels in a gene dose-dependent manner.","method":"Co-immunoprecipitation, siRNA knockdown, confocal immunofluorescence, HIF-1α protein quantification, N-terminal deletion mapping","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and colocalization with functional knockdown and deletion mapping, single lab","pmids":["17178925"],"is_preprint":false},{"year":2008,"finding":"The E3 ubiquitin ligase RNF182 physically interacts with ATP6V0C (identified by yeast two-hybrid and co-precipitation) and targets it for degradation via the ubiquitin-proteasome pathway; RNF182 possesses E3 ligase activity stimulating E2-dependent polyubiquitination in vitro.","method":"Yeast two-hybrid screening, co-immunoprecipitation, overexpression studies, in vitro ubiquitination assay","journal":"Molecular neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 2-3 — yeast two-hybrid confirmed by co-IP and in vitro ubiquitination assay, single lab","pmids":["18298843"],"is_preprint":false},{"year":2009,"finding":"ATP6V0C (ATP6L) siRNA knockdown in drug-resistant MCF-7/ADR breast cancer cells increases lysosomal pH, causes retention of basic chemotherapeutic agents (doxorubicin, 5-FU, vincristine) in cell nuclei rather than endo-lysosomes, and sensitizes cells to drug cytotoxicity.","method":"siRNA knockdown, qRT-PCR, Western blot, intracellular drug distribution assay, cytotoxicity assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway placement (lysosomal pH → drug sequestration) with multiple readouts, single lab","pmids":["19299075"],"is_preprint":false},{"year":2014,"finding":"ATP6V0C knockdown in differentiated SH-SY5Y neuroblastoma cells reduces lysosomal acidification, inhibits autophagic flux, increases basal LC3-II levels and accumulation of α-synuclein high-molecular-weight species and APP C-terminal fragments, and reduces neurite length; the block in flux occurs at the lysosomal degradation step (not vesicular fusion) as shown by enhanced LC3/LAMP-1 co-localization.","method":"siRNA knockdown, LysoTracker staining, LC3-II Western blot, immunofluorescence colocalization (LC3/LAMP-1), autophagic flux assay, propidium iodide viability assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal assays establishing ALP function, single lab","pmids":["24695574"],"is_preprint":false},{"year":2017,"finding":"ATP6V0C interacts with LASS2/TMSG1 (co-localized by confocal immunofluorescence); siRNA silencing of ATP6V0C in PC-3M-1E8 prostate cancer cells inhibits V-ATPase activity (~5-fold), decreases extracellular proton concentration, reduces secreted MMP-9 activation (~3.6-fold), and inhibits cell migration and invasion independent of LASS2/TMSG1.","method":"siRNA knockdown, V-ATPase activity assay, extracellular pH measurement, gelatin zymography for MMP-9, Matrigel invasion assay, confocal immunofluorescence co-localization","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — enzymatic activity plus co-localization and functional readouts, single lab","pmids":["29138865"],"is_preprint":false},{"year":2020,"finding":"ATP6V0C is identified as a Vpu-binding protein by yeast two-hybrid; ATP6V0C depletion impairs Vpu-mediated tetherin degradation and reduces HIV-1 release; ATP6V0C overexpression sequesters tetherin in CD63/LAMP1-positive intracellular compartments, an effect specific to ATP6V0C and not shared by the paralog ATP6V0C″.","method":"Yeast two-hybrid, siRNA knockdown, overexpression, Western blot, HIV-1 release assay, immunofluorescence localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — yeast two-hybrid confirmed with KD/OE functional readouts and localization, single lab","pmids":["32291285"],"is_preprint":false},{"year":2023,"finding":"Heterozygous point variants in ATP6V0C impair V-ATPase function as demonstrated by reduced LysoSensor fluorescence and impaired growth on CaCl2 media in S. cerevisiae; in silico modelling shows variants interfere with ATP6V0C–ATP6V0A subunit interactions during ATP hydrolysis; Drosophila ATP6V0C knockdown increases seizure-like behaviour duration; C. elegans expressing patient variants show reduced growth, motor dysfunction, and reduced lifespan.","method":"Yeast functional complementation (LysoSensor fluorescence, CaCl2 growth assay), in silico structural modelling, Drosophila knockdown seizure assay, C. elegans variant expression phenotyping","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple model organisms with orthogonal functional assays plus structural modelling, moderate-strong evidence base","pmids":["36074901"],"is_preprint":false},{"year":2024,"finding":"TFEB directly binds the ATP6V0C promoter at a specific site to transcriptionally activate ATP6V0C expression (validated by CUT&Run-qPCR and luciferase reporter assay); ATP6V0C acts as a scaffold protein bridging STX17 and VAMP8 (SNARE complex) to mediate autophagosome-lysosome fusion, independent of its role in lysosomal acidification.","method":"CUT&Tag, CUT&Run-qPCR, luciferase reporter assay, co-immunoprecipitation (ATP6V0C with STX17/VAMP8), RNA-seq, siRNA knockdown, autophagic flux assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP-seq, reporter assay, Co-IP) establishing new scaffold function, single lab","pmids":["38481802"],"is_preprint":false},{"year":2026,"finding":"ATP6V0C overexpression via AAV2 transgene in retinal ganglion cells promotes neuroprotection and long-distance axon regeneration after optic nerve crush, comparable in efficacy to Pten and Klf9 targeting; ATP6V0C plays a role in lysosomal acidification and degradation of misfolded proteins in response to ER stress in injured neurons.","method":"AAV2-mediated transgene expression, optic nerve crush model, axon regeneration quantification, RGC survival assay","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO/OE with defined cellular phenotype (axon regeneration, neuroprotection), single study","pmids":["42023031"],"is_preprint":false},{"year":2026,"finding":"ATP6V0C knockout specifically in alveolar epithelial cells (AT2-specific Cre) attenuates LPS-induced acute lung injury hallmarks; co-immunoprecipitation confirms direct ATP6V0C–HIF-1α interaction in injured lungs; HIF-1α transcriptionally upregulates ATP6V0C expression, forming a positive feedback loop that drives epithelial apoptosis and inflammation.","method":"Conditional (alveolar-specific) ATP6V0C knockout mice, co-immunoprecipitation, transcriptomic (RNA-seq) analysis, AAV-mediated ATP6V0C overexpression in HIF-1α knockout background, LPS-induced ALI model","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 — conditional KO with specific phenotypic readout, Co-IP confirming interaction, epistasis via dual KO, multiple orthogonal methods","pmids":["41738275"],"is_preprint":false}],"current_model":"ATP6V0C (the 16-kDa proteolipid c-subunit of the V0 domain of vacuolar H+-ATPase) is essential for V-ATPase complex assembly and proton pumping across organellar membranes, thereby acidifying lysosomes and endosomes to regulate autophagy-lysosome pathway flux, intracellular/extracellular pH, and neurotransmitter release; it also functions as a scaffold bridging SNARE proteins STX17 and VAMP8 to mediate autophagosome-lysosome fusion, directly binds and stabilizes HIF-1α (competing with VHL) in a reciprocal feedback loop, is ubiquitinated and degraded by the E3 ligase RNF182, interacts with HIV-1 Vpu to traffic tetherin into intracellular compartments, and its haploinsufficiency causes a neurodevelopmental/epilepsy syndrome in humans."},"narrative":{"teleology":[{"year":1990,"claim":"Establishing that subunit c is indispensable for V-ATPase assembly and vacuolar function answered the foundational question of whether this small proteolipid is merely a structural repeat or a functional requirement for the holoenzyme.","evidence":"VMA3 gene disruption in S. cerevisiae with biochemical ATPase activity, vacuolar acidification, protein sorting, and endocytosis assays","pmids":["2145283"],"confidence":"High","gaps":["Mammalian requirement not yet demonstrated","Stoichiometry of c-subunit ring not defined","No information on tissue-specific roles"]},{"year":2002,"claim":"Defining the transcriptional control of ATP6V0C by Sp1/Oct1 on a GC-rich, TATA-less promoter established how basal expression of this housekeeping subunit is maintained and can be pharmacologically modulated.","evidence":"In vivo footprinting, promoter-reporter mutagenesis, EMSA, and drug treatment in human cells","pmids":["12133827"],"confidence":"High","gaps":["Chromatin-level regulation not addressed","Tissue-specific transcription factors not explored","TFEB regulation not yet identified"]},{"year":2005,"claim":"Demonstrating that ATP6V0C knockdown impairs proton secretion, intracellular pH recovery, MMP-2 activity, and in vivo tumor growth linked V-ATPase c-subunit function to cancer cell invasion and the tumor microenvironment.","evidence":"siRNA knockdown in hepatocellular carcinoma cells with pH measurement, zymography, and xenograft model","pmids":["16061667"],"confidence":"High","gaps":["Whether effect is specific to ATP6V0C versus other V-ATPase subunits","Mechanism linking extracellular acidification to MMP activation not fully defined"]},{"year":2006,"claim":"Identification of a direct ATP6V0C–HIF-1α interaction that competes with VHL binding revealed an unexpected non-canonical role for the c-subunit in oxygen-sensing signaling, independent of proton pumping.","evidence":"Co-immunoprecipitation, N-terminal deletion mapping, confocal colocalization, and siRNA knockdown","pmids":["17178925"],"confidence":"Medium","gaps":["Single-lab observation at the time","Physiological context for nuclear translocation unclear","No in vivo validation"]},{"year":2008,"claim":"Discovery that the E3 ligase RNF182 ubiquitinates ATP6V0C for proteasomal degradation established a post-translational regulatory axis controlling c-subunit abundance.","evidence":"Yeast two-hybrid confirmed by co-immunoprecipitation and in vitro ubiquitination assay","pmids":["18298843"],"confidence":"Medium","gaps":["Physiological consequence of RNF182-mediated degradation on V-ATPase activity not tested","No in vivo confirmation","Ubiquitination sites on ATP6V0C not mapped"]},{"year":2009,"claim":"Showing that ATP6V0C depletion raises lysosomal pH and redirects sequestered chemotherapeutics to the nucleus in drug-resistant cells mechanistically explained V-ATPase's role in multidrug resistance.","evidence":"siRNA knockdown in MCF-7/ADR cells with intracellular drug distribution and cytotoxicity assays","pmids":["19299075"],"confidence":"Medium","gaps":["Contribution of ATP6V0C versus whole V-ATPase not dissected","Clinical relevance not established"]},{"year":2014,"claim":"Demonstrating that ATP6V0C loss blocks autophagic flux at the lysosomal degradation step, with accumulation of α-synuclein and APP-CTFs, directly implicated the c-subunit in neurodegeneration-relevant proteostasis.","evidence":"siRNA knockdown in differentiated SH-SY5Y cells with LysoTracker, LC3-II flux assay, LC3/LAMP-1 colocalization","pmids":["24695574"],"confidence":"Medium","gaps":["In vivo neuronal validation lacking","Whether partial loss mirrors disease conditions unknown","No rescue experiment"]},{"year":2020,"claim":"Identifying ATP6V0C as a Vpu-binding partner that mediates tetherin sequestration into endo-lysosomes revealed how HIV-1 hijacks the V-ATPase c-subunit to counteract innate restriction.","evidence":"Yeast two-hybrid, siRNA knockdown, overexpression, HIV-1 release assay, and immunofluorescence colocalization","pmids":["32291285"],"confidence":"Medium","gaps":["Structural basis of Vpu–ATP6V0C interaction not resolved","Relevance in primary T cells or in vivo not shown","ATP6V0C'' paralog specificity mechanism unclear"]},{"year":2023,"claim":"Cross-species functional validation of heterozygous ATP6V0C variants as causative for a neurodevelopmental/epilepsy syndrome established ATP6V0C haploinsufficiency as a Mendelian disease gene.","evidence":"Yeast complementation (LysoSensor, CaCl2 growth), Drosophila seizure assay, C. elegans variant phenotyping, in silico structural modelling","pmids":["36074901"],"confidence":"High","gaps":["Patient iPSC-derived neuronal model not yet reported","Genotype-phenotype correlation across variant types not fully resolved","Whether seizures arise from impaired acidification, fusion, or both is unknown"]},{"year":2024,"claim":"Demonstrating that TFEB transcriptionally activates ATP6V0C and that ATP6V0C scaffolds STX17–VAMP8 for autophagosome–lysosome fusion uncovered a second, acidification-independent function in membrane fusion.","evidence":"CUT&Run-qPCR, luciferase reporter, co-immunoprecipitation of ATP6V0C with STX17/VAMP8, siRNA flux assays","pmids":["38481802"],"confidence":"Medium","gaps":["Structural basis of the scaffold function not defined","Whether SNARE-bridging and proton-pumping roles are mutually exclusive or concurrent is unclear","Single-lab finding awaiting independent replication"]},{"year":2026,"claim":"Conditional alveolar-specific ATP6V0C knockout attenuating lung injury and epistasis with HIF-1α knockout validated the ATP6V0C–HIF-1α positive feedback loop in vivo, resolving the physiological relevance of the 2006 binding observation.","evidence":"AT2-specific Cre conditional KO mice, Co-IP in injured lung, RNA-seq, AAV-mediated overexpression in HIF-1α KO background, LPS-induced ALI model","pmids":["41738275"],"confidence":"High","gaps":["Whether the feedback loop operates in non-pulmonary tissues is untested","Molecular determinants governing V-ATPase-dependent vs HIF-1α-dependent ATP6V0C functions not separated"]},{"year":2026,"claim":"AAV2-mediated ATP6V0C overexpression promoting axon regeneration after optic nerve crush revealed a neuroprotective gain-of-function linked to enhanced lysosomal clearance under ER stress.","evidence":"AAV2 transgene in retinal ganglion cells, optic nerve crush model, axon regeneration and RGC survival quantification","pmids":["42023031"],"confidence":"Medium","gaps":["Mechanism connecting lysosomal acidification to axon regrowth signaling not delineated","Long-term efficacy and functional recovery not assessed","Single model system"]},{"year":null,"claim":"Key unresolved questions include the structural basis of ATP6V0C's dual role as a proton channel subunit and SNARE scaffold, whether its HIF-1α-stabilizing function is mechanistically separable from V-ATPase activity in vivo, and how disease-causing variants differentially impact acidification versus membrane fusion.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of mammalian ATP6V0C in the assembled V0 ring with bound SNAREs","Separation-of-function mutants distinguishing proton pumping from scaffold activity not generated","Genotype-phenotype studies in patient-derived neurons for the epilepsy syndrome are lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,5,6,7]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[5,6,8,11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[8]},{"term_id":"GO:0005773","term_label":"vacuole","supporting_discovery_ids":[0]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,10,11]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,2,5,7]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,12]}],"complexes":["V-ATPase (V0 sector)"],"partners":["HIF1A","STX17","VAMP8","RNF182","VPU","CERS2","ATP6V0A1"],"other_free_text":[]},"mechanistic_narrative":"ATP6V0C encodes the 16-kDa proteolipid c-subunit of the V0 sector of vacuolar H+-ATPase (V-ATPase), essential for complex assembly, proton translocation, and acidification of lysosomes, endosomes, and vacuoles, thereby governing autophagy-lysosome pathway flux, intracellular pH homeostasis, and neurotransmitter vesicle loading [PMID:2145283, PMID:24695574, PMID:16061667]. Beyond its canonical role in proton pumping, ATP6V0C serves as a scaffold that bridges the SNARE proteins STX17 and VAMP8 to promote autophagosome–lysosome fusion independently of lysosomal acidification, and it directly binds and stabilizes HIF-1α by competing with VHL, participating in a positive transcriptional feedback loop in which HIF-1α reciprocally induces ATP6V0C expression [PMID:38481802, PMID:17178925, PMID:41738275]. Heterozygous loss-of-function variants in ATP6V0C cause a neurodevelopmental syndrome with epilepsy, confirmed by impaired V-ATPase function in yeast complementation assays and seizure phenotypes in Drosophila and C. elegans disease models [PMID:36074901]. ATP6V0C is also exploited by HIV-1 Vpu to redirect tetherin into intracellular compartments, facilitating viral release [PMID:32291285]."},"prefetch_data":{"uniprot":{"accession":"P27449","full_name":"V-type proton ATPase 16 kDa proteolipid subunit c","aliases":["Vacuolar proton pump 16 kDa proteolipid subunit c"],"length_aa":155,"mass_kda":15.7,"function":"Proton-conducting pore forming subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:33065002, PubMed:36074901). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments, and in some cell types, it is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (By similarity)","subcellular_location":"Cytoplasmic vesicle, clathrin-coated vesicle membrane; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/P27449/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP6V0C","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATP6AP2","stoichiometry":10.0},{"gene":"ATP6AP1","stoichiometry":0.2},{"gene":"ATP6V0A1","stoichiometry":0.2},{"gene":"ATP6V0A2","stoichiometry":0.2},{"gene":"ATP6V0D1","stoichiometry":0.2},{"gene":"ATP6V1B2","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"STX12","stoichiometry":0.2},{"gene":"VAMP3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATP6V0C","total_profiled":1310},"omim":[{"mim_id":"621525","title":"NEURODEGENERATIVE DISORDER WITH CEREBELLAR AND CAUDATE ATROPHY; NDCCA","url":"https://www.omim.org/entry/621525"},{"mim_id":"621026","title":"RING FINGER PROTEIN 182; RNF182","url":"https://www.omim.org/entry/621026"},{"mim_id":"620465","title":"EPILEPSY, EARLY-ONSET, 3, WITH OR WITHOUT DEVELOPMENTAL DELAY; EPEO3","url":"https://www.omim.org/entry/620465"},{"mim_id":"617290","title":"EPILEPSY, EARLY-ONSET, 1, VITAMIN B6-DEPENDENT; EPEO1","url":"https://www.omim.org/entry/617290"},{"mim_id":"615338","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 16; DEE16","url":"https://www.omim.org/entry/615338"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATP6V0C"},"hgnc":{"alias_symbol":["VATL","Vma3"],"prev_symbol":["ATPL","ATP6C","ATP6L"]},"alphafold":{"accession":"P27449","domains":[{"cath_id":"1.20.120.610","chopping":"27-155","consensus_level":"high","plddt":91.3459,"start":27,"end":155}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P27449","model_url":"https://alphafold.ebi.ac.uk/files/AF-P27449-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P27449-F1-predicted_aligned_error_v6.png","plddt_mean":88.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP6V0C","jax_strain_url":"https://www.jax.org/strain/search?query=ATP6V0C"},"sequence":{"accession":"P27449","fasta_url":"https://rest.uniprot.org/uniprotkb/P27449.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P27449/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P27449"}},"corpus_meta":[{"pmid":"16061667","id":"PMC_16061667","title":"The growth and metastasis of human hepatocellular carcinoma xenografts are inhibited by small interfering RNA targeting to the subunit ATP6L of proton pump.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16061667","citation_count":130,"is_preprint":false},{"pmid":"2145283","id":"PMC_2145283","title":"Roles of the VMA3 gene product, subunit c of the vacuolar membrane H(+)-ATPase on vacuolar acidification and protein transport. A study with VMA3-disrupted mutants of Saccharomyces cerevisiae.","date":"1990","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2145283","citation_count":121,"is_preprint":false},{"pmid":"12133827","id":"PMC_12133827","title":"Enhanced expression of the human vacuolar H+-ATPase c subunit gene (ATP6L) in response to anticancer agents.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12133827","citation_count":70,"is_preprint":false},{"pmid":"19299075","id":"PMC_19299075","title":"Small interfering RNA targeting the subunit ATP6L of proton pump V-ATPase overcomes chemoresistance of breast cancer cells.","date":"2009","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/19299075","citation_count":68,"is_preprint":false},{"pmid":"24695574","id":"PMC_24695574","title":"ATP6V0C knockdown in neuroblastoma cells alters autophagy-lysosome pathway function and metabolism of proteins that accumulate in neurodegenerative disease.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24695574","citation_count":53,"is_preprint":false},{"pmid":"18298843","id":"PMC_18298843","title":"A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradation.","date":"2008","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/18298843","citation_count":49,"is_preprint":false},{"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},{"pmid":"23913543","id":"PMC_23913543","title":"Candida albicans VMA3 is necessary for V-ATPase assembly and function and contributes to secretion and filamentation.","date":"2013","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/23913543","citation_count":39,"is_preprint":false},{"pmid":"17178925","id":"PMC_17178925","title":"ATP6V0C competes with von Hippel-Lindau protein in hypoxia-inducible factor 1alpha (HIF-1alpha) binding and mediates HIF-1alpha expression by bafilomycin A1.","date":"2006","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17178925","citation_count":27,"is_preprint":false},{"pmid":"30245510","id":"PMC_30245510","title":"A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay.","date":"2018","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30245510","citation_count":24,"is_preprint":false},{"pmid":"36074901","id":"PMC_36074901","title":"ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.","date":"2023","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36074901","citation_count":23,"is_preprint":false},{"pmid":"30420612","id":"PMC_30420612","title":"Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer.","date":"2018","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30420612","citation_count":22,"is_preprint":false},{"pmid":"35600075","id":"PMC_35600075","title":"ATP6V0C Is Associated With Febrile Seizures and Epilepsy With Febrile Seizures Plus.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35600075","citation_count":20,"is_preprint":false},{"pmid":"31471894","id":"PMC_31471894","title":"High glucose disrupts autophagy lysosomal pathway in gingival epithelial cells via ATP6V0C.","date":"2019","source":"Journal of periodontology","url":"https://pubmed.ncbi.nlm.nih.gov/31471894","citation_count":16,"is_preprint":false},{"pmid":"29138865","id":"PMC_29138865","title":"Silencing of vacuolar ATPase c subunit ATP6V0C inhibits the invasion of prostate cancer cells through a LASS2/TMSG1-independent manner.","date":"2017","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/29138865","citation_count":16,"is_preprint":false},{"pmid":"38481802","id":"PMC_38481802","title":"Impaired TFEB-mediated autophagy-lysosome fusion promotes tubular cell cycle G2/M arrest and renal fibrosis by suppressing ATP6V0C expression and interacting with SNAREs.","date":"2024","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38481802","citation_count":15,"is_preprint":false},{"pmid":"33090716","id":"PMC_33090716","title":"Haploinsufficiency of ATP6V0C possibly underlies 16p13.3 deletions that cause microcephaly, seizures, and neurodevelopmental disorder.","date":"2020","source":"American journal of medical genetics. 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disruption of VMA3 completely abolishes vacuolar H+-ATPase activity.\",\n      \"method\": \"VMA3 gene disruption in Saccharomyces cerevisiae, biochemical subunit assembly analysis, in vivo vacuolar acidification assay, lucifer yellow endocytosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO with multiple orthogonal readouts (ATPase activity, vacuolar acidification, protein transport, endocytosis), foundational study replicated across fungi\",\n      \"pmids\": [\"2145283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The human ATP6V0C (ATP6L) promoter is GC-rich, lacks TATA/CCAAT boxes, and is regulated by cooperative binding of transcription factors Sp1 and Oct1; anticancer agent TAS-103 increases nuclear Sp1/Sp3 and Oct1 levels and induces promoter activity via the Oct1-binding site, while cisplatin stabilizes ATP6L mRNA rather than activating the promoter.\",\n      \"method\": \"In vivo footprint analysis, promoter-reporter luciferase assay, site-directed mutagenesis of Oct1-binding site, nuclear extract gel-shift (EMSA), qRT-PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (footprint, mutagenesis, EMSA, luciferase) in a single rigorous study\",\n      \"pmids\": [\"12133827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Knockdown of ATP6V0C (ATP6L) in hepatocellular carcinoma cells inhibits proton secretion, impairs intracellular pH recovery from acidification, reduces MMP-2 expression and gelatinase activity, and suppresses tumor growth and metastasis in vivo.\",\n      \"method\": \"DNA vector-based siRNA knockdown, intracellular pH measurement, Matrigel invasion assay, gelatin zymography, xenograft mouse model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vitro and in vivo readouts; highly cited foundational study\",\n      \"pmids\": [\"16061667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ATP6V0C directly binds to HIF-1α at its N-terminal amino acids 1-16, competes with VHL protein for HIF-1α binding, stabilizes HIF-1α in a pH-independent manner, and translocates together with HIF-1α to the nucleus upon bafilomycin A1 treatment; ATP6V0C overexpression increases HIF-1α levels in a gene dose-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, confocal immunofluorescence, HIF-1α protein quantification, N-terminal deletion mapping\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and colocalization with functional knockdown and deletion mapping, single lab\",\n      \"pmids\": [\"17178925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The E3 ubiquitin ligase RNF182 physically interacts with ATP6V0C (identified by yeast two-hybrid and co-precipitation) and targets it for degradation via the ubiquitin-proteasome pathway; RNF182 possesses E3 ligase activity stimulating E2-dependent polyubiquitination in vitro.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, overexpression studies, in vitro ubiquitination assay\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — yeast two-hybrid confirmed by co-IP and in vitro ubiquitination assay, single lab\",\n      \"pmids\": [\"18298843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ATP6V0C (ATP6L) siRNA knockdown in drug-resistant MCF-7/ADR breast cancer cells increases lysosomal pH, causes retention of basic chemotherapeutic agents (doxorubicin, 5-FU, vincristine) in cell nuclei rather than endo-lysosomes, and sensitizes cells to drug cytotoxicity.\",\n      \"method\": \"siRNA knockdown, qRT-PCR, Western blot, intracellular drug distribution assay, cytotoxicity assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement (lysosomal pH → drug sequestration) with multiple readouts, single lab\",\n      \"pmids\": [\"19299075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ATP6V0C knockdown in differentiated SH-SY5Y neuroblastoma cells reduces lysosomal acidification, inhibits autophagic flux, increases basal LC3-II levels and accumulation of α-synuclein high-molecular-weight species and APP C-terminal fragments, and reduces neurite length; the block in flux occurs at the lysosomal degradation step (not vesicular fusion) as shown by enhanced LC3/LAMP-1 co-localization.\",\n      \"method\": \"siRNA knockdown, LysoTracker staining, LC3-II Western blot, immunofluorescence colocalization (LC3/LAMP-1), autophagic flux assay, propidium iodide viability assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays establishing ALP function, single lab\",\n      \"pmids\": [\"24695574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATP6V0C interacts with LASS2/TMSG1 (co-localized by confocal immunofluorescence); siRNA silencing of ATP6V0C in PC-3M-1E8 prostate cancer cells inhibits V-ATPase activity (~5-fold), decreases extracellular proton concentration, reduces secreted MMP-9 activation (~3.6-fold), and inhibits cell migration and invasion independent of LASS2/TMSG1.\",\n      \"method\": \"siRNA knockdown, V-ATPase activity assay, extracellular pH measurement, gelatin zymography for MMP-9, Matrigel invasion assay, confocal immunofluorescence co-localization\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — enzymatic activity plus co-localization and functional readouts, single lab\",\n      \"pmids\": [\"29138865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATP6V0C is identified as a Vpu-binding protein by yeast two-hybrid; ATP6V0C depletion impairs Vpu-mediated tetherin degradation and reduces HIV-1 release; ATP6V0C overexpression sequesters tetherin in CD63/LAMP1-positive intracellular compartments, an effect specific to ATP6V0C and not shared by the paralog ATP6V0C″.\",\n      \"method\": \"Yeast two-hybrid, siRNA knockdown, overexpression, Western blot, HIV-1 release assay, immunofluorescence localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — yeast two-hybrid confirmed with KD/OE functional readouts and localization, single lab\",\n      \"pmids\": [\"32291285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Heterozygous point variants in ATP6V0C impair V-ATPase function as demonstrated by reduced LysoSensor fluorescence and impaired growth on CaCl2 media in S. cerevisiae; in silico modelling shows variants interfere with ATP6V0C–ATP6V0A subunit interactions during ATP hydrolysis; Drosophila ATP6V0C knockdown increases seizure-like behaviour duration; C. elegans expressing patient variants show reduced growth, motor dysfunction, and reduced lifespan.\",\n      \"method\": \"Yeast functional complementation (LysoSensor fluorescence, CaCl2 growth assay), in silico structural modelling, Drosophila knockdown seizure assay, C. elegans variant expression phenotyping\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple model organisms with orthogonal functional assays plus structural modelling, moderate-strong evidence base\",\n      \"pmids\": [\"36074901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TFEB directly binds the ATP6V0C promoter at a specific site to transcriptionally activate ATP6V0C expression (validated by CUT&Run-qPCR and luciferase reporter assay); ATP6V0C acts as a scaffold protein bridging STX17 and VAMP8 (SNARE complex) to mediate autophagosome-lysosome fusion, independent of its role in lysosomal acidification.\",\n      \"method\": \"CUT&Tag, CUT&Run-qPCR, luciferase reporter assay, co-immunoprecipitation (ATP6V0C with STX17/VAMP8), RNA-seq, siRNA knockdown, autophagic flux assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP-seq, reporter assay, Co-IP) establishing new scaffold function, single lab\",\n      \"pmids\": [\"38481802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATP6V0C overexpression via AAV2 transgene in retinal ganglion cells promotes neuroprotection and long-distance axon regeneration after optic nerve crush, comparable in efficacy to Pten and Klf9 targeting; ATP6V0C plays a role in lysosomal acidification and degradation of misfolded proteins in response to ER stress in injured neurons.\",\n      \"method\": \"AAV2-mediated transgene expression, optic nerve crush model, axon regeneration quantification, RGC survival assay\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO/OE with defined cellular phenotype (axon regeneration, neuroprotection), single study\",\n      \"pmids\": [\"42023031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATP6V0C knockout specifically in alveolar epithelial cells (AT2-specific Cre) attenuates LPS-induced acute lung injury hallmarks; co-immunoprecipitation confirms direct ATP6V0C–HIF-1α interaction in injured lungs; HIF-1α transcriptionally upregulates ATP6V0C expression, forming a positive feedback loop that drives epithelial apoptosis and inflammation.\",\n      \"method\": \"Conditional (alveolar-specific) ATP6V0C knockout mice, co-immunoprecipitation, transcriptomic (RNA-seq) analysis, AAV-mediated ATP6V0C overexpression in HIF-1α knockout background, LPS-induced ALI model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — conditional KO with specific phenotypic readout, Co-IP confirming interaction, epistasis via dual KO, multiple orthogonal methods\",\n      \"pmids\": [\"41738275\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V0C (the 16-kDa proteolipid c-subunit of the V0 domain of vacuolar H+-ATPase) is essential for V-ATPase complex assembly and proton pumping across organellar membranes, thereby acidifying lysosomes and endosomes to regulate autophagy-lysosome pathway flux, intracellular/extracellular pH, and neurotransmitter release; it also functions as a scaffold bridging SNARE proteins STX17 and VAMP8 to mediate autophagosome-lysosome fusion, directly binds and stabilizes HIF-1α (competing with VHL) in a reciprocal feedback loop, is ubiquitinated and degraded by the E3 ligase RNF182, interacts with HIV-1 Vpu to traffic tetherin into intracellular compartments, and its haploinsufficiency causes a neurodevelopmental/epilepsy syndrome in humans.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATP6V0C encodes the 16-kDa proteolipid c-subunit of the V0 sector of vacuolar H+-ATPase (V-ATPase), essential for complex assembly, proton translocation, and acidification of lysosomes, endosomes, and vacuoles, thereby governing autophagy-lysosome pathway flux, intracellular pH homeostasis, and neurotransmitter vesicle loading [PMID:2145283, PMID:24695574, PMID:16061667]. Beyond its canonical role in proton pumping, ATP6V0C serves as a scaffold that bridges the SNARE proteins STX17 and VAMP8 to promote autophagosome–lysosome fusion independently of lysosomal acidification, and it directly binds and stabilizes HIF-1α by competing with VHL, participating in a positive transcriptional feedback loop in which HIF-1α reciprocally induces ATP6V0C expression [PMID:38481802, PMID:17178925, PMID:41738275]. Heterozygous loss-of-function variants in ATP6V0C cause a neurodevelopmental syndrome with epilepsy, confirmed by impaired V-ATPase function in yeast complementation assays and seizure phenotypes in Drosophila and C. elegans disease models [PMID:36074901]. ATP6V0C is also exploited by HIV-1 Vpu to redirect tetherin into intracellular compartments, facilitating viral release [PMID:32291285].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Establishing that subunit c is indispensable for V-ATPase assembly and vacuolar function answered the foundational question of whether this small proteolipid is merely a structural repeat or a functional requirement for the holoenzyme.\",\n      \"evidence\": \"VMA3 gene disruption in S. cerevisiae with biochemical ATPase activity, vacuolar acidification, protein sorting, and endocytosis assays\",\n      \"pmids\": [\"2145283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian requirement not yet demonstrated\", \"Stoichiometry of c-subunit ring not defined\", \"No information on tissue-specific roles\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defining the transcriptional control of ATP6V0C by Sp1/Oct1 on a GC-rich, TATA-less promoter established how basal expression of this housekeeping subunit is maintained and can be pharmacologically modulated.\",\n      \"evidence\": \"In vivo footprinting, promoter-reporter mutagenesis, EMSA, and drug treatment in human cells\",\n      \"pmids\": [\"12133827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin-level regulation not addressed\", \"Tissue-specific transcription factors not explored\", \"TFEB regulation not yet identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that ATP6V0C knockdown impairs proton secretion, intracellular pH recovery, MMP-2 activity, and in vivo tumor growth linked V-ATPase c-subunit function to cancer cell invasion and the tumor microenvironment.\",\n      \"evidence\": \"siRNA knockdown in hepatocellular carcinoma cells with pH measurement, zymography, and xenograft model\",\n      \"pmids\": [\"16061667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether effect is specific to ATP6V0C versus other V-ATPase subunits\", \"Mechanism linking extracellular acidification to MMP activation not fully defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of a direct ATP6V0C–HIF-1α interaction that competes with VHL binding revealed an unexpected non-canonical role for the c-subunit in oxygen-sensing signaling, independent of proton pumping.\",\n      \"evidence\": \"Co-immunoprecipitation, N-terminal deletion mapping, confocal colocalization, and siRNA knockdown\",\n      \"pmids\": [\"17178925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab observation at the time\", \"Physiological context for nuclear translocation unclear\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that the E3 ligase RNF182 ubiquitinates ATP6V0C for proteasomal degradation established a post-translational regulatory axis controlling c-subunit abundance.\",\n      \"evidence\": \"Yeast two-hybrid confirmed by co-immunoprecipitation and in vitro ubiquitination assay\",\n      \"pmids\": [\"18298843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological consequence of RNF182-mediated degradation on V-ATPase activity not tested\", \"No in vivo confirmation\", \"Ubiquitination sites on ATP6V0C not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing that ATP6V0C depletion raises lysosomal pH and redirects sequestered chemotherapeutics to the nucleus in drug-resistant cells mechanistically explained V-ATPase's role in multidrug resistance.\",\n      \"evidence\": \"siRNA knockdown in MCF-7/ADR cells with intracellular drug distribution and cytotoxicity assays\",\n      \"pmids\": [\"19299075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of ATP6V0C versus whole V-ATPase not dissected\", \"Clinical relevance not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that ATP6V0C loss blocks autophagic flux at the lysosomal degradation step, with accumulation of α-synuclein and APP-CTFs, directly implicated the c-subunit in neurodegeneration-relevant proteostasis.\",\n      \"evidence\": \"siRNA knockdown in differentiated SH-SY5Y cells with LysoTracker, LC3-II flux assay, LC3/LAMP-1 colocalization\",\n      \"pmids\": [\"24695574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo neuronal validation lacking\", \"Whether partial loss mirrors disease conditions unknown\", \"No rescue experiment\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying ATP6V0C as a Vpu-binding partner that mediates tetherin sequestration into endo-lysosomes revealed how HIV-1 hijacks the V-ATPase c-subunit to counteract innate restriction.\",\n      \"evidence\": \"Yeast two-hybrid, siRNA knockdown, overexpression, HIV-1 release assay, and immunofluorescence colocalization\",\n      \"pmids\": [\"32291285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of Vpu–ATP6V0C interaction not resolved\", \"Relevance in primary T cells or in vivo not shown\", \"ATP6V0C'' paralog specificity mechanism unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cross-species functional validation of heterozygous ATP6V0C variants as causative for a neurodevelopmental/epilepsy syndrome established ATP6V0C haploinsufficiency as a Mendelian disease gene.\",\n      \"evidence\": \"Yeast complementation (LysoSensor, CaCl2 growth), Drosophila seizure assay, C. elegans variant phenotyping, in silico structural modelling\",\n      \"pmids\": [\"36074901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Patient iPSC-derived neuronal model not yet reported\", \"Genotype-phenotype correlation across variant types not fully resolved\", \"Whether seizures arise from impaired acidification, fusion, or both is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that TFEB transcriptionally activates ATP6V0C and that ATP6V0C scaffolds STX17–VAMP8 for autophagosome–lysosome fusion uncovered a second, acidification-independent function in membrane fusion.\",\n      \"evidence\": \"CUT&Run-qPCR, luciferase reporter, co-immunoprecipitation of ATP6V0C with STX17/VAMP8, siRNA flux assays\",\n      \"pmids\": [\"38481802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the scaffold function not defined\", \"Whether SNARE-bridging and proton-pumping roles are mutually exclusive or concurrent is unclear\", \"Single-lab finding awaiting independent replication\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Conditional alveolar-specific ATP6V0C knockout attenuating lung injury and epistasis with HIF-1α knockout validated the ATP6V0C–HIF-1α positive feedback loop in vivo, resolving the physiological relevance of the 2006 binding observation.\",\n      \"evidence\": \"AT2-specific Cre conditional KO mice, Co-IP in injured lung, RNA-seq, AAV-mediated overexpression in HIF-1α KO background, LPS-induced ALI model\",\n      \"pmids\": [\"41738275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the feedback loop operates in non-pulmonary tissues is untested\", \"Molecular determinants governing V-ATPase-dependent vs HIF-1α-dependent ATP6V0C functions not separated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"AAV2-mediated ATP6V0C overexpression promoting axon regeneration after optic nerve crush revealed a neuroprotective gain-of-function linked to enhanced lysosomal clearance under ER stress.\",\n      \"evidence\": \"AAV2 transgene in retinal ganglion cells, optic nerve crush model, axon regeneration and RGC survival quantification\",\n      \"pmids\": [\"42023031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting lysosomal acidification to axon regrowth signaling not delineated\", \"Long-term efficacy and functional recovery not assessed\", \"Single model system\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of ATP6V0C's dual role as a proton channel subunit and SNARE scaffold, whether its HIF-1α-stabilizing function is mechanistically separable from V-ATPase activity in vivo, and how disease-causing variants differentially impact acidification versus membrane fusion.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of mammalian ATP6V0C in the assembled V0 ring with bound SNAREs\", \"Separation-of-function mutants distinguishing proton pumping from scaffold activity not generated\", \"Genotype-phenotype studies in patient-derived neurons for the epilepsy syndrome are lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 5, 6, 7]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [5, 6, 8, 11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 10, 11]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 2, 5, 7]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 12]}\n    ],\n    \"complexes\": [\n      \"V-ATPase (V0 sector)\"\n    ],\n    \"partners\": [\n      \"HIF1A\",\n      \"STX17\",\n      \"VAMP8\",\n      \"RNF182\",\n      \"VPU\",\n      \"CERS2\",\n      \"ATP6V0A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}