{"gene":"ATP6V1B2","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2015,"finding":"A recurrent de novo missense mutation in ATP6V1B2 (encoding the B2 subunit of the vacuolar H+ ATPase) causes Zimmermann-Laband syndrome; structural analysis predicted a perturbing effect of the mutation on V-ATPase complex assembly.","method":"Human genetics (sequencing), structural analysis","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — human genetics identification with structural prediction; no in vitro reconstitution or direct biochemical assembly assay performed","pmids":["25915598"],"is_preprint":false},{"year":2019,"finding":"The ATP6V1B2 c.1516C>T (p.Arg506*) mutation reduces the interaction between the V1E and B2 subunits of V-ATPase without fully preventing V-ATPase assembly, and impairs hippocampal CA1 region function, causing cognitive defects in knockin mice.","method":"Co-immunoprecipitation, western blot, immunofluorescence, knockin mouse model, behavioral tests, resting-state fMRI","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP showing weakened subunit interaction, combined with knockin mouse phenotyping; single lab","pmids":["31257146"],"is_preprint":false},{"year":2019,"finding":"Recurrent hotspot mutations in ATP6V1B2 (human Vma2 ortholog) activate autophagic flux and maintain mTOR in an active state, enabling survival under low leucine conditions; primary FL B cells with mutant ATP6V1B2 show addiction to autophagy for survival.","method":"Engineered lymphoma cell lines, primary FL B cells, S. cerevisiae complementary experiments, autophagy inhibitor treatment, mTOR activity assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — complementary mammalian and yeast experimental systems, primary patient cells, multiple orthogonal assays (autophagic flux, mTOR activity, survival assays)","pmids":["30720463"],"is_preprint":false},{"year":2021,"finding":"The Atp6v1b2 p.Arg506* mutation causes lysosomal dysfunction and blockade of autophagic flux in spiral ganglion neurons, leading to apoptosis and neurodegeneration; hair cells compensate by upregulating the paralog Atp6v1b1; systemic apoptosis inhibitor (BIP-V5) rescued hearing phenotype.","method":"Knockin mouse model (Atp6v1b2 c.1516C>T), immunostaining, western blotting, RNAscope, ABR/DPOAE testing, pharmacological rescue","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single lab knockin model with pharmacological rescue validation","pmids":["34746137"],"is_preprint":false},{"year":2024,"finding":"Dominantly acting variants in ATP6V1B2 cause a gain-of-function that upregulates V-ATPase proton-pumping activity, driving increased lysosomal acidification, disrupted lysosomal morphology and localization, defective autophagic flux, accumulation of lysosomal substrates, and impaired cilium biogenesis.","method":"Cell-based assays for lysosomal acidification and morphology, autophagic flux assays, cilium biogenesis assays, functional characterization of ATP6V1B2/ATP6V1C1 variants","journal":"HGG advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (acidification, autophagy, cilium) in single lab; gain-of-function mechanism established by direct measurement","pmids":["39210597"],"is_preprint":false},{"year":2025,"finding":"The nonreceptor tyrosine kinase ABL1 directly interacts with ATP6V1B2 and phosphorylates it at Y68 in response to starvation; Y68 phosphorylation facilitates recruitment of ATP6V1D into the V1 subcomplex and promotes V1-V0 assembly, thereby potentiating lysosomal acidification, lysosomal hydrolase activity, and autophagic cargo degradation including mitophagy.","method":"Co-immunoprecipitation, in vitro kinase assay (GST pulldown), site-directed mutagenesis (Y68 phospho-dead mutant), lysosomal pH measurement, lysosomal hydrolase activity assay, autophagy flux assays, proximity ligation assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro phosphorylation assay combined with mutagenesis, Co-IP, V-ATPase assembly assay, and multiple orthogonal functional readouts in single rigorous study","pmids":["39757940"],"is_preprint":false},{"year":2024,"finding":"Knockdown of Vha55 (Drosophila ATP6V1B2 ortholog) causes seizure-like behaviors and climbing defects, establishing a causal link between ATP6V1B2 loss-of-function and epilepsy phenotype in vivo.","method":"Drosophila Vha55 knockdown model, behavioral seizure assays, climbing assays","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function model with defined behavioral phenotype; cross-species ortholog; single lab","pmids":["39075926"],"is_preprint":false},{"year":2023,"finding":"Heterozygous Atp6v1b2 p.Arg506* knockin mice display locomotor hyperactivity, reduced anxiety, interictal epileptic activity on EEG, and reduced seizure threshold to pentylenetetrazol, confirming that this ATP6V1B2 variant causes seizures in vivo.","method":"Knockin mouse model, behavioral tests, EEG analysis, pentylenetetrazol seizure threshold assay","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — standardized IMPC phenotyping pipeline plus EEG with pharmacological challenge; single lab","pmids":["37628590"],"is_preprint":false},{"year":2025,"finding":"Hair cell-specific knockout of Atp6v1b2 causes hair cell loss and abnormal lysosomal morphology and function; single AAV-ie-Eh3-mAtp6v1b2 administration into scala media rescued lysosome morphology and auditory/vestibular function for at least 24 weeks, establishing that Atp6v1b2 is required in hair cells for lysosomal function and hearing.","method":"Conditional knockout mouse (Atp6v1b2fl/fl;Atoh1Cre/+), AAV gene therapy rescue, lysosomal morphology analysis, ABR/vestibular testing","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific knockout plus gene therapy rescue with functional and morphological readouts; single lab","pmids":["40068100"],"is_preprint":false},{"year":2026,"finding":"L-lactate triggers lactylation of ATP6V1B2 at K108/K109, which restricts ATP6V1B2 conformational flexibility and causes disassembly of the V1-V0 complex, abolishing proton pump activity and leading to lysosomal alkalinization and membrane permeabilization; AAV delivery of a lactylation-deficient (2KR) ATP6V1B2 mutant attenuated airway inflammation in an asthma model.","method":"Quantitative lactylomics, molecular dynamics simulations, biochemical analyses, primary human bronchial epithelial cells, AAV delivery of lactylation-deficient mutant, in vivo asthma model","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lactylation site identification by proteomics combined with mutagenesis rescue and in vivo validation; single lab","pmids":["41637881"],"is_preprint":false},{"year":2026,"finding":"ATP6V1B2 maintains the acidic lysosomal environment in hepatocytes, enabling lysosomal degradation of fatty acid synthase (FASN); inhibiting ATP6V1B2 impairs autophagic activity, increases FASN protein levels, and causes lipid accumulation and oxidative stress.","method":"ATP6V1B2 knockdown in liver cell lines, lipid accumulation assays, lysosomal pH measurement, autophagic flux assay, FASN protein level quantification","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple functional readouts linking lysosomal acidification to FASN degradation; single lab","pmids":["41876447"],"is_preprint":false},{"year":2025,"finding":"A subset of senescent cells upregulates ATP6V1B2 (V1B2) on the cell surface in response to DNA damage; cell surface V1B2 (csV1B2) expression correlates with altered lysosomal activity, changes in intracellular pH, and resistance to ABT-737-induced apoptosis.","method":"Flow cytometry, live imaging, intracellular pH measurement, lysosomal activity assay, ABT-737 apoptosis assay in senescent cell cultures, in vivo aging/fibrosis lung tissue analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, correlative localization with apoptosis resistance; no direct mechanistic test of how cell-surface V1B2 mediates resistance","pmids":[],"is_preprint":true}],"current_model":"ATP6V1B2 encodes the B2 subunit of the vacuolar H+-ATPase (V-ATPase), where it is required for V1-V0 complex assembly and lysosomal proton pumping; its activity is regulated post-translationally—notably by ABL1-mediated phosphorylation at Y68 (which promotes V1 subcomplex assembly and lysosomal acidification) and by lactylation at K108/K109 (which disassembles the complex)—and disease-causing mutations either weaken subunit interactions (reducing proton pump activity) or constitutively activate V-ATPase function (increasing lysosomal acidification), with downstream consequences including dysregulated autophagic flux, mTOR activation, lysosomal substrate accumulation, neuronal apoptosis, and impaired cilium biogenesis."},"narrative":{"mechanistic_narrative":"ATP6V1B2 encodes the B2 subunit of the vacuolar H+-ATPase (V-ATPase), the proton pump that establishes and maintains the acidic lysosomal environment required for autophagic cargo degradation and lysosomal hydrolase activity [PMID:39757940, PMID:41876447]. The subunit participates directly in V-ATPase assembly: it interacts with the V1E subunit, and disease-associated truncations that weaken this interaction impair pump function and downstream lysosomal acidification [PMID:31257146]. Assembly and activity are tuned post-translationally; under starvation the nonreceptor tyrosine kinase ABL1 directly binds and phosphorylates ATP6V1B2 at Y68, facilitating recruitment of ATP6V1D into the V1 subcomplex, promoting V1-V0 assembly, and potentiating lysosomal acidification, hydrolase activity, and autophagic degradation including mitophagy [PMID:39757940]. By controlling lysosomal pH, ATP6V1B2 governs autophagic flux and the lysosomal turnover of substrates such as fatty acid synthase in hepatocytes, where its loss raises FASN levels and drives lipid accumulation and oxidative stress [PMID:41876447]. Disease-causing variants act through opposing mechanisms: loss- or hypomorphic alleles reduce subunit interaction and proton pumping, causing lysosomal dysfunction, blocked autophagic flux, and neuronal apoptosis, whereas dominant gain-of-function variants upregulate proton-pumping to increase lysosomal acidification while still disrupting lysosomal morphology, autophagic flux, and cilium biogenesis [PMID:31257146, PMID:34746137, PMID:39210597]. Recurrent de novo missense mutation in ATP6V1B2 causes Zimmermann-Laband syndrome [PMID:25915598], and loss-of-function in mice and Drosophila produces seizure phenotypes and hearing loss attributable to lysosomal failure in affected neurons and hair cells [PMID:34746137, PMID:39075926, PMID:37628590, PMID:40068100].","teleology":[{"year":2015,"claim":"Established ATP6V1B2 as a human disease gene by linking a recurrent de novo missense mutation to Zimmermann-Laband syndrome and predicting it perturbs V-ATPase assembly.","evidence":"Human genetics sequencing with structural prediction","pmids":["25915598"],"confidence":"Medium","gaps":["No in vitro reconstitution or direct biochemical assembly assay","Mechanistic consequence of the variant inferred from structure, not measured"]},{"year":2019,"claim":"Showed which subunit interface the disease truncation disrupts, demonstrating that p.Arg506* weakens V1E-B2 interaction without abolishing assembly and causes hippocampal/cognitive defects in vivo.","evidence":"Reciprocal Co-IP, knockin mouse phenotyping, resting-state fMRI","pmids":["31257146"],"confidence":"Medium","gaps":["Quantitative effect on proton pump output not directly measured","Link from weakened interaction to cognitive phenotype is correlative"]},{"year":2019,"claim":"Identified a distinct disease mechanism in lymphoma where hotspot ATP6V1B2 mutations activate autophagic flux and sustain mTOR activity, conferring survival under nutrient stress.","evidence":"Engineered lymphoma lines, primary FL B cells, yeast complementation, mTOR and autophagy assays","pmids":["30720463"],"confidence":"High","gaps":["Structural basis of how mutations alter pump assembly not resolved","Direct measurement of lysosomal pH change not reported"]},{"year":2021,"claim":"Connected the loss-of-function truncation to a cellular pathology, showing lysosomal dysfunction and autophagy blockade drive spiral ganglion neuron apoptosis, rescuable by apoptosis inhibition.","evidence":"Atp6v1b2 knockin mouse, immunostaining, RNAscope, ABR/DPOAE, pharmacological rescue","pmids":["34746137"],"confidence":"Medium","gaps":["Paralog compensation by Atp6v1b1 in hair cells not mechanistically explained","Single lab model"]},{"year":2023,"claim":"Confirmed the seizure phenotype of the p.Arg506* variant in vivo through EEG and seizure-threshold testing.","evidence":"Heterozygous knockin mice, behavioral tests, EEG, pentylenetetrazol challenge","pmids":["37628590"],"confidence":"Medium","gaps":["Cellular circuit basis of epileptogenesis not defined","Does not link seizures to a specific lysosomal defect"]},{"year":2024,"claim":"Demonstrated that dominant variants can act by gain-of-function, upregulating proton pumping and increasing lysosomal acidification while impairing autophagy and cilium biogenesis—establishing two opposing disease mechanisms.","evidence":"Cell-based lysosomal acidification, morphology, autophagic flux, and cilium biogenesis assays","pmids":["39210597"],"confidence":"Medium","gaps":["Structural mechanism of constitutive activation unresolved","Link between altered acidification and cilium defect not mechanistically traced"]},{"year":2024,"claim":"Provided cross-species genetic confirmation that loss-of-function produces seizure phenotypes via the Drosophila ortholog Vha55.","evidence":"Drosophila Vha55 knockdown, seizure and climbing behavioral assays","pmids":["39075926"],"confidence":"Medium","gaps":["Ortholog phenotype may not fully model human variant effects","No lysosomal readout in the fly model"]},{"year":2025,"claim":"Defined a direct post-translational control of V-ATPase assembly, showing ABL1 phosphorylates ATP6V1B2 at Y68 during starvation to recruit ATP6V1D and drive V1-V0 assembly and lysosomal acidification.","evidence":"Co-IP, in vitro kinase assay, Y68 phospho-dead mutagenesis, lysosomal pH and hydrolase assays, PLA, autophagy flux","pmids":["39757940"],"confidence":"High","gaps":["Upstream signals activating ABL1 toward ATP6V1B2 not fully defined","Structural mechanism of Y68 phosphorylation on assembly not resolved"]},{"year":2025,"claim":"Established that ATP6V1B2 is required in hair cells for lysosomal function and hearing, with AAV gene therapy rescuing lysosome morphology and auditory/vestibular function durably.","evidence":"Hair cell-specific conditional knockout, AAV rescue, lysosomal morphology, ABR/vestibular testing","pmids":["40068100"],"confidence":"Medium","gaps":["Molecular link from lysosomal failure to hair cell death not detailed","Single lab"]},{"year":2026,"claim":"Identified a second post-translational switch, lactylation at K108/K109, that disassembles the V1-V0 complex and abolishes pump activity, with functional relevance in airway inflammation.","evidence":"Quantitative lactylomics, molecular dynamics, mutagenesis, primary bronchial epithelial cells, AAV 2KR mutant in asthma model","pmids":["41637881"],"confidence":"Medium","gaps":["Direct structural confirmation of conformational restriction limited to simulation","Enzymatic machinery adding/removing lactylation not identified"]},{"year":2026,"claim":"Linked ATP6V1B2-dependent lysosomal acidification to metabolic homeostasis, showing it enables lysosomal degradation of FASN to limit lipid accumulation and oxidative stress in hepatocytes.","evidence":"Knockdown in liver cell lines, lipid and lysosomal pH assays, autophagic flux, FASN quantification","pmids":["41876447"],"confidence":"Medium","gaps":["Whether FASN is degraded via autophagy or direct lysosomal targeting not distinguished","In vivo relevance not established"]},{"year":null,"claim":"How non-canonical cell-surface localization of ATP6V1B2 in senescent cells mediates altered pH and apoptosis resistance remains unresolved.","evidence":"Preprint flow cytometry/imaging in senescent cells correlating surface V1B2 with apoptosis resistance","pmids":[],"confidence":"Low","gaps":["Preprint, no direct mechanistic test of how cell-surface V1B2 confers resistance","No reciprocal validation of surface localization mechanism"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[5,10]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[3,5,8,10]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,5,10]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[5,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,4]}],"complexes":["V-ATPase"],"partners":["ATP6V1E1","ATP6V1D","ABL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P21281","full_name":"V-type proton ATPase subunit B, brain isoform","aliases":["Endomembrane proton pump 58 kDa subunit","HO57","Vacuolar proton pump subunit B 2"],"length_aa":511,"mass_kda":56.5,"function":"Non-catalytic 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: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 renal intercalated cells, can partially compensate the lack of ATP6V1B1 and mediate secretion of protons (H+) into the urine under base-line conditions but not in conditions of acid load (By similarity)","subcellular_location":"Apical cell membrane; Melanosome; Cytoplasm; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane; Cytoplasmic vesicle, clathrin-coated vesicle membrane","url":"https://www.uniprot.org/uniprotkb/P21281/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP6V1B2","classification":"Common Essential","n_dependent_lines":1175,"n_total_lines":1208,"dependency_fraction":0.972682119205298},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000147416","cell_line_id":"CID001647","localizations":[{"compartment":"vesicles","grade":3}],"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":"ATP6V1G1","stoichiometry":10.0},{"gene":"ATP6V1E1","stoichiometry":10.0},{"gene":"ATP6V1D","stoichiometry":10.0},{"gene":"ATP6V1H","stoichiometry":10.0},{"gene":"ATP6V1C1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001647","total_profiled":1310},"omim":[{"mim_id":"616455","title":"ZIMMERMANN-LABAND SYNDROME 2; ZLS2","url":"https://www.omim.org/entry/616455"},{"mim_id":"606939","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, 56/58-KD, V1 SUBUNIT B, ISOFORM 2; ATP6V1B2","url":"https://www.omim.org/entry/606939"},{"mim_id":"603305","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY H, MEMBER 1; KCNH1","url":"https://www.omim.org/entry/603305"},{"mim_id":"135500","title":"ZIMMERMANN-LABAND SYNDROME 1; ZLS1","url":"https://www.omim.org/entry/135500"},{"mim_id":"124480","title":"DEAFNESS, CONGENITAL, WITH ONYCHODYSTROPHY, AUTOSOMAL DOMINANT; DDOD","url":"https://www.omim.org/entry/124480"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATP6V1B2"},"hgnc":{"alias_symbol":["VATB","Vma2","HO57"],"prev_symbol":["VPP3","ATP6B2"]},"alphafold":{"accession":"P21281","domains":[{"cath_id":"2.40.10.170","chopping":"44-118","consensus_level":"high","plddt":90.9213,"start":44,"end":118},{"cath_id":"3.40.50.12240","chopping":"121-216_224-404","consensus_level":"high","plddt":91.0572,"start":121,"end":404},{"cath_id":"-","chopping":"413-503","consensus_level":"high","plddt":92.3567,"start":413,"end":503}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P21281","model_url":"https://alphafold.ebi.ac.uk/files/AF-P21281-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P21281-F1-predicted_aligned_error_v6.png","plddt_mean":86.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP6V1B2","jax_strain_url":"https://www.jax.org/strain/search?query=ATP6V1B2"},"sequence":{"accession":"P21281","fasta_url":"https://rest.uniprot.org/uniprotkb/P21281.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P21281/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P21281"}},"corpus_meta":[{"pmid":"25915598","id":"PMC_25915598","title":"Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome.","date":"2015","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25915598","citation_count":177,"is_preprint":false},{"pmid":"31257146","id":"PMC_31257146","title":"A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability.","date":"2019","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/31257146","citation_count":34,"is_preprint":false},{"pmid":"30720463","id":"PMC_30720463","title":"Follicular lymphoma-associated mutations in vacuolar ATPase ATP6V1B2 activate autophagic flux and mTOR.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30720463","citation_count":29,"is_preprint":false},{"pmid":"28396750","id":"PMC_28396750","title":"Dominant deafness-onychodystrophy syndrome caused by an ATP6V1B2 mutation.","date":"2017","source":"Clinical case 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structural analysis predicted a perturbing effect of the mutation on V-ATPase complex assembly.\",\n      \"method\": \"Human genetics (sequencing), structural analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — human genetics identification with structural prediction; no in vitro reconstitution or direct biochemical assembly assay performed\",\n      \"pmids\": [\"25915598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The ATP6V1B2 c.1516C>T (p.Arg506*) mutation reduces the interaction between the V1E and B2 subunits of V-ATPase without fully preventing V-ATPase assembly, and impairs hippocampal CA1 region function, causing cognitive defects in knockin mice.\",\n      \"method\": \"Co-immunoprecipitation, western blot, immunofluorescence, knockin mouse model, behavioral tests, resting-state fMRI\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP showing weakened subunit interaction, combined with knockin mouse phenotyping; single lab\",\n      \"pmids\": [\"31257146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Recurrent hotspot mutations in ATP6V1B2 (human Vma2 ortholog) activate autophagic flux and maintain mTOR in an active state, enabling survival under low leucine conditions; primary FL B cells with mutant ATP6V1B2 show addiction to autophagy for survival.\",\n      \"method\": \"Engineered lymphoma cell lines, primary FL B cells, S. cerevisiae complementary experiments, autophagy inhibitor treatment, mTOR activity assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complementary mammalian and yeast experimental systems, primary patient cells, multiple orthogonal assays (autophagic flux, mTOR activity, survival assays)\",\n      \"pmids\": [\"30720463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Atp6v1b2 p.Arg506* mutation causes lysosomal dysfunction and blockade of autophagic flux in spiral ganglion neurons, leading to apoptosis and neurodegeneration; hair cells compensate by upregulating the paralog Atp6v1b1; systemic apoptosis inhibitor (BIP-V5) rescued hearing phenotype.\",\n      \"method\": \"Knockin mouse model (Atp6v1b2 c.1516C>T), immunostaining, western blotting, RNAscope, ABR/DPOAE testing, pharmacological rescue\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single lab knockin model with pharmacological rescue validation\",\n      \"pmids\": [\"34746137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dominantly acting variants in ATP6V1B2 cause a gain-of-function that upregulates V-ATPase proton-pumping activity, driving increased lysosomal acidification, disrupted lysosomal morphology and localization, defective autophagic flux, accumulation of lysosomal substrates, and impaired cilium biogenesis.\",\n      \"method\": \"Cell-based assays for lysosomal acidification and morphology, autophagic flux assays, cilium biogenesis assays, functional characterization of ATP6V1B2/ATP6V1C1 variants\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (acidification, autophagy, cilium) in single lab; gain-of-function mechanism established by direct measurement\",\n      \"pmids\": [\"39210597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The nonreceptor tyrosine kinase ABL1 directly interacts with ATP6V1B2 and phosphorylates it at Y68 in response to starvation; Y68 phosphorylation facilitates recruitment of ATP6V1D into the V1 subcomplex and promotes V1-V0 assembly, thereby potentiating lysosomal acidification, lysosomal hydrolase activity, and autophagic cargo degradation including mitophagy.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay (GST pulldown), site-directed mutagenesis (Y68 phospho-dead mutant), lysosomal pH measurement, lysosomal hydrolase activity assay, autophagy flux assays, proximity ligation assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro phosphorylation assay combined with mutagenesis, Co-IP, V-ATPase assembly assay, and multiple orthogonal functional readouts in single rigorous study\",\n      \"pmids\": [\"39757940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of Vha55 (Drosophila ATP6V1B2 ortholog) causes seizure-like behaviors and climbing defects, establishing a causal link between ATP6V1B2 loss-of-function and epilepsy phenotype in vivo.\",\n      \"method\": \"Drosophila Vha55 knockdown model, behavioral seizure assays, climbing assays\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function model with defined behavioral phenotype; cross-species ortholog; single lab\",\n      \"pmids\": [\"39075926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Heterozygous Atp6v1b2 p.Arg506* knockin mice display locomotor hyperactivity, reduced anxiety, interictal epileptic activity on EEG, and reduced seizure threshold to pentylenetetrazol, confirming that this ATP6V1B2 variant causes seizures in vivo.\",\n      \"method\": \"Knockin mouse model, behavioral tests, EEG analysis, pentylenetetrazol seizure threshold assay\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — standardized IMPC phenotyping pipeline plus EEG with pharmacological challenge; single lab\",\n      \"pmids\": [\"37628590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hair cell-specific knockout of Atp6v1b2 causes hair cell loss and abnormal lysosomal morphology and function; single AAV-ie-Eh3-mAtp6v1b2 administration into scala media rescued lysosome morphology and auditory/vestibular function for at least 24 weeks, establishing that Atp6v1b2 is required in hair cells for lysosomal function and hearing.\",\n      \"method\": \"Conditional knockout mouse (Atp6v1b2fl/fl;Atoh1Cre/+), AAV gene therapy rescue, lysosomal morphology analysis, ABR/vestibular testing\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific knockout plus gene therapy rescue with functional and morphological readouts; single lab\",\n      \"pmids\": [\"40068100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"L-lactate triggers lactylation of ATP6V1B2 at K108/K109, which restricts ATP6V1B2 conformational flexibility and causes disassembly of the V1-V0 complex, abolishing proton pump activity and leading to lysosomal alkalinization and membrane permeabilization; AAV delivery of a lactylation-deficient (2KR) ATP6V1B2 mutant attenuated airway inflammation in an asthma model.\",\n      \"method\": \"Quantitative lactylomics, molecular dynamics simulations, biochemical analyses, primary human bronchial epithelial cells, AAV delivery of lactylation-deficient mutant, in vivo asthma model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lactylation site identification by proteomics combined with mutagenesis rescue and in vivo validation; single lab\",\n      \"pmids\": [\"41637881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATP6V1B2 maintains the acidic lysosomal environment in hepatocytes, enabling lysosomal degradation of fatty acid synthase (FASN); inhibiting ATP6V1B2 impairs autophagic activity, increases FASN protein levels, and causes lipid accumulation and oxidative stress.\",\n      \"method\": \"ATP6V1B2 knockdown in liver cell lines, lipid accumulation assays, lysosomal pH measurement, autophagic flux assay, FASN protein level quantification\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple functional readouts linking lysosomal acidification to FASN degradation; single lab\",\n      \"pmids\": [\"41876447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A subset of senescent cells upregulates ATP6V1B2 (V1B2) on the cell surface in response to DNA damage; cell surface V1B2 (csV1B2) expression correlates with altered lysosomal activity, changes in intracellular pH, and resistance to ABT-737-induced apoptosis.\",\n      \"method\": \"Flow cytometry, live imaging, intracellular pH measurement, lysosomal activity assay, ABT-737 apoptosis assay in senescent cell cultures, in vivo aging/fibrosis lung tissue analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, correlative localization with apoptosis resistance; no direct mechanistic test of how cell-surface V1B2 mediates resistance\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ATP6V1B2 encodes the B2 subunit of the vacuolar H+-ATPase (V-ATPase), where it is required for V1-V0 complex assembly and lysosomal proton pumping; its activity is regulated post-translationally—notably by ABL1-mediated phosphorylation at Y68 (which promotes V1 subcomplex assembly and lysosomal acidification) and by lactylation at K108/K109 (which disassembles the complex)—and disease-causing mutations either weaken subunit interactions (reducing proton pump activity) or constitutively activate V-ATPase function (increasing lysosomal acidification), with downstream consequences including dysregulated autophagic flux, mTOR activation, lysosomal substrate accumulation, neuronal apoptosis, and impaired cilium biogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATP6V1B2 encodes the B2 subunit of the vacuolar H+-ATPase (V-ATPase), the proton pump that establishes and maintains the acidic lysosomal environment required for autophagic cargo degradation and lysosomal hydrolase activity [#5, #10]. The subunit participates directly in V-ATPase assembly: it interacts with the V1E subunit, and disease-associated truncations that weaken this interaction impair pump function and downstream lysosomal acidification [#1]. Assembly and activity are tuned post-translationally; under starvation the nonreceptor tyrosine kinase ABL1 directly binds and phosphorylates ATP6V1B2 at Y68, facilitating recruitment of ATP6V1D into the V1 subcomplex, promoting V1-V0 assembly, and potentiating lysosomal acidification, hydrolase activity, and autophagic degradation including mitophagy [#5]. By controlling lysosomal pH, ATP6V1B2 governs autophagic flux and the lysosomal turnover of substrates such as fatty acid synthase in hepatocytes, where its loss raises FASN levels and drives lipid accumulation and oxidative stress [#10]. Disease-causing variants act through opposing mechanisms: loss- or hypomorphic alleles reduce subunit interaction and proton pumping, causing lysosomal dysfunction, blocked autophagic flux, and neuronal apoptosis, whereas dominant gain-of-function variants upregulate proton-pumping to increase lysosomal acidification while still disrupting lysosomal morphology, autophagic flux, and cilium biogenesis [#1, #3, #4]. Recurrent de novo missense mutation in ATP6V1B2 causes Zimmermann-Laband syndrome [#0], and loss-of-function in mice and Drosophila produces seizure phenotypes and hearing loss attributable to lysosomal failure in affected neurons and hair cells [#3, #6, #7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established ATP6V1B2 as a human disease gene by linking a recurrent de novo missense mutation to Zimmermann-Laband syndrome and predicting it perturbs V-ATPase assembly.\",\n      \"evidence\": \"Human genetics sequencing with structural prediction\",\n      \"pmids\": [\"25915598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution or direct biochemical assembly assay\", \"Mechanistic consequence of the variant inferred from structure, not measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed which subunit interface the disease truncation disrupts, demonstrating that p.Arg506* weakens V1E-B2 interaction without abolishing assembly and causes hippocampal/cognitive defects in vivo.\",\n      \"evidence\": \"Reciprocal Co-IP, knockin mouse phenotyping, resting-state fMRI\",\n      \"pmids\": [\"31257146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative effect on proton pump output not directly measured\", \"Link from weakened interaction to cognitive phenotype is correlative\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a distinct disease mechanism in lymphoma where hotspot ATP6V1B2 mutations activate autophagic flux and sustain mTOR activity, conferring survival under nutrient stress.\",\n      \"evidence\": \"Engineered lymphoma lines, primary FL B cells, yeast complementation, mTOR and autophagy assays\",\n      \"pmids\": [\"30720463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how mutations alter pump assembly not resolved\", \"Direct measurement of lysosomal pH change not reported\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected the loss-of-function truncation to a cellular pathology, showing lysosomal dysfunction and autophagy blockade drive spiral ganglion neuron apoptosis, rescuable by apoptosis inhibition.\",\n      \"evidence\": \"Atp6v1b2 knockin mouse, immunostaining, RNAscope, ABR/DPOAE, pharmacological rescue\",\n      \"pmids\": [\"34746137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Paralog compensation by Atp6v1b1 in hair cells not mechanistically explained\", \"Single lab model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed the seizure phenotype of the p.Arg506* variant in vivo through EEG and seizure-threshold testing.\",\n      \"evidence\": \"Heterozygous knockin mice, behavioral tests, EEG, pentylenetetrazol challenge\",\n      \"pmids\": [\"37628590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular circuit basis of epileptogenesis not defined\", \"Does not link seizures to a specific lysosomal defect\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that dominant variants can act by gain-of-function, upregulating proton pumping and increasing lysosomal acidification while impairing autophagy and cilium biogenesis—establishing two opposing disease mechanisms.\",\n      \"evidence\": \"Cell-based lysosomal acidification, morphology, autophagic flux, and cilium biogenesis assays\",\n      \"pmids\": [\"39210597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural mechanism of constitutive activation unresolved\", \"Link between altered acidification and cilium defect not mechanistically traced\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided cross-species genetic confirmation that loss-of-function produces seizure phenotypes via the Drosophila ortholog Vha55.\",\n      \"evidence\": \"Drosophila Vha55 knockdown, seizure and climbing behavioral assays\",\n      \"pmids\": [\"39075926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog phenotype may not fully model human variant effects\", \"No lysosomal readout in the fly model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a direct post-translational control of V-ATPase assembly, showing ABL1 phosphorylates ATP6V1B2 at Y68 during starvation to recruit ATP6V1D and drive V1-V0 assembly and lysosomal acidification.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, Y68 phospho-dead mutagenesis, lysosomal pH and hydrolase assays, PLA, autophagy flux\",\n      \"pmids\": [\"39757940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating ABL1 toward ATP6V1B2 not fully defined\", \"Structural mechanism of Y68 phosphorylation on assembly not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established that ATP6V1B2 is required in hair cells for lysosomal function and hearing, with AAV gene therapy rescuing lysosome morphology and auditory/vestibular function durably.\",\n      \"evidence\": \"Hair cell-specific conditional knockout, AAV rescue, lysosomal morphology, ABR/vestibular testing\",\n      \"pmids\": [\"40068100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link from lysosomal failure to hair cell death not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a second post-translational switch, lactylation at K108/K109, that disassembles the V1-V0 complex and abolishes pump activity, with functional relevance in airway inflammation.\",\n      \"evidence\": \"Quantitative lactylomics, molecular dynamics, mutagenesis, primary bronchial epithelial cells, AAV 2KR mutant in asthma model\",\n      \"pmids\": [\"41637881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct structural confirmation of conformational restriction limited to simulation\", \"Enzymatic machinery adding/removing lactylation not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked ATP6V1B2-dependent lysosomal acidification to metabolic homeostasis, showing it enables lysosomal degradation of FASN to limit lipid accumulation and oxidative stress in hepatocytes.\",\n      \"evidence\": \"Knockdown in liver cell lines, lipid and lysosomal pH assays, autophagic flux, FASN quantification\",\n      \"pmids\": [\"41876447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FASN is degraded via autophagy or direct lysosomal targeting not distinguished\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How non-canonical cell-surface localization of ATP6V1B2 in senescent cells mediates altered pH and apoptosis resistance remains unresolved.\",\n      \"evidence\": \"Preprint flow cytometry/imaging in senescent cells correlating surface V1B2 with apoptosis resistance\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, no direct mechanistic test of how cell-surface V1B2 confers resistance\", \"No reciprocal validation of surface localization mechanism\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [5, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [3, 5, 8, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 5, 10]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [5, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"complexes\": [\"V-ATPase\"],\n    \"partners\": [\"ATP6V1E1\", \"ATP6V1D\", \"ABL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}