{"gene":"ATP6V0C","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1990,"finding":"The VMA3 gene product (subunit c of vacuolar H+-ATPase, ortholog of ATP6V0C) is essential for vacuolar H+-ATPase activity and vacuolar acidification in vivo; deletion of VMA3 abolishes ATPase activity and the subunit c is indispensable for assembly of subunits a and b of the H+-ATPase complex. Loss of VMA3 also impairs vacuolar biogenesis, protein transport to the vacuole, and completely inhibits endocytosis.","method":"VMA3 gene disruption in S. cerevisiae, measurement of vacuolar ATPase activity, in vivo acidification assay, endocytosis assay with lucifer yellow CH, subunit assembly analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct genetic reconstitution with multiple orthogonal functional readouts in yeast ortholog","pmids":["2145283"],"is_preprint":false},{"year":2002,"finding":"The ATP6V0C promoter contains four GC boxes and an Oct1-binding site occupied by Sp1 and Oct1 in vivo. Cooperative binding of Sp1 and Oct1 to the promoter is required for transcriptional activation by the topoisomerase II inhibitor TAS-103, while cisplatin regulates ATP6L expression post-transcriptionally via mRNA stability. Induction of V-ATPase expression acts as an anti-apoptotic defense.","method":"Genomic cloning, in vivo footprint analysis, promoter-reporter assays, site-directed mutagenesis of Oct1 site, electrophoretic mobility shift assay (EMSA), RT-PCR for mRNA stability","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (footprint, mutagenesis, EMSA, reporter) in a single study","pmids":["12133827"],"is_preprint":false},{"year":2005,"finding":"Knockdown of ATP6L (ATP6V0C) using siRNA in highly metastatic hepatocellular carcinoma cells inhibits proton secretion, intracellular pH recovery from acidification, reduces MMP-2 expression and gelatinase activity, suppresses invasion in vitro, and dramatically reduces tumor growth and metastasis in vivo in a xenograft mouse model.","method":"DNA vector-based siRNA stable transfection, intracellular pH measurement, Matrigel invasion assay, gelatin zymography, nude mouse xenograft implantation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple orthogonal functional readouts in vitro and in vivo","pmids":["16061667"],"is_preprint":false},{"year":2006,"finding":"ATP6V0C directly interacts with HIF-1α through the N-terminal end (amino acids 1-16) of HIF-1α, competing with Von Hippel-Lindau protein for HIF-1α binding. ATP6V0C overexpression increases HIF-1α levels in a gene dose-dependent manner, and bafilomycin A1 stimulates this interaction and causes co-translocation of ATP6V0C with HIF-1α from the cytoplasm to the nucleus.","method":"ATP6V0C knockdown by siRNA, overexpression, co-immunoprecipitation, confocal immunofluorescence microscopy, HIF-1α domain mapping","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal co-IP and localization with functional readout (HIF-1α stabilization), single lab, multiple methods","pmids":["17178925"],"is_preprint":false},{"year":2008,"finding":"The E3 ubiquitin ligase RNF182 directly interacts with ATP6V0C (identified by yeast two-hybrid screening and confirmed by co-precipitation in vitro and in vivo) and targets ATP6V0C for degradation via the ubiquitin-proteasome pathway.","method":"Yeast two-hybrid screening, overexpression and co-precipitation (in vitro and in vivo), E3 ligase activity assay, proteasome degradation assay","journal":"Molecular neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid plus co-precipitation plus degradation assay, single lab","pmids":["18298843"],"is_preprint":false},{"year":2009,"finding":"Knockdown of ATP6L (ATP6V0C) in drug-resistant breast cancer cells (MCF-7/ADR) increases lysosomal pH and causes retention of anticancer drugs (doxorubicin, 5-fluorouracil, vincristine) in nuclei rather than sequestration in acidic lysosomes, sensitizing cells to chemotherapy. This identifies V-ATPase c subunit as a regulator of intracellular pH-dependent drug distribution.","method":"siRNA knockdown, qRT-PCR, Western blot, lysosomal pH measurement, drug distribution/nuclear retention assay, cytotoxicity assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — clean KD with mechanistic pH and drug-localization readouts, single lab","pmids":["19299075"],"is_preprint":false},{"year":2013,"finding":"In Candida albicans, VMA3 repression prevents V-ATPase assembly at the vacuolar membrane, reduces concanamycin A-sensitive ATPase activity and proton transport by >90%, alkalinizes the vacuolar lumen, impairs aspartyl protease and lipase secretion, and suppresses filamentation. V-ATPase-dependent filamentation defects are not rescued by overexpression of RIM8, MDS3, EFG1, CST20, or UME6, suggesting V-ATPase functions downstream or independently of these regulators.","method":"Conditional tetracycline-regulated promoter replacement, ATPase activity assay, proton transport assay, vacuolar pH measurement, vacuolar morphology analysis, secretion assays, genetic epistasis with filamentation regulators","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution of assembly defect, direct ATPase/transport assays, multiple orthogonal phenotypic readouts, genetic epistasis","pmids":["23913543"],"is_preprint":false},{"year":2014,"finding":"ATP6V0C is the bafilomycin A1-binding subunit of vacuolar ATPase in neuronal cells. Knockdown of ATP6V0C reduces lysosomal acidity (LysoTracker staining), increases basal LC3-II levels, α-synuclein high molecular weight species, and APP C-terminal fragments, inhibits autophagic flux, and reduces neurite length. Enhanced LC3/LAMP-1 co-localization indicates the autophagic flux block occurs at the lysosomal degradation step, not at vesicular fusion.","method":"siRNA knockdown in differentiated SH-SY5Y cells, quantitative RT-PCR, LysoTracker Red staining, immunofluorescence (LC3/LAMP-1 co-localization), Western blot for LC3-II/α-synuclein/APP-CTF, neurite length measurement, propidium iodide viability assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple orthogonal mechanistic readouts (lysosomal pH, autophagic substrates, flux, morphology), single lab","pmids":["24695574"],"is_preprint":false},{"year":2017,"finding":"Silencing of ATP6V0C in highly metastatic prostate cancer cells inhibits V-ATPase activity (~5-fold), decreases extracellular hydrogen ion concentration, reduces activation of secreted MMP-9 (~3.6-fold), and inhibits cell migration and invasion. ATP6V0C co-localizes with LASS2/TMSG1 at the plasma membrane, and silencing ATP6V0C reduces LASS2/TMSG1 expression, suggesting a feedback regulatory relationship. The invasion suppression is not LASS2/TMSG1-dependent.","method":"siRNA knockdown, V-ATPase activity assay, extracellular pH measurement, gelatin zymography (MMP-9 activation), Matrigel invasion assay, wound migration assay, confocal immunofluorescence co-localization","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple functional readouts with enzymatic assay, single lab","pmids":["29138865"],"is_preprint":false},{"year":2020,"finding":"ATP6V0C interacts with HIV-1 accessory protein Vpu (identified by yeast two-hybrid screening). ATP6V0C depletion by knockdown impairs Vpu-mediated tetherin degradation and results in defective HIV-1 release. ATP6V0C overexpression stabilizes tetherin expression and sequesters it in CD63/LAMP1-positive intracellular compartments. This effect is specific to ATP6V0C, as overexpression of ATP6V0C″ (another V-ATPase subunit) had no effect on tetherin.","method":"Yeast two-hybrid screening, siRNA knockdown in HeLa cells, overexpression, immunofluorescence localization, HIV-1 release assay, Western blot for tetherin","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid plus KD and OE with functional HIV release readout, single lab, multiple methods","pmids":["32291285"],"is_preprint":false},{"year":2023,"finding":"Heterozygous point variants in ATP6V0C impair V-ATPase function: functional analyses in S. cerevisiae showed reduced LysoSensor fluorescence (decreased vacuolar acidification) and reduced growth in CaCl2-containing media. In silico modelling indicated variants interfere with ATP6V0C–ATP6V0A subunit interactions during ATP hydrolysis. Knockdown of ATP6V0C in Drosophila increased duration of seizure-like behaviour, and expression of patient variants in C. elegans led to reduced growth, motor dysfunction, and reduced lifespan.","method":"Patient variant identification, yeast functional complementation assay (LysoSensor fluorescence, calcium sensitivity growth assay), in silico structural modelling, Drosophila knockdown seizure assay, C. elegans variant expression with behavioral/viability assays","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple model organism functional assays with orthogonal readouts across three species, combined with structural modelling","pmids":["36074901"],"is_preprint":false},{"year":2024,"finding":"TFEB directly binds the ATP6V0C promoter at a specific site to transcriptionally activate ATP6V0C expression, as demonstrated by CUT&Run-qPCR and luciferase reporter assay. ATP6V0C acts as a scaffold protein that mediates autophagosome-lysosome fusion by bridging with STX17 and VAMP8 (SNARE complex), independently of its role in lysosomal acidification/degradation. Loss of TFEB in renal fibrosis reduces ATP6V0C expression, impairing autophagic flux and causing tubular cell G2/M arrest.","method":"RNA-seq, CUT&Tag, CUT&Run-qPCR, luciferase reporter assay, co-immunoprecipitation (ATP6V0C with STX17 and VAMP8), AAV9-TFEB overexpression in UUO mouse model, autophagic flux assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP for SNARE complex, direct promoter binding assays, in vivo model, single lab with multiple methods","pmids":["38481802"],"is_preprint":false},{"year":2026,"finding":"ATP6V0C and HIF-1α form a positive feedback loop in acute lung injury: ATP6V0C interacts with HIF-1α (confirmed by co-immunoprecipitation), HIF-1α transcriptionally regulates ATP6V0C expression, and ATP6V0C in turn promotes HIF-1α upregulation. Alveolar-specific ATP6V0C knockout mice show attenuated LPS-induced acute lung injury (reduced inflammation and epithelial apoptosis), and overexpression of ATP6V0C exacerbates ALI in a HIF-1α-dependent manner.","method":"Alveolar-specific conditional knockout (Atp6v0cAT2-KO), HIF-1α knockout (Hif1aAT2-KO), co-immunoprecipitation, transcriptomic analysis, AAV-mediated overexpression, LPS-induced ALI model","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO and OE in vivo with co-IP confirmation and transcriptomic validation, multiple genetic models in single study","pmids":["41738275"],"is_preprint":false},{"year":2026,"finding":"In T. spiralis, the HRG-1/ATP6V0C complex is essential for heme acquisition by the parasite. Ts-ATP6V0C interacts with Ts-HRG-1 to form a functional complex required for heme transport. RNAi knockdown of Ts-ATP6V0C or inhibition by bafilomycin A1 impairs heme uptake, causes developmental arrest, and reduces larval burden in mouse hosts.","method":"Protein-protein interaction studies (HRG-1/ATP6V0C complex), RNAi knockdown of Ts-ATP6V0C, bafilomycin A1 inhibition, heme uptake assay, in vivo mouse infection model","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNAi and pharmacological inhibition with functional heme uptake readout in parasite ortholog, single study","pmids":["41838682"],"is_preprint":false},{"year":2026,"finding":"Atp6v0c transgene expression in retinal ganglion cells (via AAV2 intravitreal injection) promotes RGC survival and long-distance axon regeneration after optic nerve crush, comparable in efficacy to targeting Pten and Klf9. This identifies ATP6V0C as an axon regeneration-promoting factor, likely through support of lysosomal acidification and degradation of misfolded proteins in response to ER stress in injured neurons.","method":"AAV2-mediated Atp6v0c transgene expression, optic nerve crush model in rodents, RGC survival quantification, axon regeneration measurement","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean in vivo gene therapy experiment with defined neuronal phenotype, single study, proposed mechanism not directly tested","pmids":["42023031"],"is_preprint":false}],"current_model":"ATP6V0C encodes the 16 kDa proteolipid c-subunit of the V0 domain of vacuolar H+-ATPase; it is essential for V-ATPase complex assembly (including subunits a and b), proton pumping across membranes to acidify lysosomes/vacuoles, and autophagic flux (acting as a scaffold bridging the SNARE proteins STX17 and VAMP8 for autophagosome-lysosome fusion); it directly interacts with HIF-1α (competing with VHL) to form a positive feedback loop regulating HIF-1α stability and nuclear translocation; it is targeted for ubiquitin-proteasome degradation by the E3 ligase RNF182; its promoter is transcriptionally activated by cooperative Sp1/Oct1 binding and by TFEB; and its activity regulates tumor invasion by controlling extracellular acidification and MMP activation, drug resistance through lysosomal pH-dependent drug sequestration, and neuronal survival/axon regeneration through lysosomal quality control."},"narrative":{"mechanistic_narrative":"ATP6V0C encodes the proteolipid c-subunit of the V0 membrane domain of the vacuolar H+-ATPase, where it is indispensable for assembly of the complex (including the a and b subunits) and for the proton pumping that acidifies the vacuolar/lysosomal lumen, supporting vacuolar biogenesis, protein transport, and endocytosis [PMID:2145283, PMID:23913543]. It is the bafilomycin A1-binding subunit of the neuronal V-ATPase, and its loss raises lysosomal pH, blocks autophagic flux at the lysosomal degradation step, and causes accumulation of α-synuclein species and APP C-terminal fragments [PMID:24695574]; beyond this acidification role, ATP6V0C acts as a scaffold that bridges the SNARE proteins STX17 and VAMP8 to mediate autophagosome-lysosome fusion, with its expression directly driven by TFEB [PMID:38481802]. Through control of intracellular and extracellular pH it governs MMP-2/MMP-9 activation and tumor invasion/metastasis [PMID:16061667, PMID:29138865] and lysosomal pH-dependent sequestration of chemotherapeutic drugs [PMID:19299075]. ATP6V0C directly binds HIF-1α at its N-terminus, competing with VHL to stabilize HIF-1α and form a positive feedback loop that drives pathology in acute lung injury [PMID:17178925, PMID:41738275], and its abundance is restrained by RNF182-mediated ubiquitin-proteasome degradation [PMID:18298843]. Heterozygous ATP6V0C variants that impair V-ATPase function cause a human neurodevelopmental/epileptic disorder, modeled across yeast, Drosophila, and C. elegans [PMID:36074901]. It is also hijacked by pathogens, interacting with HIV-1 Vpu to promote tetherin degradation [PMID:32291285] and forming an HRG-1 complex required for parasite heme acquisition [PMID:41838682], and transgenic expression promotes retinal ganglion cell survival and axon regeneration [PMID:42023031].","teleology":[{"year":1990,"claim":"Established that the c-subunit is not merely structural but genetically essential for V-ATPase activity, complex assembly, and downstream acidification-dependent cell biology.","evidence":"VMA3 gene disruption in S. cerevisiae with ATPase activity, in vivo acidification, endocytosis, and subunit-assembly assays","pmids":["2145283"],"confidence":"High","gaps":["Done in yeast ortholog; human subunit assembly contribution inferred","Atomic mechanism of how c-subunit nucleates a/b assembly not resolved"]},{"year":2002,"claim":"Defined how ATP6V0C transcription is controlled, identifying cooperative Sp1/Oct1 promoter occupancy as the basis for drug-induced, anti-apoptotic V-ATPase induction.","evidence":"Genomic cloning, in vivo footprinting, EMSA, promoter-reporter and site-directed mutagenesis assays","pmids":["12133827"],"confidence":"High","gaps":["Signaling upstream of Sp1/Oct1 recruitment not mapped","Generality beyond topoisomerase-inhibitor stress unclear"]},{"year":2005,"claim":"Connected ATP6V0C proton secretion to a malignant phenotype, showing it controls intracellular pH recovery, MMP-2 activation, and metastasis.","evidence":"Stable siRNA knockdown in hepatocellular carcinoma, pH measurement, zymography, Matrigel invasion, and xenograft assays","pmids":["16061667"],"confidence":"High","gaps":["Mechanistic link between pH change and MMP-2 transcription/activation not dissected","Whether plasma-membrane vs lysosomal V-ATPase pool drives invasion unresolved"]},{"year":2006,"claim":"Revealed a non-canonical role: direct binding to HIF-1α competing with VHL to stabilize and co-translocate HIF-1α, linking V-ATPase to hypoxia signaling.","evidence":"siRNA, overexpression, reciprocal co-IP, confocal microscopy, and HIF-1α domain mapping","pmids":["17178925"],"confidence":"Medium","gaps":["Single lab; structural basis of the ATP6V0C–HIF-1α interface undefined","How a membrane proteolipid reaches nuclear HIF-1α mechanistically unclear"]},{"year":2008,"claim":"Identified post-translational control of ATP6V0C abundance through RNF182-mediated ubiquitination and proteasomal degradation.","evidence":"Yeast two-hybrid screen, in vitro/in vivo co-precipitation, E3 ligase and proteasome degradation assays","pmids":["18298843"],"confidence":"Medium","gaps":["Ubiquitination sites on ATP6V0C not mapped","Physiological conditions triggering RNF182-dependent turnover unknown"]},{"year":2009,"claim":"Demonstrated ATP6V0C governs chemoresistance by setting lysosomal pH that sequesters drugs away from the nucleus.","evidence":"siRNA knockdown in MCF-7/ADR cells, lysosomal pH and drug-distribution/cytotoxicity assays","pmids":["19299075"],"confidence":"Medium","gaps":["Single lab; in vivo relevance to resistant tumors not tested","Quantitative contribution vs other resistance mechanisms unclear"]},{"year":2013,"claim":"Confirmed conserved essentiality of the c-subunit for V-ATPase assembly, proton transport, and virulence-associated secretion/filamentation in a fungal pathogen.","evidence":"Tetracycline-regulated VMA3 repression in C. albicans with ATPase, transport, pH, secretion, and epistasis assays","pmids":["23913543"],"confidence":"High","gaps":["Direct molecular link between V-ATPase and filamentation regulators not established","Fungal-specific; human counterpart of secretion phenotype untested"]},{"year":2014,"claim":"Placed ATP6V0C at the lysosomal degradation step of autophagy in neurons, showing its loss impairs flux and accumulates neurodegeneration-associated substrates.","evidence":"siRNA in differentiated SH-SY5Y cells, LysoTracker, LC3/LAMP-1 co-localization, substrate Western blots, neurite measurement","pmids":["24695574"],"confidence":"High","gaps":["Distinguished flux block from fusion defect here but mechanism of substrate selectivity unclear","Causality for in vivo neurodegeneration not addressed"]},{"year":2017,"claim":"Extended the invasion role to prostate cancer and linked ATP6V0C to plasma-membrane LASS2/TMSG1 in a feedback relationship.","evidence":"siRNA, V-ATPase activity, extracellular pH, MMP-9 zymography, invasion/migration, and co-localization assays","pmids":["29138865"],"confidence":"Medium","gaps":["Nature of ATP6V0C–LASS2/TMSG1 regulation not mechanistically defined","Invasion effect shown LASS2-independent but alternate effector unidentified"]},{"year":2020,"claim":"Showed pathogen exploitation: ATP6V0C interacts with HIV-1 Vpu and is required for Vpu-mediated tetherin degradation and viral release.","evidence":"Yeast two-hybrid, siRNA in HeLa, overexpression, immunofluorescence, HIV-1 release and tetherin Western assays","pmids":["32291285"],"confidence":"Medium","gaps":["Whether interaction requires assembled V-ATPase or free c-subunit unclear","Trafficking step where tetherin is routed for degradation not pinpointed"]},{"year":2023,"claim":"Established ATP6V0C as a human disease gene, with heterozygous variants impairing acidification and producing neurological phenotypes across model species.","evidence":"Patient variants tested by yeast complementation, in silico modelling, Drosophila knockdown seizure, and C. elegans variant-expression assays","pmids":["36074901"],"confidence":"High","gaps":["Variant effects on the human complex not directly measured","Mechanism linking acidification deficit to seizures undefined"]},{"year":2024,"claim":"Separated ATP6V0C's scaffolding function from its pump function, showing it bridges STX17/VAMP8 for autophagosome-lysosome fusion and is a direct TFEB target.","evidence":"CUT&Run-qPCR, luciferase reporter, co-IP with STX17/VAMP8, AAV9-TFEB in UUO mouse model, autophagic flux assays","pmids":["38481802"],"confidence":"Medium","gaps":["Structural basis of SNARE bridging unresolved","How scaffold and pump roles are partitioned within the same molecule unclear"]},{"year":2026,"claim":"Confirmed in vivo the ATP6V0C–HIF-1α positive feedback loop as a driver of acute lung injury.","evidence":"Alveolar-specific Atp6v0c and Hif1a conditional knockouts, co-IP, transcriptomics, AAV overexpression in LPS-induced ALI model","pmids":["41738275"],"confidence":"High","gaps":["Direct transcription-factor mechanism by which HIF-1α induces ATP6V0C not detailed","Whether feedback operates in other inflammatory tissues untested"]},{"year":2026,"claim":"Identified an additional pathogen-cofactor role, with the parasite ATP6V0C–HRG-1 complex required for heme acquisition and development.","evidence":"HRG-1/ATP6V0C interaction studies, RNAi, bafilomycin inhibition, heme uptake and mouse infection assays in T. spiralis","pmids":["41838682"],"confidence":"Medium","gaps":["Whether heme transport depends on acidification or direct complex function unclear","Parasite ortholog; human heme-transport relevance untested"]},{"year":2026,"claim":"Demonstrated therapeutic potential, with ATP6V0C overexpression promoting RGC survival and axon regeneration after optic nerve injury.","evidence":"AAV2 Atp6v0c transgene, optic nerve crush model, RGC survival and axon regeneration quantification","pmids":["42023031"],"confidence":"Medium","gaps":["Proposed lysosomal/ER-stress mechanism not directly tested","Single study; dependence on V-ATPase activity vs scaffold role unresolved"]},{"year":null,"claim":"How a single proteolipid subunit partitions between proton-pumping, SNARE-scaffolding, HIF-1α-binding, and pathogen-cofactor functions, and the structural basis of its non-canonical interactions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ATP6V0C bound to HIF-1α or STX17/VAMP8","Whether moonlighting functions require assembled V-ATPase or free subunit unknown","Mechanism connecting acidification loss to specific neurological phenotypes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,6,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[5,7,9]},{"term_id":"GO:0005773","term_label":"vacuole","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","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":[7,11]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,12]}],"complexes":["vacuolar H+-ATPase (V0 domain)"],"partners":["HIF1A","STX17","VAMP8","RNF182","ATP6V0A","LASS2/TMSG1","HRG-1"],"other_free_text":[]}},"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. 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Loss of VMA3 also impairs vacuolar biogenesis, protein transport to the vacuole, and completely inhibits endocytosis.\",\n      \"method\": \"VMA3 gene disruption in S. cerevisiae, measurement of vacuolar ATPase activity, in vivo acidification assay, endocytosis assay with lucifer yellow CH, subunit assembly analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct genetic reconstitution with multiple orthogonal functional readouts in yeast ortholog\",\n      \"pmids\": [\"2145283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The ATP6V0C promoter contains four GC boxes and an Oct1-binding site occupied by Sp1 and Oct1 in vivo. Cooperative binding of Sp1 and Oct1 to the promoter is required for transcriptional activation by the topoisomerase II inhibitor TAS-103, while cisplatin regulates ATP6L expression post-transcriptionally via mRNA stability. Induction of V-ATPase expression acts as an anti-apoptotic defense.\",\n      \"method\": \"Genomic cloning, in vivo footprint analysis, promoter-reporter assays, site-directed mutagenesis of Oct1 site, electrophoretic mobility shift assay (EMSA), RT-PCR for mRNA stability\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (footprint, mutagenesis, EMSA, reporter) in a single study\",\n      \"pmids\": [\"12133827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Knockdown of ATP6L (ATP6V0C) using siRNA in highly metastatic hepatocellular carcinoma cells inhibits proton secretion, intracellular pH recovery from acidification, reduces MMP-2 expression and gelatinase activity, suppresses invasion in vitro, and dramatically reduces tumor growth and metastasis in vivo in a xenograft mouse model.\",\n      \"method\": \"DNA vector-based siRNA stable transfection, intracellular pH measurement, Matrigel invasion assay, gelatin zymography, nude mouse xenograft implantation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple orthogonal functional readouts in vitro and in vivo\",\n      \"pmids\": [\"16061667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ATP6V0C directly interacts with HIF-1α through the N-terminal end (amino acids 1-16) of HIF-1α, competing with Von Hippel-Lindau protein for HIF-1α binding. ATP6V0C overexpression increases HIF-1α levels in a gene dose-dependent manner, and bafilomycin A1 stimulates this interaction and causes co-translocation of ATP6V0C with HIF-1α from the cytoplasm to the nucleus.\",\n      \"method\": \"ATP6V0C knockdown by siRNA, overexpression, co-immunoprecipitation, confocal immunofluorescence microscopy, HIF-1α domain mapping\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal co-IP and localization with functional readout (HIF-1α stabilization), single lab, multiple methods\",\n      \"pmids\": [\"17178925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The E3 ubiquitin ligase RNF182 directly interacts with ATP6V0C (identified by yeast two-hybrid screening and confirmed by co-precipitation in vitro and in vivo) and targets ATP6V0C for degradation via the ubiquitin-proteasome pathway.\",\n      \"method\": \"Yeast two-hybrid screening, overexpression and co-precipitation (in vitro and in vivo), E3 ligase activity assay, proteasome degradation assay\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid plus co-precipitation plus degradation assay, single lab\",\n      \"pmids\": [\"18298843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Knockdown of ATP6L (ATP6V0C) in drug-resistant breast cancer cells (MCF-7/ADR) increases lysosomal pH and causes retention of anticancer drugs (doxorubicin, 5-fluorouracil, vincristine) in nuclei rather than sequestration in acidic lysosomes, sensitizing cells to chemotherapy. This identifies V-ATPase c subunit as a regulator of intracellular pH-dependent drug distribution.\",\n      \"method\": \"siRNA knockdown, qRT-PCR, Western blot, lysosomal pH measurement, drug distribution/nuclear retention assay, cytotoxicity assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — clean KD with mechanistic pH and drug-localization readouts, single lab\",\n      \"pmids\": [\"19299075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Candida albicans, VMA3 repression prevents V-ATPase assembly at the vacuolar membrane, reduces concanamycin A-sensitive ATPase activity and proton transport by >90%, alkalinizes the vacuolar lumen, impairs aspartyl protease and lipase secretion, and suppresses filamentation. V-ATPase-dependent filamentation defects are not rescued by overexpression of RIM8, MDS3, EFG1, CST20, or UME6, suggesting V-ATPase functions downstream or independently of these regulators.\",\n      \"method\": \"Conditional tetracycline-regulated promoter replacement, ATPase activity assay, proton transport assay, vacuolar pH measurement, vacuolar morphology analysis, secretion assays, genetic epistasis with filamentation regulators\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution of assembly defect, direct ATPase/transport assays, multiple orthogonal phenotypic readouts, genetic epistasis\",\n      \"pmids\": [\"23913543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ATP6V0C is the bafilomycin A1-binding subunit of vacuolar ATPase in neuronal cells. Knockdown of ATP6V0C reduces lysosomal acidity (LysoTracker staining), increases basal LC3-II levels, α-synuclein high molecular weight species, and APP C-terminal fragments, inhibits autophagic flux, and reduces neurite length. Enhanced LC3/LAMP-1 co-localization indicates the autophagic flux block occurs at the lysosomal degradation step, not at vesicular fusion.\",\n      \"method\": \"siRNA knockdown in differentiated SH-SY5Y cells, quantitative RT-PCR, LysoTracker Red staining, immunofluorescence (LC3/LAMP-1 co-localization), Western blot for LC3-II/α-synuclein/APP-CTF, neurite length measurement, propidium iodide viability assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple orthogonal mechanistic readouts (lysosomal pH, autophagic substrates, flux, morphology), single lab\",\n      \"pmids\": [\"24695574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Silencing of ATP6V0C in highly metastatic prostate cancer cells inhibits V-ATPase activity (~5-fold), decreases extracellular hydrogen ion concentration, reduces activation of secreted MMP-9 (~3.6-fold), and inhibits cell migration and invasion. ATP6V0C co-localizes with LASS2/TMSG1 at the plasma membrane, and silencing ATP6V0C reduces LASS2/TMSG1 expression, suggesting a feedback regulatory relationship. The invasion suppression is not LASS2/TMSG1-dependent.\",\n      \"method\": \"siRNA knockdown, V-ATPase activity assay, extracellular pH measurement, gelatin zymography (MMP-9 activation), Matrigel invasion assay, wound migration assay, confocal immunofluorescence co-localization\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple functional readouts with enzymatic assay, single lab\",\n      \"pmids\": [\"29138865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATP6V0C interacts with HIV-1 accessory protein Vpu (identified by yeast two-hybrid screening). ATP6V0C depletion by knockdown impairs Vpu-mediated tetherin degradation and results in defective HIV-1 release. ATP6V0C overexpression stabilizes tetherin expression and sequesters it in CD63/LAMP1-positive intracellular compartments. This effect is specific to ATP6V0C, as overexpression of ATP6V0C″ (another V-ATPase subunit) had no effect on tetherin.\",\n      \"method\": \"Yeast two-hybrid screening, siRNA knockdown in HeLa cells, overexpression, immunofluorescence localization, HIV-1 release assay, Western blot for tetherin\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid plus KD and OE with functional HIV release readout, single lab, multiple methods\",\n      \"pmids\": [\"32291285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Heterozygous point variants in ATP6V0C impair V-ATPase function: functional analyses in S. cerevisiae showed reduced LysoSensor fluorescence (decreased vacuolar acidification) and reduced growth in CaCl2-containing media. In silico modelling indicated variants interfere with ATP6V0C–ATP6V0A subunit interactions during ATP hydrolysis. Knockdown of ATP6V0C in Drosophila increased duration of seizure-like behaviour, and expression of patient variants in C. elegans led to reduced growth, motor dysfunction, and reduced lifespan.\",\n      \"method\": \"Patient variant identification, yeast functional complementation assay (LysoSensor fluorescence, calcium sensitivity growth assay), in silico structural modelling, Drosophila knockdown seizure assay, C. elegans variant expression with behavioral/viability assays\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple model organism functional assays with orthogonal readouts across three species, combined with structural modelling\",\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, as demonstrated by CUT&Run-qPCR and luciferase reporter assay. ATP6V0C acts as a scaffold protein that mediates autophagosome-lysosome fusion by bridging with STX17 and VAMP8 (SNARE complex), independently of its role in lysosomal acidification/degradation. Loss of TFEB in renal fibrosis reduces ATP6V0C expression, impairing autophagic flux and causing tubular cell G2/M arrest.\",\n      \"method\": \"RNA-seq, CUT&Tag, CUT&Run-qPCR, luciferase reporter assay, co-immunoprecipitation (ATP6V0C with STX17 and VAMP8), AAV9-TFEB overexpression in UUO mouse model, autophagic flux assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP for SNARE complex, direct promoter binding assays, in vivo model, single lab with multiple methods\",\n      \"pmids\": [\"38481802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATP6V0C and HIF-1α form a positive feedback loop in acute lung injury: ATP6V0C interacts with HIF-1α (confirmed by co-immunoprecipitation), HIF-1α transcriptionally regulates ATP6V0C expression, and ATP6V0C in turn promotes HIF-1α upregulation. Alveolar-specific ATP6V0C knockout mice show attenuated LPS-induced acute lung injury (reduced inflammation and epithelial apoptosis), and overexpression of ATP6V0C exacerbates ALI in a HIF-1α-dependent manner.\",\n      \"method\": \"Alveolar-specific conditional knockout (Atp6v0cAT2-KO), HIF-1α knockout (Hif1aAT2-KO), co-immunoprecipitation, transcriptomic analysis, AAV-mediated overexpression, LPS-induced ALI model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO and OE in vivo with co-IP confirmation and transcriptomic validation, multiple genetic models in single study\",\n      \"pmids\": [\"41738275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In T. spiralis, the HRG-1/ATP6V0C complex is essential for heme acquisition by the parasite. Ts-ATP6V0C interacts with Ts-HRG-1 to form a functional complex required for heme transport. RNAi knockdown of Ts-ATP6V0C or inhibition by bafilomycin A1 impairs heme uptake, causes developmental arrest, and reduces larval burden in mouse hosts.\",\n      \"method\": \"Protein-protein interaction studies (HRG-1/ATP6V0C complex), RNAi knockdown of Ts-ATP6V0C, bafilomycin A1 inhibition, heme uptake assay, in vivo mouse infection model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNAi and pharmacological inhibition with functional heme uptake readout in parasite ortholog, single study\",\n      \"pmids\": [\"41838682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Atp6v0c transgene expression in retinal ganglion cells (via AAV2 intravitreal injection) promotes RGC survival and long-distance axon regeneration after optic nerve crush, comparable in efficacy to targeting Pten and Klf9. This identifies ATP6V0C as an axon regeneration-promoting factor, likely through support of lysosomal acidification and degradation of misfolded proteins in response to ER stress in injured neurons.\",\n      \"method\": \"AAV2-mediated Atp6v0c transgene expression, optic nerve crush model in rodents, RGC survival quantification, axon regeneration measurement\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean in vivo gene therapy experiment with defined neuronal phenotype, single study, proposed mechanism not directly tested\",\n      \"pmids\": [\"42023031\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V0C encodes the 16 kDa proteolipid c-subunit of the V0 domain of vacuolar H+-ATPase; it is essential for V-ATPase complex assembly (including subunits a and b), proton pumping across membranes to acidify lysosomes/vacuoles, and autophagic flux (acting as a scaffold bridging the SNARE proteins STX17 and VAMP8 for autophagosome-lysosome fusion); it directly interacts with HIF-1α (competing with VHL) to form a positive feedback loop regulating HIF-1α stability and nuclear translocation; it is targeted for ubiquitin-proteasome degradation by the E3 ligase RNF182; its promoter is transcriptionally activated by cooperative Sp1/Oct1 binding and by TFEB; and its activity regulates tumor invasion by controlling extracellular acidification and MMP activation, drug resistance through lysosomal pH-dependent drug sequestration, and neuronal survival/axon regeneration through lysosomal quality control.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATP6V0C encodes the proteolipid c-subunit of the V0 membrane domain of the vacuolar H+-ATPase, where it is indispensable for assembly of the complex (including the a and b subunits) and for the proton pumping that acidifies the vacuolar/lysosomal lumen, supporting vacuolar biogenesis, protein transport, and endocytosis [#0, #6]. It is the bafilomycin A1-binding subunit of the neuronal V-ATPase, and its loss raises lysosomal pH, blocks autophagic flux at the lysosomal degradation step, and causes accumulation of \\u03b1-synuclein species and APP C-terminal fragments [#7]; beyond this acidification role, ATP6V0C acts as a scaffold that bridges the SNARE proteins STX17 and VAMP8 to mediate autophagosome-lysosome fusion, with its expression directly driven by TFEB [#11]. Through control of intracellular and extracellular pH it governs MMP-2/MMP-9 activation and tumor invasion/metastasis [#2, #8] and lysosomal pH-dependent sequestration of chemotherapeutic drugs [#5]. ATP6V0C directly binds HIF-1\\u03b1 at its N-terminus, competing with VHL to stabilize HIF-1\\u03b1 and form a positive feedback loop that drives pathology in acute lung injury [#3, #12], and its abundance is restrained by RNF182-mediated ubiquitin-proteasome degradation [#4]. Heterozygous ATP6V0C variants that impair V-ATPase function cause a human neurodevelopmental/epileptic disorder, modeled across yeast, Drosophila, and C. elegans [#10]. It is also hijacked by pathogens, interacting with HIV-1 Vpu to promote tetherin degradation [#9] and forming an HRG-1 complex required for parasite heme acquisition [#13], and transgenic expression promotes retinal ganglion cell survival and axon regeneration [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that the c-subunit is not merely structural but genetically essential for V-ATPase activity, complex assembly, and downstream acidification-dependent cell biology.\",\n      \"evidence\": \"VMA3 gene disruption in S. cerevisiae with ATPase activity, in vivo acidification, endocytosis, and subunit-assembly assays\",\n      \"pmids\": [\"2145283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Done in yeast ortholog; human subunit assembly contribution inferred\", \"Atomic mechanism of how c-subunit nucleates a/b assembly not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined how ATP6V0C transcription is controlled, identifying cooperative Sp1/Oct1 promoter occupancy as the basis for drug-induced, anti-apoptotic V-ATPase induction.\",\n      \"evidence\": \"Genomic cloning, in vivo footprinting, EMSA, promoter-reporter and site-directed mutagenesis assays\",\n      \"pmids\": [\"12133827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling upstream of Sp1/Oct1 recruitment not mapped\", \"Generality beyond topoisomerase-inhibitor stress unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected ATP6V0C proton secretion to a malignant phenotype, showing it controls intracellular pH recovery, MMP-2 activation, and metastasis.\",\n      \"evidence\": \"Stable siRNA knockdown in hepatocellular carcinoma, pH measurement, zymography, Matrigel invasion, and xenograft assays\",\n      \"pmids\": [\"16061667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between pH change and MMP-2 transcription/activation not dissected\", \"Whether plasma-membrane vs lysosomal V-ATPase pool drives invasion unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a non-canonical role: direct binding to HIF-1\\u03b1 competing with VHL to stabilize and co-translocate HIF-1\\u03b1, linking V-ATPase to hypoxia signaling.\",\n      \"evidence\": \"siRNA, overexpression, reciprocal co-IP, confocal microscopy, and HIF-1\\u03b1 domain mapping\",\n      \"pmids\": [\"17178925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; structural basis of the ATP6V0C\\u2013HIF-1\\u03b1 interface undefined\", \"How a membrane proteolipid reaches nuclear HIF-1\\u03b1 mechanistically unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified post-translational control of ATP6V0C abundance through RNF182-mediated ubiquitination and proteasomal degradation.\",\n      \"evidence\": \"Yeast two-hybrid screen, in vitro/in vivo co-precipitation, E3 ligase and proteasome degradation assays\",\n      \"pmids\": [\"18298843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites on ATP6V0C not mapped\", \"Physiological conditions triggering RNF182-dependent turnover unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated ATP6V0C governs chemoresistance by setting lysosomal pH that sequesters drugs away from the nucleus.\",\n      \"evidence\": \"siRNA knockdown in MCF-7/ADR cells, lysosomal pH and drug-distribution/cytotoxicity assays\",\n      \"pmids\": [\"19299075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; in vivo relevance to resistant tumors not tested\", \"Quantitative contribution vs other resistance mechanisms unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Confirmed conserved essentiality of the c-subunit for V-ATPase assembly, proton transport, and virulence-associated secretion/filamentation in a fungal pathogen.\",\n      \"evidence\": \"Tetracycline-regulated VMA3 repression in C. albicans with ATPase, transport, pH, secretion, and epistasis assays\",\n      \"pmids\": [\"23913543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between V-ATPase and filamentation regulators not established\", \"Fungal-specific; human counterpart of secretion phenotype untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed ATP6V0C at the lysosomal degradation step of autophagy in neurons, showing its loss impairs flux and accumulates neurodegeneration-associated substrates.\",\n      \"evidence\": \"siRNA in differentiated SH-SY5Y cells, LysoTracker, LC3/LAMP-1 co-localization, substrate Western blots, neurite measurement\",\n      \"pmids\": [\"24695574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinguished flux block from fusion defect here but mechanism of substrate selectivity unclear\", \"Causality for in vivo neurodegeneration not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the invasion role to prostate cancer and linked ATP6V0C to plasma-membrane LASS2/TMSG1 in a feedback relationship.\",\n      \"evidence\": \"siRNA, V-ATPase activity, extracellular pH, MMP-9 zymography, invasion/migration, and co-localization assays\",\n      \"pmids\": [\"29138865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nature of ATP6V0C\\u2013LASS2/TMSG1 regulation not mechanistically defined\", \"Invasion effect shown LASS2-independent but alternate effector unidentified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed pathogen exploitation: ATP6V0C interacts with HIV-1 Vpu and is required for Vpu-mediated tetherin degradation and viral release.\",\n      \"evidence\": \"Yeast two-hybrid, siRNA in HeLa, overexpression, immunofluorescence, HIV-1 release and tetherin Western assays\",\n      \"pmids\": [\"32291285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether interaction requires assembled V-ATPase or free c-subunit unclear\", \"Trafficking step where tetherin is routed for degradation not pinpointed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established ATP6V0C as a human disease gene, with heterozygous variants impairing acidification and producing neurological phenotypes across model species.\",\n      \"evidence\": \"Patient variants tested by yeast complementation, in silico modelling, Drosophila knockdown seizure, and C. elegans variant-expression assays\",\n      \"pmids\": [\"36074901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Variant effects on the human complex not directly measured\", \"Mechanism linking acidification deficit to seizures undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Separated ATP6V0C's scaffolding function from its pump function, showing it bridges STX17/VAMP8 for autophagosome-lysosome fusion and is a direct TFEB target.\",\n      \"evidence\": \"CUT&Run-qPCR, luciferase reporter, co-IP with STX17/VAMP8, AAV9-TFEB in UUO mouse model, autophagic flux assays\",\n      \"pmids\": [\"38481802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of SNARE bridging unresolved\", \"How scaffold and pump roles are partitioned within the same molecule unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed in vivo the ATP6V0C\\u2013HIF-1\\u03b1 positive feedback loop as a driver of acute lung injury.\",\n      \"evidence\": \"Alveolar-specific Atp6v0c and Hif1a conditional knockouts, co-IP, transcriptomics, AAV overexpression in LPS-induced ALI model\",\n      \"pmids\": [\"41738275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcription-factor mechanism by which HIF-1\\u03b1 induces ATP6V0C not detailed\", \"Whether feedback operates in other inflammatory tissues untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified an additional pathogen-cofactor role, with the parasite ATP6V0C\\u2013HRG-1 complex required for heme acquisition and development.\",\n      \"evidence\": \"HRG-1/ATP6V0C interaction studies, RNAi, bafilomycin inhibition, heme uptake and mouse infection assays in T. spiralis\",\n      \"pmids\": [\"41838682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether heme transport depends on acidification or direct complex function unclear\", \"Parasite ortholog; human heme-transport relevance untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated therapeutic potential, with ATP6V0C overexpression promoting RGC survival and axon regeneration after optic nerve injury.\",\n      \"evidence\": \"AAV2 Atp6v0c transgene, optic nerve crush model, RGC survival and axon regeneration quantification\",\n      \"pmids\": [\"42023031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proposed lysosomal/ER-stress mechanism not directly tested\", \"Single study; dependence on V-ATPase activity vs scaffold role unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single proteolipid subunit partitions between proton-pumping, SNARE-scaffolding, HIF-1\\u03b1-binding, and pathogen-cofactor functions, and the structural basis of its non-canonical interactions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ATP6V0C bound to HIF-1\\u03b1 or STX17/VAMP8\", \"Whether moonlighting functions require assembled V-ATPase or free subunit unknown\", \"Mechanism connecting acidification loss to specific neurological phenotypes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [5, 7, 9]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005886\", \"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\": [7, 11]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 12]}\n    ],\n    \"complexes\": [\"vacuolar H+-ATPase (V0 domain)\"],\n    \"partners\": [\"HIF1A\", \"STX17\", \"VAMP8\", \"RNF182\", \"ATP6V0A\", \"LASS2/TMSG1\", \"HRG-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}