Affinage

ATP6V1G1

V-type proton ATPase subunit G 1 · UniProt O75348

Length
118 aa
Mass
13.8 kDa
Annotated
2026-06-09
31 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 High

    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

    PMID:12133826

    Open questions at the time
    • Did not define structural position within the stalk
    • No regulation of assembly addressed
  2. 2005 Medium

    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

    PMID:16192400

    Open questions at the time
    • Descriptive localization without functional perturbation
    • Single tissue context
  3. 2014 High

    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

    PMID:24762812 PMID:26843904

    Open questions at the time
    • E3 ligase mediating ubiquitylation not identified
    • Stoichiometry of RILP-driven turnover unresolved
  4. 2015 Medium

    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

    PMID:26020805

    Open questions at the time
    • Downstream effectors of acidification loss not defined
    • Single tumor model
  5. 2017 High

    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

    PMID:28346404

    Open questions at the time
    • Precise phosphosite(s) on ATP6V1G1 not mapped here
    • Structural basis of E–G disruption not resolved
  6. 2020 High

    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

    PMID:32513711

    Open questions at the time
    • Mechanism by which UBQLN2 promotes biogenesis vs turnover not fully defined
    • Interplay with RILP-driven degradation untested
  7. 2020 Medium

    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

    PMID:32753475

    Open questions at the time
    • Direct mechanistic link from ATP6V1G1 to EV cargo indirect
    • ERK activation mechanism in recipients incompletely defined
  8. 2021 Medium

    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

    PMID:34545708

    Open questions at the time
    • No in vitro reconstitution of the phosphorylation event
    • Role of BNIP3 relative to ATP6V1G1 not dissected
  9. 2021 Medium

    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

    PMID:34558854

    Open questions at the time
    • Direct promoter binding not demonstrated
    • Single tissue
  10. 2024 Medium

    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

    PMID:38578235

    Open questions at the time
    • Molecular interface of V1G1-RILP-Rab7 stabilization not structurally defined
    • Single cell system
  11. 2024 Medium

    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

    PMID:38702933

    Open questions at the time
    • Exosomal factor reducing ATP6V1G1 not identified
    • Single disease model
  12. 2025 Medium

    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

    PMID:41191778

    Open questions at the time
    • Specific m6A sites on ATP6V1G1 transcript not mapped
    • Direct vs indirect FTO effect not fully separated
  13. 2026 High

    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

    PMID:41432243

    Open questions at the time
    • Cardiac-specific compensation by other G isoforms not addressed
    • Disease relevance in human cardiac pathology untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0005215 transporter activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005764 lysosome 3 GO:0005768 endosome 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-382551 Transport of small molecules 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ATMATP6V0A2ATP6V1E1RILPUBQLN2
Complex memberships
V-ATPase (vacuolar H+-ATPase)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 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). Co-immunoprecipitation, subcellular fractionation, electron microscopy, enzymatic kinetics, yeast complementation assay The Journal of biological chemistry High 12133826
2005 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. Immunohistochemistry with isoform-specific antibodies, subcellular localization in epithelial tissue sections Biology of reproduction Medium 16192400
2014 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. Yeast two-hybrid, co-immunoprecipitation, pulldown, ubiquitylation assay, proteasome inhibitor experiments, V-ATPase activity assay Journal of cell science High 24762812
2014 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. Summary/commentary of experimental data from PMID 24762812; confirmed by co-immunoprecipitation and functional assays Communicative & integrative biology Medium 26843904
2015 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. siRNA knockdown, neurosphere formation assay, cell viability assay, invasion assay, pharmacological V-ATPase inhibition Oncotarget Medium 26020805
2017 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. Yeast two-hybrid, co-immunoprecipitation, direct phosphorylation assay, lysosomal pH measurement, autophagy flux assay Nature chemical biology High 28346404
2020 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. In vitro protein interaction assay, immunoblot, proteomic analysis, siRNA/KO, overexpression rescue, autophagosome acidification assay Proceedings of the National Academy of Sciences of the United States of America High 32513711
2020 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. EV isolation, miRNA profiling, ERK1/2 signaling assay, V-ATPase inhibitor (bafilomycin), miRNA overexpression, proliferation/motility assay Molecular cancer research : MCR Medium 32753475
2021 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. Phosphorylation assay, shRNA knockdown, lysosomal pH measurement, autophagosome/MVB trafficking assay, exosome release quantification Journal of extracellular vesicles Medium 34545708
2021 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. Hepatocyte-specific knockout mouse, adenoviral overexpression, LysoSensor lysosomal pH measurement, gene expression analysis Hepatology communications Medium 34558854
2024 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. Live-cell imaging, immunofluorescence, pharmacological pH neutralization (LLOMe, NH4Cl), expression of Rab7 mutants, functional trafficking assays Journal of cell science Medium 38578235
2024 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. siRNA knockdown, lentiviral overexpression, LysoSensor pH measurement, immunofluorescence, western blotting, MPTP mouse model, behavioral assays CNS neuroscience & therapeutics Medium 38702933
2025 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. FTO knockout/overexpression, m6A modification analysis, V-ATPase activity assay, lysosomal autophagy assay, mitochondrial function measurement, B cell differentiation assay, lupus mouse model Science translational medicine Medium 41191778
2026 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. Heart-specific knockout mouse, subcellular fractionation, immunoprecipitation, immunofluorescence, proximity ligation assay, colorimetric proton-pumping assay, autophagy flux assay Autophagy High 41432243

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Chemical screening identifies ATM as a target for alleviating senescence. Nature chemical biology 149 28346404
2005 Distinct expression patterns of different subunit isoforms of the V-ATPase in the rat epididymis. Biology of reproduction 141 16192400
2021 Hypoxia-stimulated ATM activation regulates autophagy-associated exosome release from cancer-associated fibroblasts to promote cancer cell invasion. Journal of extracellular vesicles 108 34545708
2020 ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function. Proceedings of the National Academy of Sciences of the United States of America 72 32513711
2014 RILP regulates vacuolar ATPase through interaction with the V1G1 subunit. Journal of cell science 65 24762812
2015 The vacuolar H+ ATPase is a novel therapeutic target for glioblastoma. Oncotarget 55 26020805
2002 Differential localization of the vacuolar H+ pump with G subunit isoforms (G1 and G2) in mouse neurons. The Journal of biological chemistry 54 12133826
2014 A new V-ATPase regulatory mechanism mediated by the Rab interacting lysosomal protein (RILP). Communicative & integrative biology 27 26843904
2024 Iron metabolism disorder and multiple sclerosis: a comprehensive analysis. Frontiers in immunology 24 38590521
2015 Bivariate Genome-Wide Association Study Implicates ATP6V1G1 as a Novel Pleiotropic Locus Underlying Osteoporosis and Age at Menarche. The Journal of clinical endocrinology and metabolism 23 26312577
2021 RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes. Hepatology communications 21 34558854
2020 Proteomic Characterization of Proliferation Inhibition of Well-Differentiated Laryngeal Squamous Cell Carcinoma Cells Under Below-Background Radiation in a Deep Underground Environment. Frontiers in public health 18 33194991
2023 Disturbance of gut microbiota aggravates cadmium-induced neurotoxicity in zebrafish larvae through V-ATPase. The Science of the total environment 12 37245817
2024 Collapse of late endosomal pH elicits a rapid Rab7 response via the V-ATPase and RILP. Journal of cell science 11 38578235
2018 Genomic regions and enrichment analyses associated with carcass composition indicator traits in Nellore cattle. Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie 11 30592105
2024 Identification and validation of cuproptosis and disulfidptosis related genes in colorectal cancer. Cellular signalling 9 38643947
2024 Plasma exosomes impair microglial degradation of α-synuclein through V-ATPase subunit V1G1. CNS neuroscience & therapeutics 8 38702933
2020 Interplay Between V-ATPase G1 and Small EV-miRNAs Modulates ERK1/2 Activation in GBM Stem Cells and Nonneoplastic Milieu. Molecular cancer research : MCR 6 32753475
2016 Methylation and expression analyses of Pallister-Killian syndrome reveal partial dosage compensation of tetrasomy 12p and hypomethylation of gene-poor regions on 12p. Epigenetics 6 26890086
2025 Identification of shared genetic loci for asthma, allergic rhinitis, and pollinosis in East Asians. Scientific reports 5 39972113
2024 Proteomic Analysis Reveals Oxidative Phosphorylation and JAK-STAT Pathways Mediated Pathogenesis of Pemphigus Vulgaris. Experimental dermatology 5 39373252
2025 CLASHub: an integrated database and analytical platform for microRNA-target interactions. bioRxiv : the preprint server for biology 4 40799581
2025 The m6A demethylase FTO links TLR7 to mitochondrial oxidation driving age-associated B cell formation in systemic lupus erythematosus. Science translational medicine 4 41191778
2025 mRNA 3' UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth. bioRxiv : the preprint server for biology 2 41279844
2024 Identification and characterization of the receptors of a microneme adhesive repeat domain of Eimeria maxima microneme protein 3 in chicken intestine epithelial cells. Poultry science 2 38350385
2026 mRNA 3' UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth. Genes & development 1 41871909
2026 CLASHub is an integrated database and analytical platform for microRNA-target interactions. Nature communications 1 42098137
2026 Comprehensive methodological evaluation of V-ATPase assembly in the context of cardiac lipid overload: implications for (endo)lysosomal function and autophagy. Autophagy 0 41432243
2026 Targeted Intracellular Delivery of Amino Acids to Trophoblast Cells Reveals Proteomic Signatures of Cellular Utilisation. Biomolecules 0 42193979
2025 Analysis of the toxicity and mechanisms of osteoporosis caused by cigarette toxicants using network toxicology and molecular docking techniques. The Science of the total environment 0 40925315
2025 Evolution of the Chick Embryo Chorioallantoic Membrane Proteome during Early Development. ACS omega 0 41552518

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