{"gene":"ATP6V1G1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1995,"finding":"The yeast VMA10 gene (ortholog of ATP6V1G1) encodes a 13-kDa subunit (M16/Vma10p) that copurifies with the V-ATPase complex, is present in multiple copies per enzyme, and is required for assembly of the catalytic V1 sector onto the vacuolar membrane; deletion causes loss of vacuolar acidification and failure to grow at neutral pH.","method":"Protein purification, amino acid sequencing, null mutant phenotyping (quinacrine accumulation, growth at pH 7.5), cold inactivation experiment placing Vma10p in the membrane sector","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution of complex assembly + multiple orthogonal assays in founding paper","pmids":["7775427"],"is_preprint":false},{"year":1997,"finding":"ATP6V1G1 (subunit G1) was purified from clathrin-coated vesicle V-ATPase, sequenced, and shown to be required for ATP hydrolysis; reconstitution of recombinant subunits A, B, C, E with recombinant G1 reconstituted ATPase activity, demonstrating G1's direct catalytic role in the V1 sector.","method":"Protein purification, direct sequencing, cDNA cloning, recombinant expression in E. coli and Sf9 cells, in vitro ATPase reconstitution assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of enzymatic activity with purified recombinant subunits","pmids":["9099722"],"is_preprint":false},{"year":1997,"finding":"Sequence analysis of the Neurospora crassa G subunit (vma-10 ortholog) showed that the N-terminal half can form an alpha-helix with all conserved residues clustered on one face, supporting a stator stalk structural model analogous to the b subunit of F-ATPases but lacking a membrane-spanning region.","method":"Gene cloning, sequence analysis, structural modeling of conserved residues","journal":"Journal of bioenergetics and biomembranes","confidence":"Medium","confidence_rationale":"Tier 3 — sequence/structural modeling without direct functional mutagenesis in this paper","pmids":["9559854"],"is_preprint":false},{"year":2000,"finding":"Site-directed mutagenesis of yeast Vma10p (ATP6V1G1 ortholog) showed that N-terminal residues (Y46, K55) are critical for stabilizing subunit E and V-ATPase assembly; R25A/R25L mutations stabilized V1-V0 association and partially prevented glucose-deprivation-induced disassembly while retaining full enzymatic activity; E14A and K50A allowed assembly but produced unstable complexes.","method":"Site-directed mutagenesis, growth assays at pH 7.5, V-ATPase assembly analysis, glucose-deprivation disassembly assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with multiple functional readouts establishing structure-function relationships","pmids":["10969085"],"is_preprint":false},{"year":2005,"finding":"ATP6V1G1 localizes to the apical pole of narrow and clear cells in rat epididymis and vas deferens, co-distributing with other V-ATPase subunits required for active proton secretion and luminal acidification, as determined by immunolocalization.","method":"Immunolocalization/immunofluorescence in epididymal tissue sections","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization experiment in tissue context, but no functional manipulation","pmids":["16192400"],"is_preprint":false},{"year":2014,"finding":"RILP (Rab7 effector) directly interacts with ATP6V1G1 (V1G1 subunit of V-ATPase) and controls its recruitment to late endosomal and lysosomal membranes, regulates V1G1 stability by promoting its ubiquitylation and proteasomal degradation, and thereby modulates V-ATPase assembly and activity; altered V1G1 expression impaired V-ATPase-dependent lysosomal acidification.","method":"Yeast two-hybrid, co-immunoprecipitation, pulldown, ubiquitylation assays, proteasome inhibitor experiments, V-ATPase activity assays, knockdown/overexpression with lysosomal acidification readout","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus multiple orthogonal functional assays establishing the regulatory mechanism","pmids":["24762812"],"is_preprint":false},{"year":2015,"finding":"ATP6V1G1 knockdown in glioblastoma neurospheres impaired sphere-forming ability, induced cell death, and decreased matrix invasion, phenocopied by bafilomycin A1 V-ATPase inhibition; this established ATP6V1G1-dependent V-ATPase activity as required for glioblastoma stem cell maintenance.","method":"siRNA knockdown, neurosphere formation assay, cell death assay, invasion assay, pharmacological inhibition with bafilomycin A1","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific cellular phenotype readouts, replicated pharmacologically","pmids":["26020805"],"is_preprint":false},{"year":2017,"finding":"ATM kinase directly interacts with V-ATPase V1 subunits ATP6V1E1 and ATP6V1G1 (identified by yeast two-hybrid), and ATM phosphorylates ATP6V1G1 to inhibit E-G dimerization; ATM inhibition restored dimerization, promoted V1-V0 domain assembly, and rescued lysosomal acidification, linking ATM activity to lysosomal dysfunction in senescence.","method":"Yeast two-hybrid screen, direct phosphorylation assay (ATM kinase assay on ATP6V1G1), co-immunoprecipitation of E-G dimerization, lysosomal acidification assay (LysoTracker), ATM inhibitor (KU-60019) treatment","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct kinase assay plus multiple orthogonal functional readouts; highly cited foundational paper","pmids":["28346404"],"is_preprint":false},{"year":2020,"finding":"UBQLN2 binds ATP6V1G1 and regulates its expression and stability; ALS/FTD mutant UBQLN2 proteins bind ATP6V1G1 more weakly than wild-type, resulting in decreased ATP6V1G1 protein levels, impaired autophagosome acidification, and reduced autophagic flux; overexpression of ATP6V1G1 in UBQLN2-knockout cells restored autophagosome acidification.","method":"In vitro interaction/pulldown assay, proteomic analysis, immunoblot, UBQLN2 knockout HeLa cells, autophagy flux assay, lysosomal pH measurement, overexpression rescue experiment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro interaction assay, KO rescue with specific acidification readout, multiple orthogonal methods","pmids":["32513711"],"is_preprint":false},{"year":2020,"finding":"ATP6V1G1 (V1G1) expression in glioblastoma stem cells modulates the miRNA composition of secreted small extracellular vesicles; V1G1-high neurospheres release EVs that activate ERK1/2 signaling in recipient cells, and this oncogenic reprogramming is reversed by V-ATPase inhibition or forced expression of MAPK-targeting miRNAs.","method":"siRNA knockdown, EV isolation, miRNA profiling, ERK1/2 phosphorylation assay, proliferation/motility assays, pharmacological V-ATPase inhibition, miRNA overexpression","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2-3 — loss-of-function with mechanistic follow-up, single lab","pmids":["32753475"],"is_preprint":false},{"year":2021,"finding":"Oxidized ATM (redox-activated, DNA-damage-independent) phosphorylates ATP6V1G1 in cancer-associated fibroblasts, causing lysosomal dysfunction; this diverts autophagosomes to fuse with multivesicular bodies rather than lysosomes, facilitating exosome release and promoting breast cancer cell invasion.","method":"ATM inhibitor (KU60019) treatment, shRNA knockdown of ATM and BNIP3, lysosomal acidification assay, autophagosome tracking, exosome quantification, cancer cell invasion assay","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with mechanistic pathway placement, but phosphorylation of ATP6V1G1 not independently confirmed beyond the earlier Kang et al. paper","pmids":["34545708"],"is_preprint":false},{"year":2021,"finding":"RORα transcriptionally induces Atp6v1g1 expression to maintain lysosomal acidification in hepatocytes; hepatocyte-specific RORα deletion reduced lysosomal acidity and impaired autophagic flux, while adenoviral RORα overexpression increased lysosomal acidity.","method":"Hepatocyte-specific knockout mouse, adenoviral overexpression, LysoSensor assay, LC3-II/p62/NBR1 accumulation, cathepsin D maturation assay, mTOR lysosomal translocation","journal":"Hepatology communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO and overexpression with multiple functional readouts; transcriptional regulation identified but direct RORα binding to Atp6v1g1 promoter not fully characterized here","pmids":["34558854"],"is_preprint":false},{"year":2024,"finding":"pH neutralization of late endosomes increases assembly of ATP6V1G1-containing V-ATPase on endosomal membranes, which stabilizes GTP-bound (active) Rab7 via RILP, leading to hyperactivation of Rab7 and disruption of CI-M6PR recycling tubulation; this defines a V-ATPase–RILP–Rab7 feedback pathway linking luminal pH to endosomal Rab7 activity.","method":"LLOMe treatment, NH4Cl pH neutralization, immunofluorescence, live imaging, proximity ligation assay for V1G1 assembly, dominant-active Rab7 mutants, CI-M6PR trafficking assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (pH manipulation, genetic mutants, PLA) establishing a mechanistic pathway in mammalian cells","pmids":["38578235"],"is_preprint":false},{"year":2024,"finding":"PD patient-derived plasma exosomes decreased ATP6V1G1 expression in microglia, impairing lysosomal acidification and causing accumulation of swollen lysosomes with reduced cathepsin activity, leading to α-synuclein accumulation; lentiviral overexpression of ATP6V1G1 in the brain of MPTP-treated mice conferred neuroprotection.","method":"Exosome isolation and stereotaxic injection, LysoSensor pH measurement, immunofluorescence, western blotting, siRNA knockdown, lentiviral ATP6V1G1 overexpression, MPTP mouse model, rotarod/pole behavioral tests, TH immunostaining","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function and gain-of-function in vivo with specific mechanistic readouts, single lab","pmids":["38702933"],"is_preprint":false},{"year":2025,"finding":"FTO (m6A demethylase), activated by TLR7-MyD88 signaling, promotes ABC B-cell differentiation by sustaining ATP6V1G1 expression in an m6A-dependent manner; FTO deficiency reduced ATP6V1G1-mediated V-ATPase activity, impairing lysosomal autophagy, causing damaged mitochondria to accumulate, and blocking ABC differentiation.","method":"FTO knockout/overexpression in murine and human B cells, m6A modification analysis, V-ATPase activity assay, lysosomal autophagy flux assay, mitochondrial function assays (OXPHOS, ROS), ABC differentiation assay","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and biochemical approaches linking m6A regulation to ATP6V1G1 function, single lab","pmids":["41191778"],"is_preprint":false},{"year":2025,"finding":"A TDMD (target-directed microRNA degradation) site in the 3' UTR of Atp6v1g1 mRNA directs the degradation of miR-335-3p in mouse models, acting in collaboration with two sites in Lpar4; this identifies ATP6V1G1 mRNA as a regulatory RNA whose 3' UTR participates in miRNA turnover.","method":"Computational prediction, mouse genetic models (site deletion), CLASH-based miRNA-target interaction, small RNA sequencing, miRNA quantification in Zswim8-/- mice","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 — computationally predicted site validated in mouse genetic models with direct miRNA quantification","pmids":["41871909"],"is_preprint":false},{"year":2026,"finding":"Heart-specific knockout of ATP6V1G1 in mice demonstrated that ATP6V1G1 is required for V-ATPase assembly and proton-pumping activity in cardiomyocytes; loss of ATP6V1G1 leads to impaired endo/lysosomal acidification and autophagy inhibition, recapitulating effects of high-fat diet-induced lipid overload.","method":"Heart-specific ATP6V1G1-knockout mouse model, fractionation, immunoprecipitation, proximity ligation assay, immunofluorescence, colorimetric proton-pumping assay, autophagy flux assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo KO with multiple validated biochemical assays measuring V-ATPase assembly and function directly","pmids":["41432243"],"is_preprint":false}],"current_model":"ATP6V1G1 encodes the G1 subunit of the peripheral stalk of the vacuolar H⁺-ATPase (V-ATPase), where it is essential for V1-V0 domain assembly, ATP hydrolysis, and lysosomal/endosomal acidification; its activity is regulated post-translationally by ATM-mediated phosphorylation (disrupting E-G dimerization and V1-V0 assembly), by RILP-mediated ubiquitylation and proteasomal degradation controlling its membrane recruitment, by FTO-dependent m6A methylation controlling its expression, and by a TDMD site in its 3' UTR that directs miR-335-3p degradation, with ATP6V1G1-dependent V-ATPase activity being required for autophagic flux, Rab7 activation on late endosomes, and diverse cellular processes including stem cell maintenance and neuroprotection."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing that the small G/Vma10p subunit is a stoichiometric V-ATPase component required for V1 sector assembly onto the membrane and for vacuolar acidification resolved the identity and essential role of this previously uncharacterized polypeptide.","evidence":"Yeast VMA10 null mutant phenotyping (quinacrine uptake, neutral pH growth), protein purification and sequencing","pmids":["7775427"],"confidence":"High","gaps":["Copy number per holoenzyme not precisely determined","No high-resolution structural data"]},{"year":1997,"claim":"Reconstitution of ATPase activity from purified recombinant subunits including G1 demonstrated that G1 is directly required for catalysis in the V1 sector, not merely for structural integrity.","evidence":"In vitro reconstitution of ATPase activity from recombinant A, B, C, E, and G1 subunits expressed in E. coli/Sf9 cells","pmids":["9099722"],"confidence":"High","gaps":["Precise catalytic contribution of G1 versus structural scaffolding not separated","Structural basis of G1 alpha-helical fold predicted but not solved"]},{"year":2000,"claim":"Systematic mutagenesis of the G subunit N-terminus revealed that specific residues control E subunit stability and the reversibility of V1-V0 association, identifying the G subunit as a regulatory determinant of glucose-dependent disassembly.","evidence":"Site-directed mutagenesis of yeast Vma10p (R25A/L, Y46A, K55A), growth assays, V-ATPase assembly and glucose-deprivation disassembly analysis","pmids":["10969085"],"confidence":"High","gaps":["Mammalian G1 residues not directly mutagenized","Molecular contacts between G and E not resolved at atomic level"]},{"year":2014,"claim":"Discovery that RILP directly binds ATP6V1G1, controls its membrane recruitment, and regulates its ubiquitylation and proteasomal degradation established the first post-translational regulatory axis controlling V-ATPase assembly through G1 subunit turnover.","evidence":"Yeast two-hybrid, reciprocal co-immunoprecipitation, ubiquitylation assays, proteasome inhibitor experiments, lysosomal acidification readout","pmids":["24762812"],"confidence":"High","gaps":["Identity of the E3 ubiquitin ligase mediating G1 ubiquitylation not determined","Whether RILP-G1 interaction is direct at endogenous stoichiometric levels in all cell types"]},{"year":2017,"claim":"Identification of ATM kinase as a direct phosphorylation-dependent inhibitor of E–G dimerization and V1-V0 assembly linked DNA damage response signaling to lysosomal dysfunction and provided a mechanistic basis for senescence-associated lysosomal defects.","evidence":"In vitro ATM kinase assay on ATP6V1G1, co-immunoprecipitation of E-G dimers ± ATM inhibitor, LysoTracker lysosomal pH assay","pmids":["28346404"],"confidence":"High","gaps":["Specific phosphorylation site(s) on G1 not mapped","Structural consequence of phosphorylation on E-G interface not resolved"]},{"year":2020,"claim":"Demonstration that UBQLN2 stabilizes ATP6V1G1 protein levels and that ALS/FTD-associated UBQLN2 mutations reduce this interaction, impairing autophagosome acidification, connected V-ATPase G1 regulation to neurodegenerative disease pathogenesis.","evidence":"In vitro pulldown, UBQLN2-KO HeLa cells, ATP6V1G1 overexpression rescue of acidification and autophagic flux","pmids":["32513711"],"confidence":"High","gaps":["Whether UBQLN2 protects G1 from ubiquitin-proteasome degradation or acts through another mechanism not fully delineated","In vivo neuronal validation not provided"]},{"year":2021,"claim":"Oxidized ATM phosphorylation of ATP6V1G1 in cancer-associated fibroblasts diverts autophagosome flux toward exosome secretion, extending the ATM-G1 axis from senescence to the tumor microenvironment and paracrine signaling.","evidence":"ATM inhibitor and shRNA in fibroblasts, lysosomal acidification, autophagosome tracking, exosome quantification, cancer cell invasion assay","pmids":["34545708"],"confidence":"Medium","gaps":["Direct phosphorylation of G1 by oxidized ATM not independently confirmed beyond prior Kang et al. study","Contribution of G1 phosphorylation versus other ATM substrates not isolated"]},{"year":2021,"claim":"Identification of RORα as a transcriptional inducer of Atp6v1g1 in hepatocytes established a transcription-level regulatory input controlling V-ATPase acidification capacity and downstream autophagic flux in a metabolic context.","evidence":"Hepatocyte-specific RORα KO mouse, adenoviral RORα overexpression, LysoSensor assay, cathepsin D maturation","pmids":["34558854"],"confidence":"Medium","gaps":["Direct RORα binding to the Atp6v1g1 promoter not demonstrated by ChIP","Whether other V-ATPase subunits are co-regulated not addressed"]},{"year":2024,"claim":"Establishing a V-ATPase–RILP–Rab7 feedback loop on late endosomes, where luminal pH neutralization increases G1-containing V-ATPase assembly and hyperactivates Rab7, revealed how organelle pH is sensed and transduced into membrane trafficking decisions.","evidence":"pH neutralization (LLOMe, NH4Cl), proximity ligation assay for V1G1 assembly, dominant-active Rab7 mutants, CI-M6PR tubulation assay","pmids":["38578235"],"confidence":"High","gaps":["Whether V-ATPase directly senses pH or responds to downstream signals not resolved","Generalizability beyond CI-M6PR cargo sorting not tested"]},{"year":2024,"claim":"In vivo gain-of-function and loss-of-function experiments in microglia and MPTP-treated mice showed that ATP6V1G1 levels control α-synuclein clearance via lysosomal acidification, positioning G1 as a neuroprotective factor in Parkinson's disease models.","evidence":"PD patient exosome treatment, siRNA knockdown, lentiviral ATP6V1G1 overexpression in mouse brain, MPTP model behavioral and histological analysis","pmids":["38702933"],"confidence":"Medium","gaps":["Mechanism by which PD exosomes reduce G1 expression not identified","Single mouse model; not confirmed in genetic PD models"]},{"year":2025,"claim":"Discovery that FTO-dependent m6A demethylation sustains ATP6V1G1 expression and that this is required for lysosomal autophagy during ABC B-cell differentiation added epitranscriptomic regulation to the multi-layered control of G1 abundance.","evidence":"FTO KO/overexpression in B cells, m6A modification analysis, V-ATPase activity assay, mitochondrial and autophagy flux assays, ABC differentiation readout","pmids":["41191778"],"confidence":"Medium","gaps":["Specific m6A sites on ATP6V1G1 mRNA not mapped","Whether FTO acts directly on G1 mRNA or indirectly through other targets not fully resolved"]},{"year":2025,"claim":"Identification of a TDMD site in the Atp6v1g1 3' UTR that directs miR-335-3p degradation revealed a non-canonical regulatory function of this mRNA beyond protein coding, linking it to miRNA homeostasis.","evidence":"Computational prediction, mouse genetic site-deletion models, CLASH-based miRNA-target mapping, small RNA sequencing in Zswim8−/− mice","pmids":["41871909"],"confidence":"Medium","gaps":["Functional consequence of miR-335-3p stabilization on V-ATPase activity or cellular phenotype not tested","Whether the TDMD function is conserved in humans not demonstrated"]},{"year":2026,"claim":"Heart-specific ATP6V1G1 knockout confirmed the subunit is indispensable for V-ATPase assembly and proton-pumping in cardiomyocytes, directly linking G1 loss to impaired endo-lysosomal acidification and autophagy block analogous to lipotoxic stress.","evidence":"Cardiac-specific KO mouse, fractionation, proximity ligation assay, colorimetric proton-pumping assay, autophagy flux analysis","pmids":["41432243"],"confidence":"High","gaps":["Whether cardiac phenotype leads to heart failure or cardiomyopathy not described","Compensatory roles of G2 or G3 isoforms not assessed"]},{"year":null,"claim":"The precise phosphorylation site(s) on ATP6V1G1 targeted by ATM, the identity of the E3 ubiquitin ligase mediating RILP-dependent G1 degradation, and the structural basis of how G1 modifications alter E–G dimerization and V1-V0 coupling remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["ATM phosphorylation site on G1 unmapped","E3 ligase for G1 ubiquitylation unknown","High-resolution structure of mammalian E-G heterodimer with post-translational modifications lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1,16]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[5,7,11,13,16]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5,12]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,12]},{"term_id":"GO:0005773","term_label":"vacuole","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8,11,13,14,16]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,7,16]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5,12]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[15]}],"complexes":["V-ATPase (V1 sector)","V-ATPase holoenzyme (V1-V0)"],"partners":["ATP6V1E1","RILP","ATM","UBQLN2","RAB7A","FTO"],"other_free_text":[]},"mechanistic_narrative":"ATP6V1G1 encodes the G1 subunit of the V-ATPase peripheral stalk and is essential for V1-V0 domain assembly, ATP hydrolysis, and proton-pumping activity required for lysosomal, endosomal, and autophagosomal acidification [PMID:7775427, PMID:9099722, PMID:41432243]. N-terminal residues of the G subunit stabilize its heterodimerization with the E subunit and control the reversible association of the V1 catalytic sector with the V0 membrane sector, a key regulatory step modulated by ATM kinase–mediated phosphorylation of ATP6V1G1, which disrupts E–G dimerization and impairs lysosomal function [PMID:10969085, PMID:28346404]. RILP directs ATP6V1G1 to late endosomal membranes and controls its turnover through ubiquitin-dependent proteasomal degradation, thereby linking Rab7 activation and endosomal pH sensing to V-ATPase assembly in a feedback circuit [PMID:24762812, PMID:38578235]. ATP6V1G1 expression is regulated transcriptionally by RORα, post-transcriptionally by FTO-dependent m6A demethylation and by a TDMD site that degrades miR-335-3p, and at the protein level by UBQLN2, whose ALS/FTD-linked mutations destabilize ATP6V1G1 and compromise autophagic flux [PMID:34558854, PMID:41191778, PMID:41871909, PMID:32513711]."},"prefetch_data":{"uniprot":{"accession":"O75348","full_name":"V-type proton ATPase subunit G 1","aliases":["V-ATPase 13 kDa subunit 1","Vacuolar proton pump subunit G 1","Vacuolar proton pump subunit M16"],"length_aa":118,"mass_kda":13.8,"function":"Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:32001091, PubMed:33065002). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (PubMed:32001091). In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation (PubMed:28296633)","subcellular_location":"Apical cell membrane","url":"https://www.uniprot.org/uniprotkb/O75348/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP6V1G1","classification":"Common Essential","n_dependent_lines":1116,"n_total_lines":1208,"dependency_fraction":0.9238410596026491},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000136888","cell_line_id":"CID001651","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"ATP6AP1","stoichiometry":10.0},{"gene":"ATP6AP2","stoichiometry":10.0},{"gene":"ATP6V0A1","stoichiometry":10.0},{"gene":"ATP6V0D1","stoichiometry":10.0},{"gene":"ATP6V1A","stoichiometry":10.0},{"gene":"ATP6V1B2","stoichiometry":10.0},{"gene":"ATP6V1D","stoichiometry":10.0},{"gene":"ATP6V1E1","stoichiometry":10.0},{"gene":"ATP6V1F","stoichiometry":10.0},{"gene":"ATP6V1H","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001651","total_profiled":1310},"omim":[{"mim_id":"607296","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, 13-KD, V1 SUBUNIT G, ISOFORM 1; ATP6V1G1","url":"https://www.omim.org/entry/607296"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATP6V1G1"},"hgnc":{"alias_symbol":["ATP6GL","Vma10","ATP6G","DKFZp547P234"],"prev_symbol":["ATP6J","ATP6G1"]},"alphafold":{"accession":"O75348","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75348","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75348-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75348-F1-predicted_aligned_error_v6.png","plddt_mean":92.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP6V1G1","jax_strain_url":"https://www.jax.org/strain/search?query=ATP6V1G1"},"sequence":{"accession":"O75348","fasta_url":"https://rest.uniprot.org/uniprotkb/O75348.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75348/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75348"}},"corpus_meta":[{"pmid":"28346404","id":"PMC_28346404","title":"Chemical screening identifies ATM as a target for alleviating senescence.","date":"2017","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/28346404","citation_count":148,"is_preprint":false},{"pmid":"16192400","id":"PMC_16192400","title":"Distinct expression patterns of different subunit isoforms of the V-ATPase in the rat epididymis.","date":"2005","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/16192400","citation_count":141,"is_preprint":false},{"pmid":"34545708","id":"PMC_34545708","title":"Hypoxia-stimulated ATM activation regulates autophagy-associated exosome release from cancer-associated fibroblasts to promote cancer cell invasion.","date":"2021","source":"Journal of extracellular vesicles","url":"https://pubmed.ncbi.nlm.nih.gov/34545708","citation_count":107,"is_preprint":false},{"pmid":"12509789","id":"PMC_12509789","title":"Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis.","date":"2002","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12509789","citation_count":100,"is_preprint":false},{"pmid":"11170743","id":"PMC_11170743","title":"A second susceptibility gene for developing rheumatoid arthritis in the human MHC is localized within a 70-kb interval telomeric of the TNF genes in the HLA class III region.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11170743","citation_count":88,"is_preprint":false},{"pmid":"7775427","id":"PMC_7775427","title":"The Saccharomyces cerevisiae VMA10 is an intron-containing gene encoding a novel 13-kDa subunit of vacuolar H(+)-ATPase.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7775427","citation_count":81,"is_preprint":false},{"pmid":"12096123","id":"PMC_12096123","title":"Systematic identification of the genes affecting glycogen storage in the yeast Saccharomyces cerevisiae: implication of the vacuole as a determinant of glycogen level.","date":"2002","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/12096123","citation_count":80,"is_preprint":false},{"pmid":"32513711","id":"PMC_32513711","title":"ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32513711","citation_count":70,"is_preprint":false},{"pmid":"24762812","id":"PMC_24762812","title":"RILP regulates vacuolar ATPase through interaction with the V1G1 subunit.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24762812","citation_count":65,"is_preprint":false},{"pmid":"9099722","id":"PMC_9099722","title":"Subunit G of the vacuolar proton pump. 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deletion causes loss of vacuolar acidification and failure to grow at neutral pH.\",\n      \"method\": \"Protein purification, amino acid sequencing, null mutant phenotyping (quinacrine accumulation, growth at pH 7.5), cold inactivation experiment placing Vma10p in the membrane sector\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of complex assembly + multiple orthogonal assays in founding paper\",\n      \"pmids\": [\"7775427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ATP6V1G1 (subunit G1) was purified from clathrin-coated vesicle V-ATPase, sequenced, and shown to be required for ATP hydrolysis; reconstitution of recombinant subunits A, B, C, E with recombinant G1 reconstituted ATPase activity, demonstrating G1's direct catalytic role in the V1 sector.\",\n      \"method\": \"Protein purification, direct sequencing, cDNA cloning, recombinant expression in E. coli and Sf9 cells, in vitro ATPase reconstitution assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of enzymatic activity with purified recombinant subunits\",\n      \"pmids\": [\"9099722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Sequence analysis of the Neurospora crassa G subunit (vma-10 ortholog) showed that the N-terminal half can form an alpha-helix with all conserved residues clustered on one face, supporting a stator stalk structural model analogous to the b subunit of F-ATPases but lacking a membrane-spanning region.\",\n      \"method\": \"Gene cloning, sequence analysis, structural modeling of conserved residues\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — sequence/structural modeling without direct functional mutagenesis in this paper\",\n      \"pmids\": [\"9559854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Site-directed mutagenesis of yeast Vma10p (ATP6V1G1 ortholog) showed that N-terminal residues (Y46, K55) are critical for stabilizing subunit E and V-ATPase assembly; R25A/R25L mutations stabilized V1-V0 association and partially prevented glucose-deprivation-induced disassembly while retaining full enzymatic activity; E14A and K50A allowed assembly but produced unstable complexes.\",\n      \"method\": \"Site-directed mutagenesis, growth assays at pH 7.5, V-ATPase assembly analysis, glucose-deprivation disassembly assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with multiple functional readouts establishing structure-function relationships\",\n      \"pmids\": [\"10969085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ATP6V1G1 localizes to the apical pole of narrow and clear cells in rat epididymis and vas deferens, co-distributing with other V-ATPase subunits required for active proton secretion and luminal acidification, as determined by immunolocalization.\",\n      \"method\": \"Immunolocalization/immunofluorescence in epididymal tissue sections\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization experiment in tissue context, but no functional manipulation\",\n      \"pmids\": [\"16192400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RILP (Rab7 effector) directly interacts with ATP6V1G1 (V1G1 subunit of V-ATPase) and controls its recruitment to late endosomal and lysosomal membranes, regulates V1G1 stability by promoting its ubiquitylation and proteasomal degradation, and thereby modulates V-ATPase assembly and activity; altered V1G1 expression impaired V-ATPase-dependent lysosomal acidification.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, pulldown, ubiquitylation assays, proteasome inhibitor experiments, V-ATPase activity assays, knockdown/overexpression with lysosomal acidification readout\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus multiple orthogonal functional assays establishing the regulatory mechanism\",\n      \"pmids\": [\"24762812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATP6V1G1 knockdown in glioblastoma neurospheres impaired sphere-forming ability, induced cell death, and decreased matrix invasion, phenocopied by bafilomycin A1 V-ATPase inhibition; this established ATP6V1G1-dependent V-ATPase activity as required for glioblastoma stem cell maintenance.\",\n      \"method\": \"siRNA knockdown, neurosphere formation assay, cell death assay, invasion assay, pharmacological inhibition with bafilomycin A1\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific cellular phenotype readouts, replicated pharmacologically\",\n      \"pmids\": [\"26020805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATM kinase directly interacts with V-ATPase V1 subunits ATP6V1E1 and ATP6V1G1 (identified by yeast two-hybrid), and ATM phosphorylates ATP6V1G1 to inhibit E-G dimerization; ATM inhibition restored dimerization, promoted V1-V0 domain assembly, and rescued lysosomal acidification, linking ATM activity to lysosomal dysfunction in senescence.\",\n      \"method\": \"Yeast two-hybrid screen, direct phosphorylation assay (ATM kinase assay on ATP6V1G1), co-immunoprecipitation of E-G dimerization, lysosomal acidification assay (LysoTracker), ATM inhibitor (KU-60019) treatment\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct kinase assay plus multiple orthogonal functional readouts; highly cited foundational paper\",\n      \"pmids\": [\"28346404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBQLN2 binds ATP6V1G1 and regulates its expression and stability; ALS/FTD mutant UBQLN2 proteins bind ATP6V1G1 more weakly than wild-type, resulting in decreased ATP6V1G1 protein levels, impaired autophagosome acidification, and reduced autophagic flux; overexpression of ATP6V1G1 in UBQLN2-knockout cells restored autophagosome acidification.\",\n      \"method\": \"In vitro interaction/pulldown assay, proteomic analysis, immunoblot, UBQLN2 knockout HeLa cells, autophagy flux assay, lysosomal pH measurement, overexpression rescue experiment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro interaction assay, KO rescue with specific acidification readout, multiple orthogonal methods\",\n      \"pmids\": [\"32513711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATP6V1G1 (V1G1) expression in glioblastoma stem cells modulates the miRNA composition of secreted small extracellular vesicles; V1G1-high neurospheres release EVs that activate ERK1/2 signaling in recipient cells, and this oncogenic reprogramming is reversed by V-ATPase inhibition or forced expression of MAPK-targeting miRNAs.\",\n      \"method\": \"siRNA knockdown, EV isolation, miRNA profiling, ERK1/2 phosphorylation assay, proliferation/motility assays, pharmacological V-ATPase inhibition, miRNA overexpression\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss-of-function with mechanistic follow-up, single lab\",\n      \"pmids\": [\"32753475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Oxidized ATM (redox-activated, DNA-damage-independent) phosphorylates ATP6V1G1 in cancer-associated fibroblasts, causing lysosomal dysfunction; this diverts autophagosomes to fuse with multivesicular bodies rather than lysosomes, facilitating exosome release and promoting breast cancer cell invasion.\",\n      \"method\": \"ATM inhibitor (KU60019) treatment, shRNA knockdown of ATM and BNIP3, lysosomal acidification assay, autophagosome tracking, exosome quantification, cancer cell invasion assay\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with mechanistic pathway placement, but phosphorylation of ATP6V1G1 not independently confirmed beyond the earlier Kang et al. paper\",\n      \"pmids\": [\"34545708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RORα transcriptionally induces Atp6v1g1 expression to maintain lysosomal acidification in hepatocytes; hepatocyte-specific RORα deletion reduced lysosomal acidity and impaired autophagic flux, while adenoviral RORα overexpression increased lysosomal acidity.\",\n      \"method\": \"Hepatocyte-specific knockout mouse, adenoviral overexpression, LysoSensor assay, LC3-II/p62/NBR1 accumulation, cathepsin D maturation assay, mTOR lysosomal translocation\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and overexpression with multiple functional readouts; transcriptional regulation identified but direct RORα binding to Atp6v1g1 promoter not fully characterized here\",\n      \"pmids\": [\"34558854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"pH neutralization of late endosomes increases assembly of ATP6V1G1-containing V-ATPase on endosomal membranes, which stabilizes GTP-bound (active) Rab7 via RILP, leading to hyperactivation of Rab7 and disruption of CI-M6PR recycling tubulation; this defines a V-ATPase–RILP–Rab7 feedback pathway linking luminal pH to endosomal Rab7 activity.\",\n      \"method\": \"LLOMe treatment, NH4Cl pH neutralization, immunofluorescence, live imaging, proximity ligation assay for V1G1 assembly, dominant-active Rab7 mutants, CI-M6PR trafficking assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (pH manipulation, genetic mutants, PLA) establishing a mechanistic pathway in mammalian cells\",\n      \"pmids\": [\"38578235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PD patient-derived plasma exosomes decreased ATP6V1G1 expression in microglia, impairing lysosomal acidification and causing accumulation of swollen lysosomes with reduced cathepsin activity, leading to α-synuclein accumulation; lentiviral overexpression of ATP6V1G1 in the brain of MPTP-treated mice conferred neuroprotection.\",\n      \"method\": \"Exosome isolation and stereotaxic injection, LysoSensor pH measurement, immunofluorescence, western blotting, siRNA knockdown, lentiviral ATP6V1G1 overexpression, MPTP mouse model, rotarod/pole behavioral tests, TH immunostaining\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function in vivo with specific mechanistic readouts, single lab\",\n      \"pmids\": [\"38702933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FTO (m6A demethylase), activated by TLR7-MyD88 signaling, promotes ABC B-cell differentiation by sustaining ATP6V1G1 expression in an m6A-dependent manner; FTO deficiency reduced ATP6V1G1-mediated V-ATPase activity, impairing lysosomal autophagy, causing damaged mitochondria to accumulate, and blocking ABC differentiation.\",\n      \"method\": \"FTO knockout/overexpression in murine and human B cells, m6A modification analysis, V-ATPase activity assay, lysosomal autophagy flux assay, mitochondrial function assays (OXPHOS, ROS), ABC differentiation assay\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and biochemical approaches linking m6A regulation to ATP6V1G1 function, single lab\",\n      \"pmids\": [\"41191778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A TDMD (target-directed microRNA degradation) site in the 3' UTR of Atp6v1g1 mRNA directs the degradation of miR-335-3p in mouse models, acting in collaboration with two sites in Lpar4; this identifies ATP6V1G1 mRNA as a regulatory RNA whose 3' UTR participates in miRNA turnover.\",\n      \"method\": \"Computational prediction, mouse genetic models (site deletion), CLASH-based miRNA-target interaction, small RNA sequencing, miRNA quantification in Zswim8-/- mice\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — computationally predicted site validated in mouse genetic models with direct miRNA quantification\",\n      \"pmids\": [\"41871909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Heart-specific knockout of ATP6V1G1 in mice demonstrated that ATP6V1G1 is required for V-ATPase assembly and proton-pumping activity in cardiomyocytes; loss of ATP6V1G1 leads to impaired endo/lysosomal acidification and autophagy inhibition, recapitulating effects of high-fat diet-induced lipid overload.\",\n      \"method\": \"Heart-specific ATP6V1G1-knockout mouse model, fractionation, immunoprecipitation, proximity ligation assay, immunofluorescence, colorimetric proton-pumping assay, autophagy flux assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo KO with multiple validated biochemical assays measuring V-ATPase assembly and function directly\",\n      \"pmids\": [\"41432243\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V1G1 encodes the G1 subunit of the peripheral stalk of the vacuolar H⁺-ATPase (V-ATPase), where it is essential for V1-V0 domain assembly, ATP hydrolysis, and lysosomal/endosomal acidification; its activity is regulated post-translationally by ATM-mediated phosphorylation (disrupting E-G dimerization and V1-V0 assembly), by RILP-mediated ubiquitylation and proteasomal degradation controlling its membrane recruitment, by FTO-dependent m6A methylation controlling its expression, and by a TDMD site in its 3' UTR that directs miR-335-3p degradation, with ATP6V1G1-dependent V-ATPase activity being required for autophagic flux, Rab7 activation on late endosomes, and diverse cellular processes including stem cell maintenance and neuroprotection.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATP6V1G1 encodes the G1 subunit of the V-ATPase peripheral stalk and is essential for V1-V0 domain assembly, ATP hydrolysis, and proton-pumping activity required for lysosomal, endosomal, and autophagosomal acidification [PMID:7775427, PMID:9099722, PMID:41432243]. N-terminal residues of the G subunit stabilize its heterodimerization with the E subunit and control the reversible association of the V1 catalytic sector with the V0 membrane sector, a key regulatory step modulated by ATM kinase–mediated phosphorylation of ATP6V1G1, which disrupts E–G dimerization and impairs lysosomal function [PMID:10969085, PMID:28346404]. RILP directs ATP6V1G1 to late endosomal membranes and controls its turnover through ubiquitin-dependent proteasomal degradation, thereby linking Rab7 activation and endosomal pH sensing to V-ATPase assembly in a feedback circuit [PMID:24762812, PMID:38578235]. ATP6V1G1 expression is regulated transcriptionally by RORα, post-transcriptionally by FTO-dependent m6A demethylation and by a TDMD site that degrades miR-335-3p, and at the protein level by UBQLN2, whose ALS/FTD-linked mutations destabilize ATP6V1G1 and compromise autophagic flux [PMID:34558854, PMID:41191778, PMID:41871909, PMID:32513711].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that the small G/Vma10p subunit is a stoichiometric V-ATPase component required for V1 sector assembly onto the membrane and for vacuolar acidification resolved the identity and essential role of this previously uncharacterized polypeptide.\",\n      \"evidence\": \"Yeast VMA10 null mutant phenotyping (quinacrine uptake, neutral pH growth), protein purification and sequencing\",\n      \"pmids\": [\"7775427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Copy number per holoenzyme not precisely determined\", \"No high-resolution structural data\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Reconstitution of ATPase activity from purified recombinant subunits including G1 demonstrated that G1 is directly required for catalysis in the V1 sector, not merely for structural integrity.\",\n      \"evidence\": \"In vitro reconstitution of ATPase activity from recombinant A, B, C, E, and G1 subunits expressed in E. coli/Sf9 cells\",\n      \"pmids\": [\"9099722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise catalytic contribution of G1 versus structural scaffolding not separated\", \"Structural basis of G1 alpha-helical fold predicted but not solved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Systematic mutagenesis of the G subunit N-terminus revealed that specific residues control E subunit stability and the reversibility of V1-V0 association, identifying the G subunit as a regulatory determinant of glucose-dependent disassembly.\",\n      \"evidence\": \"Site-directed mutagenesis of yeast Vma10p (R25A/L, Y46A, K55A), growth assays, V-ATPase assembly and glucose-deprivation disassembly analysis\",\n      \"pmids\": [\"10969085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian G1 residues not directly mutagenized\", \"Molecular contacts between G and E not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that RILP directly binds ATP6V1G1, controls its membrane recruitment, and regulates its ubiquitylation and proteasomal degradation established the first post-translational regulatory axis controlling V-ATPase assembly through G1 subunit turnover.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-immunoprecipitation, ubiquitylation assays, proteasome inhibitor experiments, lysosomal acidification readout\",\n      \"pmids\": [\"24762812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the E3 ubiquitin ligase mediating G1 ubiquitylation not determined\", \"Whether RILP-G1 interaction is direct at endogenous stoichiometric levels in all cell types\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of ATM kinase as a direct phosphorylation-dependent inhibitor of E–G dimerization and V1-V0 assembly linked DNA damage response signaling to lysosomal dysfunction and provided a mechanistic basis for senescence-associated lysosomal defects.\",\n      \"evidence\": \"In vitro ATM kinase assay on ATP6V1G1, co-immunoprecipitation of E-G dimers ± ATM inhibitor, LysoTracker lysosomal pH assay\",\n      \"pmids\": [\"28346404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation site(s) on G1 not mapped\", \"Structural consequence of phosphorylation on E-G interface not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstration that UBQLN2 stabilizes ATP6V1G1 protein levels and that ALS/FTD-associated UBQLN2 mutations reduce this interaction, impairing autophagosome acidification, connected V-ATPase G1 regulation to neurodegenerative disease pathogenesis.\",\n      \"evidence\": \"In vitro pulldown, UBQLN2-KO HeLa cells, ATP6V1G1 overexpression rescue of acidification and autophagic flux\",\n      \"pmids\": [\"32513711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether UBQLN2 protects G1 from ubiquitin-proteasome degradation or acts through another mechanism not fully delineated\", \"In vivo neuronal validation not provided\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Oxidized ATM phosphorylation of ATP6V1G1 in cancer-associated fibroblasts diverts autophagosome flux toward exosome secretion, extending the ATM-G1 axis from senescence to the tumor microenvironment and paracrine signaling.\",\n      \"evidence\": \"ATM inhibitor and shRNA in fibroblasts, lysosomal acidification, autophagosome tracking, exosome quantification, cancer cell invasion assay\",\n      \"pmids\": [\"34545708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation of G1 by oxidized ATM not independently confirmed beyond prior Kang et al. study\", \"Contribution of G1 phosphorylation versus other ATM substrates not isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of RORα as a transcriptional inducer of Atp6v1g1 in hepatocytes established a transcription-level regulatory input controlling V-ATPase acidification capacity and downstream autophagic flux in a metabolic context.\",\n      \"evidence\": \"Hepatocyte-specific RORα KO mouse, adenoviral RORα overexpression, LysoSensor assay, cathepsin D maturation\",\n      \"pmids\": [\"34558854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RORα binding to the Atp6v1g1 promoter not demonstrated by ChIP\", \"Whether other V-ATPase subunits are co-regulated not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Establishing a V-ATPase–RILP–Rab7 feedback loop on late endosomes, where luminal pH neutralization increases G1-containing V-ATPase assembly and hyperactivates Rab7, revealed how organelle pH is sensed and transduced into membrane trafficking decisions.\",\n      \"evidence\": \"pH neutralization (LLOMe, NH4Cl), proximity ligation assay for V1G1 assembly, dominant-active Rab7 mutants, CI-M6PR tubulation assay\",\n      \"pmids\": [\"38578235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether V-ATPase directly senses pH or responds to downstream signals not resolved\", \"Generalizability beyond CI-M6PR cargo sorting not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"In vivo gain-of-function and loss-of-function experiments in microglia and MPTP-treated mice showed that ATP6V1G1 levels control α-synuclein clearance via lysosomal acidification, positioning G1 as a neuroprotective factor in Parkinson's disease models.\",\n      \"evidence\": \"PD patient exosome treatment, siRNA knockdown, lentiviral ATP6V1G1 overexpression in mouse brain, MPTP model behavioral and histological analysis\",\n      \"pmids\": [\"38702933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PD exosomes reduce G1 expression not identified\", \"Single mouse model; not confirmed in genetic PD models\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that FTO-dependent m6A demethylation sustains ATP6V1G1 expression and that this is required for lysosomal autophagy during ABC B-cell differentiation added epitranscriptomic regulation to the multi-layered control of G1 abundance.\",\n      \"evidence\": \"FTO KO/overexpression in B cells, m6A modification analysis, V-ATPase activity assay, mitochondrial and autophagy flux assays, ABC differentiation readout\",\n      \"pmids\": [\"41191778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific m6A sites on ATP6V1G1 mRNA not mapped\", \"Whether FTO acts directly on G1 mRNA or indirectly through other targets not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of a TDMD site in the Atp6v1g1 3' UTR that directs miR-335-3p degradation revealed a non-canonical regulatory function of this mRNA beyond protein coding, linking it to miRNA homeostasis.\",\n      \"evidence\": \"Computational prediction, mouse genetic site-deletion models, CLASH-based miRNA-target mapping, small RNA sequencing in Zswim8−/− mice\",\n      \"pmids\": [\"41871909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of miR-335-3p stabilization on V-ATPase activity or cellular phenotype not tested\", \"Whether the TDMD function is conserved in humans not demonstrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Heart-specific ATP6V1G1 knockout confirmed the subunit is indispensable for V-ATPase assembly and proton-pumping in cardiomyocytes, directly linking G1 loss to impaired endo-lysosomal acidification and autophagy block analogous to lipotoxic stress.\",\n      \"evidence\": \"Cardiac-specific KO mouse, fractionation, proximity ligation assay, colorimetric proton-pumping assay, autophagy flux analysis\",\n      \"pmids\": [\"41432243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cardiac phenotype leads to heart failure or cardiomyopathy not described\", \"Compensatory roles of G2 or G3 isoforms not assessed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise phosphorylation site(s) on ATP6V1G1 targeted by ATM, the identity of the E3 ubiquitin ligase mediating RILP-dependent G1 degradation, and the structural basis of how G1 modifications alter E–G dimerization and V1-V0 coupling remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ATM phosphorylation site on G1 unmapped\", \"E3 ligase for G1 ubiquitylation unknown\", \"High-resolution structure of mammalian E-G heterodimer with post-translational modifications lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1, 16]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [5, 7, 11, 13, 16]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 11, 13, 14, 16]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 7, 16]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [\n      \"V-ATPase (V1 sector)\",\n      \"V-ATPase holoenzyme (V1-V0)\"\n    ],\n    \"partners\": [\n      \"ATP6V1E1\",\n      \"RILP\",\n      \"ATM\",\n      \"UBQLN2\",\n      \"RAB7A\",\n      \"FTO\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}