{"gene":"ATP6V1G1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2002,"finding":"ATP6V1G1 (G1 isoform) is a bona fide subunit of the V-ATPase complex: it co-immunoprecipitates with V-ATPase subunits c and A, and the G1-containing V-ATPase shows defined Km(ATP) and Vmax values. G1 is ubiquitously expressed and localizes to intracellular compartments but is not detectable in synaptic vesicles (unlike the G2 isoform).","method":"Co-immunoprecipitation, subcellular fractionation, electron microscopy, enzymatic kinetics, yeast complementation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, fractionation, EM, kinetics, complementation) in a single rigorous study","pmids":["12133826"],"is_preprint":false},{"year":2005,"finding":"ATP6V1G1 localizes to the apical pole of narrow and clear cells in the rat epididymis, co-distributing with other V-ATPase subunits, consistent with its role in active proton secretion at the apical membrane; it is distinct from the intracellular localization of ATP6V0A2.","method":"Immunohistochemistry with isoform-specific antibodies, subcellular localization in epithelial tissue sections","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunohistochemistry across multiple subunits and cell types, single lab","pmids":["16192400"],"is_preprint":false},{"year":2014,"finding":"RILP (Rab7 effector) directly interacts with the ATP6V1G1 subunit of V-ATPase. RILP controls ATP6V1G1 recruitment to late endosomal/lysosomal membranes and its stability: RILP promotes proteasomal degradation of ATP6V1G1 via ubiquitylation. Alterations in ATP6V1G1 expression impair V-ATPase activity.","method":"Yeast two-hybrid, co-immunoprecipitation, pulldown, ubiquitylation assay, proteasome inhibitor experiments, V-ATPase activity assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, reciprocal co-IP, ubiquitylation, functional V-ATPase activity assay) in single study, with mechanistic follow-up","pmids":["24762812"],"is_preprint":false},{"year":2014,"finding":"RILP regulates V-ATPase activity through its specific interaction with the ATP6V1G1 subunit, controlling V1G1 localization and stability, thereby modulating V-ATPase assembly and function at endosomes and lysosomes.","method":"Summary/commentary of experimental data from PMID 24762812; confirmed by co-immunoprecipitation and functional assays","journal":"Communicative & integrative biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — review/commentary corroborating primary experimental findings; no new primary data beyond PMID 24762812","pmids":["26843904"],"is_preprint":false},{"year":2015,"finding":"ATP6V1G1 knockdown in glioblastoma neurospheres impairs sphere-forming ability, induces cell death, and decreases matrix invasion, phenocopied by V-ATPase inhibitor bafilomycin A1, establishing ATP6V1G1 as functionally required for V-ATPase-dependent GBM stem cell maintenance.","method":"siRNA knockdown, neurosphere formation assay, cell viability assay, invasion assay, pharmacological V-ATPase inhibition","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — clean KD with defined cellular phenotype, pharmacological rescue, single lab","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). ATM phosphorylates ATP6V1G1, which disrupts the E–G subunit dimerization required for V-ATPase assembly. Inhibition of ATM restores E–G dimerization, promotes V1–V0 domain assembly, and reacidifies lysosomes, thereby recovering lysosome/autophagy function.","method":"Yeast two-hybrid, co-immunoprecipitation, direct phosphorylation assay, lysosomal pH measurement, autophagy flux assay","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — yeast two-hybrid interaction + direct phosphorylation assay + functional rescue of dimerization and lysosomal acidification in single study with multiple orthogonal methods","pmids":["28346404"],"is_preprint":false},{"year":2020,"finding":"UBQLN2 physically interacts with ATP6V1G1 (in vitro binding assays show stronger binding of WT UBQLN2 than ALS/FTD mutants). UBQLN2 regulates the stability and expression of ATP6V1G1: UBQLN2 knockout reduces ATP6V1G1 protein levels and decreases its turnover, while WT UBQLN2 overexpression increases ATP6V1G1 biogenesis. Overexpression of ATP6V1G1 in UBQLN2 knockout cells rescues autophagosome acidification defects.","method":"In vitro protein interaction assay, immunoblot, proteomic analysis, siRNA/KO, overexpression rescue, autophagosome acidification assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding, proteomics, KO/rescue with functional acidification assay, multiple orthogonal methods in single study","pmids":["32513711"],"is_preprint":false},{"year":2020,"finding":"ATP6V1G1-high glioblastoma stem cells release small extracellular vesicles that activate ERK1/2 signaling in recipient cells. The EVs from V1G1-high cells have a distinct miRNA profile, and V-ATPase inhibition in producer cells blocks the pro-oncogenic EV effects. Mechanistically, forced expression of MAPK-targeting miRNAs in recipient cells suppresses ERK activation downstream of V1G1-high EVs.","method":"EV isolation, miRNA profiling, ERK1/2 signaling assay, V-ATPase inhibitor (bafilomycin), miRNA overexpression, proliferation/motility assay","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional assays with V-ATPase inhibitor and miRNA overexpression, single lab, indirect mechanistic link for ATP6V1G1 specifically","pmids":["32753475"],"is_preprint":false},{"year":2021,"finding":"Oxidized ATM in breast cancer-associated fibroblasts phosphorylates ATP6V1G1, impairing lysosomal acidification, which leads to autophagosome fusion with multivesicular bodies rather than lysosomes, facilitating exosome release. Knockdown of ATM or BNIP3 blocks this pathway.","method":"Phosphorylation assay, shRNA knockdown, lysosomal pH measurement, autophagosome/MVB trafficking assay, exosome release quantification","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — phosphorylation and functional pH/trafficking assays, shRNA knockdown, single lab with multiple methods but no in vitro reconstitution","pmids":["34545708"],"is_preprint":false},{"year":2021,"finding":"RORα transcriptionally induces Atp6v1g1 expression in hepatocytes; hepatocyte-specific RORα deletion reduces lysosomal acidity (measured by LysoSensor), and RORα infusion increases lysosomal acidity. This demonstrates that RORα controls lysosomal V-ATPase function through regulation of ATP6V1G1 transcription.","method":"Hepatocyte-specific knockout mouse, adenoviral overexpression, LysoSensor lysosomal pH measurement, gene expression analysis","journal":"Hepatology communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO and overexpression with functional pH readout, single lab, transcriptional mechanism inferred but not directly demonstrated by promoter binding","pmids":["34558854"],"is_preprint":false},{"year":2024,"finding":"pH neutralization of late endosomes by LLOMe increases assembly (recruitment) of V1G1 (ATP6V1G1) onto endosomal membranes. Increased V1G1 assembly stabilizes GTP-bound Rab7 via its known interactor RILP, leading to Rab7 hyperactivation, disrupted tubulation, and impaired mannose-6-phosphate receptor recycling. This defines a V-ATPase–RILP–Rab7 pathway for controlling late endosomal pH and function.","method":"Live-cell imaging, immunofluorescence, pharmacological pH neutralization (LLOMe, NH4Cl), expression of Rab7 mutants, functional trafficking assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple methods (live imaging, pharmacology, mutant expression, trafficking assay), single lab, mechanistic pathway established","pmids":["38578235"],"is_preprint":false},{"year":2024,"finding":"PD patient-derived plasma exosomes decrease ATP6V1G1 expression in microglia, impairing lysosomal acidification and causing accumulation of abnormally swollen lysosomes with reduced cathepsin activity, leading to α-synuclein accumulation. Lentiviral overexpression of ATP6V1G1 in the brain of MPTP-treated mice restores lysosomal function and confers neuroprotection.","method":"siRNA knockdown, lentiviral overexpression, LysoSensor pH measurement, immunofluorescence, western blotting, MPTP mouse model, behavioral assays","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vitro KD and in vivo overexpression with functional lysosomal and behavioral readouts, single lab","pmids":["38702933"],"is_preprint":false},{"year":2025,"finding":"FTO (m6A demethylase) promotes ATP6V1G1 expression in an m6A-dependent manner downstream of TLR7-MyD88 signaling in B cells. FTO deficiency reduces ATP6V1G1-mediated V-ATPase activity, impairing lysosomal autophagy, causing accumulation of damaged mitochondria with reduced oxidative phosphorylation and elevated ROS, which limits age-associated B cell (ABC) differentiation.","method":"FTO knockout/overexpression, m6A modification analysis, V-ATPase activity assay, lysosomal autophagy assay, mitochondrial function measurement, B cell differentiation assay, lupus mouse model","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (V-ATPase activity, lysosomal autophagy, mitochondrial function, cell differentiation) with KO/OE, single lab","pmids":["41191778"],"is_preprint":false},{"year":2026,"finding":"Heart-specific knockout of ATP6V1G1 in mice causes V-ATPase disassembly, inhibits proton-pumping activity, impairs endo/lysosomal acidification, and blocks autophagy at the autophagosome-lysosome fusion step, demonstrating an essential role for ATP6V1G1 in cardiac V-ATPase assembly and autophagic flux in vivo.","method":"Heart-specific knockout mouse, subcellular fractionation, immunoprecipitation, immunofluorescence, proximity ligation assay, colorimetric proton-pumping assay, autophagy flux assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — heart-specific KO with multiple validated methodologies (fractionation, IP, PLA, functional proton-pumping assay, autophagy assay) and complementary in vivo HFD model","pmids":["41432243"],"is_preprint":false}],"current_model":"ATP6V1G1 is a peripheral stalk subunit of the vacuolar H+-ATPase (V-ATPase) that is essential for V1–V0 domain assembly and proton-pumping activity; its stability and lysosomal/endosomal recruitment are regulated by RILP (which promotes its ubiquitylation and proteasomal degradation), by ATM kinase (which phosphorylates ATP6V1G1 to disrupt E–G dimerization and impair V-ATPase assembly), and by the m6A demethylase FTO downstream of TLR7 signaling; loss of ATP6V1G1 impairs lysosomal acidification, autophagic flux, and proteostasis, with consequences for senescence, neurodegeneration, cancer stem cell maintenance, and B cell differentiation."},"narrative":{"mechanistic_narrative":"ATP6V1G1 is the G1 isoform of the peripheral stalk of the vacuolar H+-ATPase (V-ATPase), a bona fide subunit that co-assembles with the membrane-integral c subunit and the catalytic A subunit and is required for proton-pumping activity at intracellular compartments [PMID:12133826]. In vivo, loss of ATP6V1G1 causes V-ATPase disassembly, abolishes proton pumping, prevents endo/lysosomal acidification, and blocks autophagy at the autophagosome-lysosome fusion step, establishing its essential role in V1–V0 assembly and autophagic flux [PMID:41432243]. ATP6V1G1 abundance and recruitment are set by several regulators: the Rab7 effector RILP binds it directly, controls its membrane recruitment, and promotes its ubiquitylation and proteasomal degradation [PMID:24762812], while UBQLN2 binds ATP6V1G1 and stabilizes it, with ATP6V1G1 re-expression rescuing autophagosome acidification defects in UBQLN2-null cells [PMID:32513711]. ATM kinase directly phosphorylates ATP6V1G1 to disrupt the E–G dimerization needed for assembly, so ATM inhibition restores assembly and reacidifies lysosomes [PMID:28346404]. Its expression is further controlled transcriptionally by RORα [PMID:34558854] and post-transcriptionally by the m6A demethylase FTO downstream of TLR7-MyD88 signaling [PMID:41191778]. Through control of lysosomal acidification, ATP6V1G1 governs proteostasis and autophagy with consequences for glioblastoma stem-cell maintenance [PMID:26020805], microglial α-synuclein clearance and neuroprotection [PMID:38702933], and age-associated B cell differentiation [PMID:41191778]; it also feeds back on late-endosomal trafficking by stabilizing GTP-bound Rab7 via RILP [PMID:38578235].","teleology":[{"year":2002,"claim":"Established that ATP6V1G1 is a genuine, ubiquitously expressed V-ATPase subunit rather than an uncharacterized homolog, fixing it as part of the proton-pumping enzyme.","evidence":"Co-IP with subunits c and A, fractionation, EM, enzyme kinetics, and yeast complementation","pmids":["12133826"],"confidence":"High","gaps":["Did not define structural position within the stalk","No regulation of assembly addressed"]},{"year":2005,"claim":"Showed isoform-specific apical localization in proton-secreting epididymal epithelium, linking G1 to physiological proton secretion at the plasma membrane.","evidence":"Isoform-specific immunohistochemistry in rat tissue sections","pmids":["16192400"],"confidence":"Medium","gaps":["Descriptive localization without functional perturbation","Single tissue context"]},{"year":2014,"claim":"Identified RILP as a direct binding partner that controls ATP6V1G1 membrane recruitment and stability, revealing a degradation-based mechanism for tuning V-ATPase activity at endosomes/lysosomes.","evidence":"Yeast two-hybrid, reciprocal co-IP, ubiquitylation assays, proteasome inhibition, V-ATPase activity assay","pmids":["24762812","26843904"],"confidence":"High","gaps":["E3 ligase mediating ubiquitylation not identified","Stoichiometry of RILP-driven turnover unresolved"]},{"year":2015,"claim":"Demonstrated that ATP6V1G1 is functionally required for glioblastoma stem-cell maintenance and invasion, moving the subunit from housekeeping role to a cancer-relevant dependency.","evidence":"siRNA knockdown with neurosphere, viability and invasion assays, phenocopied by bafilomycin A1","pmids":["26020805"],"confidence":"Medium","gaps":["Downstream effectors of acidification loss not defined","Single tumor model"]},{"year":2017,"claim":"Defined ATM phosphorylation of ATP6V1G1 as a switch that disrupts E–G dimerization and blocks V-ATPase assembly, providing a kinase-controlled mechanism of lysosomal acidification.","evidence":"Yeast two-hybrid, co-IP, direct phosphorylation assay, lysosomal pH and autophagy flux measurements with ATM inhibition rescue","pmids":["28346404"],"confidence":"High","gaps":["Precise phosphosite(s) on ATP6V1G1 not mapped here","Structural basis of E–G disruption not resolved"]},{"year":2020,"claim":"Showed UBQLN2 binds and stabilizes ATP6V1G1, linking an ALS/FTD-associated protein to V-ATPase-dependent autophagosome acidification.","evidence":"In vitro binding (WT vs mutant UBQLN2), proteomics, KO/overexpression, autophagosome acidification rescue","pmids":["32513711"],"confidence":"High","gaps":["Mechanism by which UBQLN2 promotes biogenesis vs turnover not fully defined","Interplay with RILP-driven degradation untested"]},{"year":2020,"claim":"Connected high ATP6V1G1 to pro-oncogenic extracellular-vesicle signaling, expanding its role beyond intracellular acidification to non-cell-autonomous tumor effects.","evidence":"EV isolation, miRNA profiling, ERK1/2 signaling assay, bafilomycin inhibition, miRNA overexpression","pmids":["32753475"],"confidence":"Medium","gaps":["Direct mechanistic link from ATP6V1G1 to EV cargo indirect","ERK activation mechanism in recipients incompletely defined"]},{"year":2021,"claim":"Extended ATM-ATP6V1G1 phosphorylation to cancer-associated fibroblasts, where impaired acidification reroutes autophagosomes to MVBs and promotes exosome release.","evidence":"Phosphorylation assay, shRNA knockdown of ATM/BNIP3, lysosomal pH and trafficking/exosome assays","pmids":["34545708"],"confidence":"Medium","gaps":["No in vitro reconstitution of the phosphorylation event","Role of BNIP3 relative to ATP6V1G1 not dissected"]},{"year":2021,"claim":"Identified RORα as a transcriptional driver of Atp6v1g1 controlling hepatocyte lysosomal acidity in vivo.","evidence":"Hepatocyte-specific KO and adenoviral overexpression with LysoSensor pH readout and expression analysis","pmids":["34558854"],"confidence":"Medium","gaps":["Direct promoter binding not demonstrated","Single tissue"]},{"year":2024,"claim":"Revealed a feedback loop in which pH-triggered V1G1 assembly stabilizes GTP-Rab7 via RILP, coupling V-ATPase to late-endosomal trafficking and receptor recycling.","evidence":"Live-cell imaging, pH neutralization (LLOMe/NH4Cl), Rab7 mutant expression, trafficking assays","pmids":["38578235"],"confidence":"Medium","gaps":["Molecular interface of V1G1-RILP-Rab7 stabilization not structurally defined","Single cell system"]},{"year":2024,"claim":"Linked reduced ATP6V1G1 to Parkinson's disease pathology, showing patient exosomes suppress it in microglia to impair lysosomal α-synuclein clearance, with overexpression neuroprotective in vivo.","evidence":"siRNA KD, lentiviral overexpression, LysoSensor pH, MPTP mouse model and behavioral assays","pmids":["38702933"],"confidence":"Medium","gaps":["Exosomal factor reducing ATP6V1G1 not identified","Single disease model"]},{"year":2025,"claim":"Showed FTO-mediated m6A demethylation promotes ATP6V1G1 expression downstream of TLR7-MyD88, tying V-ATPase function to mitochondrial quality control and B cell differentiation.","evidence":"FTO KO/OE, m6A analysis, V-ATPase activity, lysosomal autophagy and mitochondrial assays, lupus mouse model","pmids":["41191778"],"confidence":"Medium","gaps":["Specific m6A sites on ATP6V1G1 transcript not mapped","Direct vs indirect FTO effect not fully separated"]},{"year":2026,"claim":"Provided definitive in vivo evidence that ATP6V1G1 is essential for V-ATPase assembly, proton pumping, and autophagic flux in the heart.","evidence":"Heart-specific KO mouse with fractionation, IP, PLA, proton-pumping and autophagy flux assays","pmids":["41432243"],"confidence":"High","gaps":["Cardiac-specific compensation by other G isoforms not addressed","Disease relevance in human cardiac pathology untested"]},{"year":null,"claim":"How the multiple regulatory inputs (RILP, UBQLN2, ATM, RORα, FTO) are integrated to set ATP6V1G1 levels and assembly in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the regulated E–G dimer interface","Cross-talk and hierarchy among the regulators untested","Isoform-specific (G1 vs G2/G3) division of labor incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,13]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,13]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2,5,11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5,6,13]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,13]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,10]}],"complexes":["V-ATPase (vacuolar H+-ATPase)"],"partners":["RILP","ATM","UBQLN2","ATP6V1E1","ATP6V0A2"],"other_free_text":[]}},"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":149,"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":108,"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":72,"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":"26020805","id":"PMC_26020805","title":"The vacuolar H+ ATPase is a novel therapeutic target for glioblastoma.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26020805","citation_count":55,"is_preprint":false},{"pmid":"12133826","id":"PMC_12133826","title":"Differential localization of the vacuolar H+ pump with G subunit isoforms (G1 and G2) in mouse neurons.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12133826","citation_count":54,"is_preprint":false},{"pmid":"26843904","id":"PMC_26843904","title":"A new V-ATPase regulatory mechanism mediated by the Rab interacting lysosomal protein (RILP).","date":"2014","source":"Communicative & integrative biology","url":"https://pubmed.ncbi.nlm.nih.gov/26843904","citation_count":27,"is_preprint":false},{"pmid":"38590521","id":"PMC_38590521","title":"Iron metabolism disorder and multiple sclerosis: a comprehensive analysis.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38590521","citation_count":24,"is_preprint":false},{"pmid":"26312577","id":"PMC_26312577","title":"Bivariate Genome-Wide Association Study Implicates ATP6V1G1 as a Novel Pleiotropic Locus Underlying Osteoporosis and Age at Menarche.","date":"2015","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26312577","citation_count":23,"is_preprint":false},{"pmid":"34558854","id":"PMC_34558854","title":"RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes.","date":"2021","source":"Hepatology communications","url":"https://pubmed.ncbi.nlm.nih.gov/34558854","citation_count":21,"is_preprint":false},{"pmid":"33194991","id":"PMC_33194991","title":"Proteomic Characterization of Proliferation Inhibition of Well-Differentiated Laryngeal Squamous Cell Carcinoma Cells Under Below-Background Radiation in a Deep Underground Environment.","date":"2020","source":"Frontiers in public health","url":"https://pubmed.ncbi.nlm.nih.gov/33194991","citation_count":18,"is_preprint":false},{"pmid":"37245817","id":"PMC_37245817","title":"Disturbance of gut microbiota aggravates cadmium-induced neurotoxicity in zebrafish larvae through V-ATPase.","date":"2023","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/37245817","citation_count":12,"is_preprint":false},{"pmid":"38578235","id":"PMC_38578235","title":"Collapse of late endosomal pH elicits a rapid Rab7 response via the V-ATPase and RILP.","date":"2024","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/38578235","citation_count":11,"is_preprint":false},{"pmid":"30592105","id":"PMC_30592105","title":"Genomic regions and enrichment analyses associated with carcass composition indicator traits in Nellore cattle.","date":"2018","source":"Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie","url":"https://pubmed.ncbi.nlm.nih.gov/30592105","citation_count":11,"is_preprint":false},{"pmid":"38643947","id":"PMC_38643947","title":"Identification and validation of cuproptosis and disulfidptosis related genes in colorectal cancer.","date":"2024","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/38643947","citation_count":9,"is_preprint":false},{"pmid":"38702933","id":"PMC_38702933","title":"Plasma exosomes impair microglial degradation of α-synuclein through V-ATPase subunit V1G1.","date":"2024","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/38702933","citation_count":8,"is_preprint":false},{"pmid":"26890086","id":"PMC_26890086","title":"Methylation and expression analyses of Pallister-Killian syndrome reveal partial dosage compensation of tetrasomy 12p and hypomethylation of gene-poor regions on 12p.","date":"2016","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26890086","citation_count":6,"is_preprint":false},{"pmid":"32753475","id":"PMC_32753475","title":"Interplay Between V-ATPase G1 and Small EV-miRNAs Modulates ERK1/2 Activation in GBM Stem Cells and Nonneoplastic Milieu.","date":"2020","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/32753475","citation_count":6,"is_preprint":false},{"pmid":"39373252","id":"PMC_39373252","title":"Proteomic Analysis Reveals Oxidative Phosphorylation and JAK-STAT Pathways Mediated Pathogenesis of Pemphigus Vulgaris.","date":"2024","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/39373252","citation_count":5,"is_preprint":false},{"pmid":"39972113","id":"PMC_39972113","title":"Identification of shared genetic loci for asthma, allergic rhinitis, and pollinosis in East Asians.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39972113","citation_count":5,"is_preprint":false},{"pmid":"41191778","id":"PMC_41191778","title":"The m6A demethylase FTO links TLR7 to mitochondrial oxidation driving age-associated B cell formation in systemic lupus erythematosus.","date":"2025","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41191778","citation_count":4,"is_preprint":false},{"pmid":"40799581","id":"PMC_40799581","title":"CLASHub: an integrated database and analytical platform for microRNA-target interactions.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40799581","citation_count":4,"is_preprint":false},{"pmid":"38350385","id":"PMC_38350385","title":"Identification and characterization of the receptors of a microneme adhesive repeat domain of Eimeria maxima microneme protein 3 in chicken intestine epithelial cells.","date":"2024","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/38350385","citation_count":2,"is_preprint":false},{"pmid":"41279844","id":"PMC_41279844","title":"mRNA 3' UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279844","citation_count":2,"is_preprint":false},{"pmid":"41871909","id":"PMC_41871909","title":"mRNA 3' UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth.","date":"2026","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/41871909","citation_count":1,"is_preprint":false},{"pmid":"42098137","id":"PMC_42098137","title":"CLASHub is an integrated database and analytical platform for microRNA-target interactions.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42098137","citation_count":1,"is_preprint":false},{"pmid":"40925315","id":"PMC_40925315","title":"Analysis of the toxicity and mechanisms of osteoporosis caused by cigarette toxicants using network toxicology and molecular docking techniques.","date":"2025","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/40925315","citation_count":0,"is_preprint":false},{"pmid":"41432243","id":"PMC_41432243","title":"Comprehensive methodological evaluation of V-ATPase assembly in the context of cardiac lipid overload: implications for (endo)lysosomal function and autophagy.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/41432243","citation_count":0,"is_preprint":false},{"pmid":"41552518","id":"PMC_41552518","title":"Evolution of the Chick Embryo Chorioallantoic Membrane Proteome during Early Development.","date":"2025","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/41552518","citation_count":0,"is_preprint":false},{"pmid":"42193979","id":"PMC_42193979","title":"Targeted Intracellular Delivery of Amino Acids to Trophoblast Cells Reveals Proteomic Signatures of Cellular Utilisation.","date":"2026","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/42193979","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.06.686990","title":"mRNA 3′ UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth","date":"2025-11-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.06.686990","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19358,"output_tokens":3847,"usd":0.05789,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11572,"output_tokens":4169,"usd":0.081043,"stage2_stop_reason":"end_turn"},"total_usd":0.138933,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"ATP6V1G1 (G1 isoform) is a bona fide subunit of the V-ATPase complex: it co-immunoprecipitates with V-ATPase subunits c and A, and the G1-containing V-ATPase shows defined Km(ATP) and Vmax values. G1 is ubiquitously expressed and localizes to intracellular compartments but is not detectable in synaptic vesicles (unlike the G2 isoform).\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, electron microscopy, enzymatic kinetics, yeast complementation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, fractionation, EM, kinetics, complementation) in a single rigorous study\",\n      \"pmids\": [\"12133826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ATP6V1G1 localizes to the apical pole of narrow and clear cells in the rat epididymis, co-distributing with other V-ATPase subunits, consistent with its role in active proton secretion at the apical membrane; it is distinct from the intracellular localization of ATP6V0A2.\",\n      \"method\": \"Immunohistochemistry with isoform-specific antibodies, subcellular localization in epithelial tissue sections\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunohistochemistry across multiple subunits and cell types, single lab\",\n      \"pmids\": [\"16192400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RILP (Rab7 effector) directly interacts with the ATP6V1G1 subunit of V-ATPase. RILP controls ATP6V1G1 recruitment to late endosomal/lysosomal membranes and its stability: RILP promotes proteasomal degradation of ATP6V1G1 via ubiquitylation. Alterations in ATP6V1G1 expression impair V-ATPase activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, pulldown, ubiquitylation assay, proteasome inhibitor experiments, V-ATPase activity assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, reciprocal co-IP, ubiquitylation, functional V-ATPase activity assay) in single study, with mechanistic follow-up\",\n      \"pmids\": [\"24762812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RILP regulates V-ATPase activity through its specific interaction with the ATP6V1G1 subunit, controlling V1G1 localization and stability, thereby modulating V-ATPase assembly and function at endosomes and lysosomes.\",\n      \"method\": \"Summary/commentary of experimental data from PMID 24762812; confirmed by co-immunoprecipitation and functional assays\",\n      \"journal\": \"Communicative & integrative biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — review/commentary corroborating primary experimental findings; no new primary data beyond PMID 24762812\",\n      \"pmids\": [\"26843904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATP6V1G1 knockdown in glioblastoma neurospheres impairs sphere-forming ability, induces cell death, and decreases matrix invasion, phenocopied by V-ATPase inhibitor bafilomycin A1, establishing ATP6V1G1 as functionally required for V-ATPase-dependent GBM stem cell maintenance.\",\n      \"method\": \"siRNA knockdown, neurosphere formation assay, cell viability assay, invasion assay, pharmacological V-ATPase inhibition\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — clean KD with defined cellular phenotype, pharmacological rescue, single lab\",\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). ATM phosphorylates ATP6V1G1, which disrupts the E–G subunit dimerization required for V-ATPase assembly. Inhibition of ATM restores E–G dimerization, promotes V1–V0 domain assembly, and reacidifies lysosomes, thereby recovering lysosome/autophagy function.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, direct phosphorylation assay, lysosomal pH measurement, autophagy flux assay\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — yeast two-hybrid interaction + direct phosphorylation assay + functional rescue of dimerization and lysosomal acidification in single study with multiple orthogonal methods\",\n      \"pmids\": [\"28346404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBQLN2 physically interacts with ATP6V1G1 (in vitro binding assays show stronger binding of WT UBQLN2 than ALS/FTD mutants). UBQLN2 regulates the stability and expression of ATP6V1G1: UBQLN2 knockout reduces ATP6V1G1 protein levels and decreases its turnover, while WT UBQLN2 overexpression increases ATP6V1G1 biogenesis. Overexpression of ATP6V1G1 in UBQLN2 knockout cells rescues autophagosome acidification defects.\",\n      \"method\": \"In vitro protein interaction assay, immunoblot, proteomic analysis, siRNA/KO, overexpression rescue, autophagosome acidification assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding, proteomics, KO/rescue with functional acidification assay, multiple orthogonal methods in single study\",\n      \"pmids\": [\"32513711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATP6V1G1-high glioblastoma stem cells release small extracellular vesicles that activate ERK1/2 signaling in recipient cells. The EVs from V1G1-high cells have a distinct miRNA profile, and V-ATPase inhibition in producer cells blocks the pro-oncogenic EV effects. Mechanistically, forced expression of MAPK-targeting miRNAs in recipient cells suppresses ERK activation downstream of V1G1-high EVs.\",\n      \"method\": \"EV isolation, miRNA profiling, ERK1/2 signaling assay, V-ATPase inhibitor (bafilomycin), miRNA overexpression, proliferation/motility assay\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional assays with V-ATPase inhibitor and miRNA overexpression, single lab, indirect mechanistic link for ATP6V1G1 specifically\",\n      \"pmids\": [\"32753475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Oxidized ATM in breast cancer-associated fibroblasts phosphorylates ATP6V1G1, impairing lysosomal acidification, which leads to autophagosome fusion with multivesicular bodies rather than lysosomes, facilitating exosome release. Knockdown of ATM or BNIP3 blocks this pathway.\",\n      \"method\": \"Phosphorylation assay, shRNA knockdown, lysosomal pH measurement, autophagosome/MVB trafficking assay, exosome release quantification\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — phosphorylation and functional pH/trafficking assays, shRNA knockdown, single lab with multiple methods but no in vitro reconstitution\",\n      \"pmids\": [\"34545708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RORα transcriptionally induces Atp6v1g1 expression in hepatocytes; hepatocyte-specific RORα deletion reduces lysosomal acidity (measured by LysoSensor), and RORα infusion increases lysosomal acidity. This demonstrates that RORα controls lysosomal V-ATPase function through regulation of ATP6V1G1 transcription.\",\n      \"method\": \"Hepatocyte-specific knockout mouse, adenoviral overexpression, LysoSensor lysosomal pH measurement, gene expression analysis\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO and overexpression with functional pH readout, single lab, transcriptional mechanism inferred but not directly demonstrated by promoter binding\",\n      \"pmids\": [\"34558854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"pH neutralization of late endosomes by LLOMe increases assembly (recruitment) of V1G1 (ATP6V1G1) onto endosomal membranes. Increased V1G1 assembly stabilizes GTP-bound Rab7 via its known interactor RILP, leading to Rab7 hyperactivation, disrupted tubulation, and impaired mannose-6-phosphate receptor recycling. This defines a V-ATPase–RILP–Rab7 pathway for controlling late endosomal pH and function.\",\n      \"method\": \"Live-cell imaging, immunofluorescence, pharmacological pH neutralization (LLOMe, NH4Cl), expression of Rab7 mutants, functional trafficking assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple methods (live imaging, pharmacology, mutant expression, trafficking assay), single lab, mechanistic pathway established\",\n      \"pmids\": [\"38578235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PD patient-derived plasma exosomes decrease ATP6V1G1 expression in microglia, impairing lysosomal acidification and causing accumulation of abnormally swollen lysosomes with reduced cathepsin activity, leading to α-synuclein accumulation. Lentiviral overexpression of ATP6V1G1 in the brain of MPTP-treated mice restores lysosomal function and confers neuroprotection.\",\n      \"method\": \"siRNA knockdown, lentiviral overexpression, LysoSensor pH measurement, immunofluorescence, western blotting, MPTP mouse model, behavioral assays\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vitro KD and in vivo overexpression with functional lysosomal and behavioral readouts, single lab\",\n      \"pmids\": [\"38702933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FTO (m6A demethylase) promotes ATP6V1G1 expression in an m6A-dependent manner downstream of TLR7-MyD88 signaling in B cells. FTO deficiency reduces ATP6V1G1-mediated V-ATPase activity, impairing lysosomal autophagy, causing accumulation of damaged mitochondria with reduced oxidative phosphorylation and elevated ROS, which limits age-associated B cell (ABC) differentiation.\",\n      \"method\": \"FTO knockout/overexpression, m6A modification analysis, V-ATPase activity assay, lysosomal autophagy assay, mitochondrial function measurement, B cell differentiation assay, lupus mouse model\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (V-ATPase activity, lysosomal autophagy, mitochondrial function, cell differentiation) with KO/OE, single lab\",\n      \"pmids\": [\"41191778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Heart-specific knockout of ATP6V1G1 in mice causes V-ATPase disassembly, inhibits proton-pumping activity, impairs endo/lysosomal acidification, and blocks autophagy at the autophagosome-lysosome fusion step, demonstrating an essential role for ATP6V1G1 in cardiac V-ATPase assembly and autophagic flux in vivo.\",\n      \"method\": \"Heart-specific knockout mouse, subcellular fractionation, immunoprecipitation, immunofluorescence, proximity ligation assay, colorimetric proton-pumping assay, autophagy flux assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — heart-specific KO with multiple validated methodologies (fractionation, IP, PLA, functional proton-pumping assay, autophagy assay) and complementary in vivo HFD model\",\n      \"pmids\": [\"41432243\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V1G1 is a peripheral stalk subunit of the vacuolar H+-ATPase (V-ATPase) that is essential for V1–V0 domain assembly and proton-pumping activity; its stability and lysosomal/endosomal recruitment are regulated by RILP (which promotes its ubiquitylation and proteasomal degradation), by ATM kinase (which phosphorylates ATP6V1G1 to disrupt E–G dimerization and impair V-ATPase assembly), and by the m6A demethylase FTO downstream of TLR7 signaling; loss of ATP6V1G1 impairs lysosomal acidification, autophagic flux, and proteostasis, with consequences for senescence, neurodegeneration, cancer stem cell maintenance, and B cell differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATP6V1G1 is the G1 isoform of the peripheral stalk of the vacuolar H+-ATPase (V-ATPase), a bona fide subunit that co-assembles with the membrane-integral c subunit and the catalytic A subunit and is required for proton-pumping activity at intracellular compartments [#0]. In vivo, loss of ATP6V1G1 causes V-ATPase disassembly, abolishes proton pumping, prevents endo/lysosomal acidification, and blocks autophagy at the autophagosome-lysosome fusion step, establishing its essential role in V1\\u2013V0 assembly and autophagic flux [#13]. ATP6V1G1 abundance and recruitment are set by several regulators: the Rab7 effector RILP binds it directly, controls its membrane recruitment, and promotes its ubiquitylation and proteasomal degradation [#2], while UBQLN2 binds ATP6V1G1 and stabilizes it, with ATP6V1G1 re-expression rescuing autophagosome acidification defects in UBQLN2-null cells [#6]. ATM kinase directly phosphorylates ATP6V1G1 to disrupt the E\\u2013G dimerization needed for assembly, so ATM inhibition restores assembly and reacidifies lysosomes [#5]. Its expression is further controlled transcriptionally by ROR\\u03b1 [#9] and post-transcriptionally by the m6A demethylase FTO downstream of TLR7-MyD88 signaling [#12]. Through control of lysosomal acidification, ATP6V1G1 governs proteostasis and autophagy with consequences for glioblastoma stem-cell maintenance [#4], microglial \\u03b1-synuclein clearance and neuroprotection [#11], and age-associated B cell differentiation [#12]; it also feeds back on late-endosomal trafficking by stabilizing GTP-bound Rab7 via RILP [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that ATP6V1G1 is a genuine, ubiquitously expressed V-ATPase subunit rather than an uncharacterized homolog, fixing it as part of the proton-pumping enzyme.\",\n      \"evidence\": \"Co-IP with subunits c and A, fractionation, EM, enzyme kinetics, and yeast complementation\",\n      \"pmids\": [\"12133826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define structural position within the stalk\", \"No regulation of assembly addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed isoform-specific apical localization in proton-secreting epididymal epithelium, linking G1 to physiological proton secretion at the plasma membrane.\",\n      \"evidence\": \"Isoform-specific immunohistochemistry in rat tissue sections\",\n      \"pmids\": [\"16192400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Descriptive localization without functional perturbation\", \"Single tissue context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified RILP as a direct binding partner that controls ATP6V1G1 membrane recruitment and stability, revealing a degradation-based mechanism for tuning V-ATPase activity at endosomes/lysosomes.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, ubiquitylation assays, proteasome inhibition, V-ATPase activity assay\",\n      \"pmids\": [\"24762812\", \"26843904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating ubiquitylation not identified\", \"Stoichiometry of RILP-driven turnover unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that ATP6V1G1 is functionally required for glioblastoma stem-cell maintenance and invasion, moving the subunit from housekeeping role to a cancer-relevant dependency.\",\n      \"evidence\": \"siRNA knockdown with neurosphere, viability and invasion assays, phenocopied by bafilomycin A1\",\n      \"pmids\": [\"26020805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of acidification loss not defined\", \"Single tumor model\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined ATM phosphorylation of ATP6V1G1 as a switch that disrupts E\\u2013G dimerization and blocks V-ATPase assembly, providing a kinase-controlled mechanism of lysosomal acidification.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, direct phosphorylation assay, lysosomal pH and autophagy flux measurements with ATM inhibition rescue\",\n      \"pmids\": [\"28346404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise phosphosite(s) on ATP6V1G1 not mapped here\", \"Structural basis of E\\u2013G disruption not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed UBQLN2 binds and stabilizes ATP6V1G1, linking an ALS/FTD-associated protein to V-ATPase-dependent autophagosome acidification.\",\n      \"evidence\": \"In vitro binding (WT vs mutant UBQLN2), proteomics, KO/overexpression, autophagosome acidification rescue\",\n      \"pmids\": [\"32513711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which UBQLN2 promotes biogenesis vs turnover not fully defined\", \"Interplay with RILP-driven degradation untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected high ATP6V1G1 to pro-oncogenic extracellular-vesicle signaling, expanding its role beyond intracellular acidification to non-cell-autonomous tumor effects.\",\n      \"evidence\": \"EV isolation, miRNA profiling, ERK1/2 signaling assay, bafilomycin inhibition, miRNA overexpression\",\n      \"pmids\": [\"32753475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanistic link from ATP6V1G1 to EV cargo indirect\", \"ERK activation mechanism in recipients incompletely defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended ATM-ATP6V1G1 phosphorylation to cancer-associated fibroblasts, where impaired acidification reroutes autophagosomes to MVBs and promotes exosome release.\",\n      \"evidence\": \"Phosphorylation assay, shRNA knockdown of ATM/BNIP3, lysosomal pH and trafficking/exosome assays\",\n      \"pmids\": [\"34545708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the phosphorylation event\", \"Role of BNIP3 relative to ATP6V1G1 not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified ROR\\u03b1 as a transcriptional driver of Atp6v1g1 controlling hepatocyte lysosomal acidity in vivo.\",\n      \"evidence\": \"Hepatocyte-specific KO and adenoviral overexpression with LysoSensor pH readout and expression analysis\",\n      \"pmids\": [\"34558854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding not demonstrated\", \"Single tissue\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a feedback loop in which pH-triggered V1G1 assembly stabilizes GTP-Rab7 via RILP, coupling V-ATPase to late-endosomal trafficking and receptor recycling.\",\n      \"evidence\": \"Live-cell imaging, pH neutralization (LLOMe/NH4Cl), Rab7 mutant expression, trafficking assays\",\n      \"pmids\": [\"38578235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular interface of V1G1-RILP-Rab7 stabilization not structurally defined\", \"Single cell system\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked reduced ATP6V1G1 to Parkinson's disease pathology, showing patient exosomes suppress it in microglia to impair lysosomal \\u03b1-synuclein clearance, with overexpression neuroprotective in vivo.\",\n      \"evidence\": \"siRNA KD, lentiviral overexpression, LysoSensor pH, MPTP mouse model and behavioral assays\",\n      \"pmids\": [\"38702933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Exosomal factor reducing ATP6V1G1 not identified\", \"Single disease model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed FTO-mediated m6A demethylation promotes ATP6V1G1 expression downstream of TLR7-MyD88, tying V-ATPase function to mitochondrial quality control and B cell differentiation.\",\n      \"evidence\": \"FTO KO/OE, m6A analysis, V-ATPase activity, lysosomal autophagy and mitochondrial assays, lupus mouse model\",\n      \"pmids\": [\"41191778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific m6A sites on ATP6V1G1 transcript not mapped\", \"Direct vs indirect FTO effect not fully separated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided definitive in vivo evidence that ATP6V1G1 is essential for V-ATPase assembly, proton pumping, and autophagic flux in the heart.\",\n      \"evidence\": \"Heart-specific KO mouse with fractionation, IP, PLA, proton-pumping and autophagy flux assays\",\n      \"pmids\": [\"41432243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cardiac-specific compensation by other G isoforms not addressed\", \"Disease relevance in human cardiac pathology untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple regulatory inputs (RILP, UBQLN2, ATM, ROR\\u03b1, FTO) are integrated to set ATP6V1G1 levels and assembly in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the regulated E\\u2013G dimer interface\", \"Cross-talk and hierarchy among the regulators untested\", \"Isoform-specific (G1 vs G2/G3) division of labor incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 5, 11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5, 6, 13]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"complexes\": [\"V-ATPase (vacuolar H+-ATPase)\"],\n    \"partners\": [\"RILP\", \"ATM\", \"UBQLN2\", \"ATP6V1E1\", \"ATP6V0A2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}