{"gene":"ATP6V1B2","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2015,"finding":"A recurrent de novo heterozygous missense mutation in ATP6V1B2 (encoding the B2 subunit of the vacuolar H+ ATPase) causes Zimmermann-Laband syndrome (ZLS). Structural analysis predicted a perturbing effect of the mutation on V-ATPase complex assembly.","method":"Exome sequencing, structural modeling","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 — human genetic discovery with structural modeling, single study","pmids":["25915598"],"is_preprint":false},{"year":1988,"finding":"The Neurospora crassa vma-2 gene encodes the 57-kDa B subunit of the vacuolar ATPase (ortholog of ATP6V1B2). The polypeptide has no membrane-spanning domains, shows ~25% amino acid identity with both the vma-1 (A subunit) gene product and the alpha/beta subunits of F0F1 ATPases, suggesting it evolved from a common ancestor and likely fulfills a function analogous to the alpha subunit of F0F1 ATPases (non-catalytic nucleotide binding).","method":"Gene isolation, DNA sequencing, sequence analysis, genetic mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1/2 — foundational biochemical/sequence analysis in fungal ortholog, single study","pmids":["2844751"],"is_preprint":false},{"year":2019,"finding":"Mutations in ATP6V1B2 found in follicular lymphoma activate autophagic flux and maintain mTOR in an active state, enabling survival under low leucine conditions. Engineered lymphoma cell lines and primary FL B cells with mutated ATP6V1B2 were addicted to autophagy for survival, demonstrating that recurrent hotspot mutations in ATP6V1B2 constitutively upregulate autophagic flux as an adaptive mechanism in lymphoma pathogenesis.","method":"Engineered lymphoma cell lines, primary FL B cells, yeast complementation (S. cerevisiae), autophagy inhibitor treatment, leucine starvation assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in mammalian cells and yeast, mechanistic pathway placement","pmids":["30720463"],"is_preprint":false},{"year":2019,"finding":"The ATP6V1B2 c.1516C>T (p.Arg506X) mutation causes cognitive defects in knockin mice via impaired hippocampal CA1 region function. Co-immunoprecipitation demonstrated a weaker interaction between the V1E and B2 subunits in Atp6v1b2 Arg506X/Arg506X mice, although overall V-ATPase assembly was not abolished, indicating the molecular mechanism involves weakened inter-subunit interactions rather than complete complex disassembly.","method":"Knockin mice (Atp6v1b2 c.1516C>T), behavioral tests, resting-state fMRI, immunofluorescence, Western blot, co-immunoprecipitation, zebrafish atp6v1b2 knockdown","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 — in vivo knockin model with multiple orthogonal methods including co-IP demonstrating specific subunit interaction defect","pmids":["31257146"],"is_preprint":false},{"year":2021,"finding":"In Atp6v1b2 Arg506X knockin mice, lysosomal dysfunction and blockade of autophagic flux in spiral ganglion neurons leads to apoptosis and neurodegeneration, causing progressive hearing loss. Atp6v1b1 transcription was upregulated in hair cells as genetic compensation, explaining milder hearing impairment in hair cells. Intraperitoneal administration of apoptosis inhibitor BIP-V5 improved phenotypic and pathological outcomes.","method":"Transgenic knockin mice, ABR, DPOAE, immunostaining, Western blotting, RNAscope, apoptosis inhibitor treatment","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 — in vivo model with multiple methods, pharmacological rescue experiment confirming mechanism","pmids":["34746137"],"is_preprint":false},{"year":2024,"finding":"Disease-associated gain-of-function variants in ATP6V1B2 (and ATP6V1C1) upregulate V-ATPase proton-pumping activity, resulting in increased lysosomal acidification, disrupted lysosomal morphology and localization, defective autophagic flux, accumulation of lysosomal substrates, and impaired cilium biogenesis. This classifies these disorders as lysosomal diseases caused by V-ATPase gain-of-function.","method":"Functional cell biology assays, lysosomal acidification measurements, autophagy flux assays, lysosomal morphology/localization imaging, cilia biogenesis assays","journal":"HGG advances","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays demonstrating gain-of-function mechanism with multiple variants","pmids":["39210597"],"is_preprint":false},{"year":2025,"finding":"In response to starvation, the nonreceptor tyrosine kinase ABL1 directly interacts with ATP6V1B2 and phosphorylates it at tyrosine 68 (Y68). This phosphorylation facilitates recruitment of the ATP6V1D subunit into the V1 subcomplex and potentiates assembly of the V1 subcomplex with the membrane-embedded V0 subcomplex to form functional V-ATPase, thereby enhancing lysosomal acidification and supporting autophagic/mitophagic degradation.","method":"Co-immunoprecipitation, in vitro phosphorylation assay, site-directed mutagenesis (Y68), proximity ligation assay, lysosomal pH measurement, lysosomal hydrolase activity assay, autophagy/mitophagy flux assays, ABL1 inhibition/knockdown","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro phosphorylation assay with mutagenesis (Y68) combined with multiple functional readouts in cells","pmids":["39757940"],"is_preprint":false},{"year":2014,"finding":"In Candida albicans (ortholog VMA2/V1B subunit), the V1B subunit is required for V-ATPase assembly at the vacuolar membrane, proton transport activity, and ATPase-specific activity. Repression of VMA2 caused vacuolar alkalinization, abnormal vacuolar morphology, impaired filamentation and virulence, defective autophagy under nitrogen starvation, and increased osmotic stress susceptibility.","method":"Tetracycline-regulatable VMA2 mutant, proton transport assay, ATPase activity assay, vacuolar morphology imaging, filamentation assays, C. elegans infection model","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 1/2 — direct enzymatic assays (proton transport, ATPase activity) combined with multiple functional phenotypic readouts in fungal ortholog","pmids":["25038082"],"is_preprint":false},{"year":2023,"finding":"Atp6v1b2 Arg506* heterozygous knockin mice display locomotor hyperactivity, reduced anxiety, interictal epileptic activity on EEG, and reduced seizure threshold to pentylenetetrazol, confirming that the ATP6V1B2 p.Arg506* variant causes seizure susceptibility in vivo.","method":"IMPC phenotyping pipeline, EEG recording, pentylenetetrazol seizure threshold assay, behavioral tests","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo heterozygous knockin mouse model with EEG and pharmacological seizure challenge, single study","pmids":["37628590"],"is_preprint":false},{"year":2024,"finding":"Knockdown of Vha55 (the Drosophila ortholog of ATP6V1B2) in flies causes seizure-like behaviors and climbing defects, establishing a causal relationship between ATP6V1B2 loss-of-function and epilepsy phenotypes.","method":"Drosophila Vha55 knockdown model, seizure-like behavior assay, climbing assay, NMD analysis","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo ortholog knockdown in Drosophila with functional behavioral readouts, single study","pmids":["39075926"],"is_preprint":false},{"year":2025,"finding":"AAV-mediated delivery of wild-type Atp6v1b2 into the scala media of hair cell-specific Atp6v1b2 knockout mice (Atp6v1b2fl/fl;Atoh1Cre/+) prevented hair cell degeneration, restored lysosomal morphology, and rescued auditory and vestibular function for at least 24 weeks, establishing that Atp6v1b2 is critical for lysosomal function in hair cells and that its loss drives hair cell degeneration and hearing loss.","method":"Hair cell-specific conditional knockout mice, AAV-ie-Eh3 gene delivery, ABR, vestibular function tests, lysosomal morphology imaging","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 — conditional KO model plus rescue by gene therapy with multiple functional readouts, single study","pmids":["40068100"],"is_preprint":false},{"year":2026,"finding":"l-Lactate-driven lactylation of ATP6V1B2 at K108/K109 restricts its conformational flexibility, causing disassembly of the V1-V0 complex and loss of proton pump activity, leading to lysosomal alkalinization and membrane permeabilization. This triggers cathepsin B leakage, mitochondrial ROS, and Caspase-8/3/GSDME-dependent pyroptosis. AAV delivery of a lactylation-deficient ATP6V1B2 (K108R/K109R) mutant attenuated airway inflammation in an asthma model.","method":"Quantitative lactylomics, molecular dynamics simulations, biochemical assays, V-ATPase assembly assay, lysosomal pH measurement, LMP assay, primary HBEs, HDM asthma model, AAV-delivered 2KR mutant","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods including structural simulations, enzymatic activity, site-specific mutant rescue in vivo","pmids":["41637881"],"is_preprint":false},{"year":2026,"finding":"ATP6V1B2 promotes lysosomal degradation of fatty acid synthase (FASN) by maintaining the acidic environment of lysosomes; loss of ATP6V1B2 in hepatocytes impairs lysosomal acidification and autophagic activity, leading to FASN accumulation and increased lipid deposition, oxidative stress, and hepatic steatosis.","method":"ATP6V1B2 siRNA knockdown in liver cells, lipid accumulation assays, oxidative stress assays, autophagic flux assays, lysosomal pH measurement, FASN protein level analysis","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function in cell model with multiple readouts linking ATP6V1B2 to lysosomal acidification and FASN degradation, single study","pmids":["41876447"],"is_preprint":false},{"year":2025,"finding":"In response to DNA damage, a subset of senescent cells upregulates ATP6V1B2 (V1B2) on the cell surface (csV1B2). This surface localization is associated with altered lysosomal activity and changes in intracellular pH. Cells expressing csV1B2 show increased resistance to ABT-737-induced apoptosis and a transcriptional signature of DNA repair and apoptosis resistance.","method":"Flow cytometry, live-cell imaging, transcriptional profiling, in vitro apoptosis resistance assay, analysis of naturally occurring senescent cells in ageing and fibrotic lungs","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, single study, correlative link between surface localization and apoptosis resistance without direct mechanistic dissection","pmids":["bio_10.1101_2025.11.30.691415"],"is_preprint":true}],"current_model":"ATP6V1B2 encodes the B2 subunit of the vacuolar H+-ATPase (V-ATPase) V1 domain, where it contributes to ATP hydrolysis and complex assembly; it is phosphorylated at Y68 by ABL1 upon starvation to promote V1-V0 subcomplex assembly and lysosomal acidification, and can be inactivated by l-lactate-driven lactylation at K108/K109, leading to V-ATPase disassembly and lysosomal dysfunction; disease-associated mutations cause either loss-of-function (weakened V1E–B2 subunit interactions, lysosomal dysfunction, and neurodegeneration/hearing loss) or gain-of-function (upregulated V-ATPase activity, increased lysosomal acidification, defective autophagic flux, and mTOR activation) depending on the specific variant, collectively classifying ATP6V1B2-related disorders as lysosomal diseases."},"narrative":{"teleology":[{"year":1988,"claim":"Identification of the V-ATPase B subunit as a soluble, non-membrane-spanning polypeptide homologous to F₁F₀-ATPase α/β subunits established that V-ATPase B functions in non-catalytic nucleotide binding rather than as a membrane pore component.","evidence":"Gene isolation, sequencing, and sequence comparison of Neurospora crassa vma-2 (B subunit ortholog)","pmids":["2844751"],"confidence":"Medium","gaps":["Catalytic versus regulatory nucleotide-binding roles of B versus A subunits not yet resolved in mammalian V-ATPase","No structural data for the B subunit at this time"]},{"year":2014,"claim":"Demonstration that the V1B subunit is required for V-ATPase membrane assembly, proton transport, and ATPase activity established its essential role in vacuolar acidification and downstream processes including autophagy and stress resistance.","evidence":"Regulatable VMA2 mutant in C. albicans with proton transport and ATPase activity assays, vacuolar morphology, and nitrogen-starvation autophagy","pmids":["25038082"],"confidence":"High","gaps":["Findings in fungal ortholog; mammalian-specific regulatory mechanisms unexplored","No post-translational regulatory input identified"]},{"year":2015,"claim":"Discovery that recurrent de novo ATP6V1B2 missense mutations cause Zimmermann-Laband syndrome linked human disease to predicted disruption of V-ATPase complex assembly.","evidence":"Exome sequencing of ZLS patients with structural modeling of variant impact on V-ATPase","pmids":["25915598"],"confidence":"Medium","gaps":["Structural prediction only; functional consequence of the ZLS variant on V-ATPase activity not directly measured","Gain- versus loss-of-function not resolved"]},{"year":2019,"claim":"Two independent studies distinguished loss-of-function from gain-of-function mechanisms: the p.Arg506* variant weakens V1E–B2 interaction causing lysosomal dysfunction and cognitive impairment, while follicular lymphoma hotspot mutations constitutively activate autophagic flux and sustain mTOR, creating autophagy dependence.","evidence":"Knockin mice (Arg506*) with co-IP showing weakened V1E–B2 interaction, behavioral/fMRI readouts; engineered lymphoma lines and primary FL B cells with autophagy inhibition and leucine-starvation assays, yeast complementation","pmids":["31257146","30720463"],"confidence":"High","gaps":["Structural basis for how specific variants produce opposite functional outcomes unknown","Whether mTOR activation is a direct consequence of enhanced V-ATPase activity or an indirect effect of altered amino acid sensing not resolved"]},{"year":2021,"claim":"The p.Arg506* variant was shown to cause progressive hearing loss through lysosomal dysfunction and autophagic flux blockade leading to spiral ganglion neuron apoptosis, while compensatory Atp6v1b1 upregulation in hair cells explained milder cochlear phenotypes.","evidence":"Knockin mouse ABR/DPOAE, immunostaining, RNAscope for Atp6v1b1, and BIP-V5 apoptosis inhibitor rescue","pmids":["34746137"],"confidence":"High","gaps":["Whether B1 compensation occurs in human cochlear hair cells not tested","Long-term therapeutic window for apoptosis inhibition not defined"]},{"year":2023,"claim":"Heterozygous Arg506* knockin mice displayed seizure susceptibility and epileptic EEG activity, confirming that partial ATP6V1B2 loss of function is sufficient to cause neuronal hyperexcitability in vivo.","evidence":"EEG recording and pentylenetetrazol seizure threshold assay in heterozygous knockin mice","pmids":["37628590"],"confidence":"Medium","gaps":["Cellular mechanism connecting lysosomal dysfunction to neuronal hyperexcitability not dissected","Single mutation tested; generalizability to other LOF variants unknown"]},{"year":2024,"claim":"Gain-of-function ATP6V1B2 variants were shown to hyperacidify lysosomes, disrupt lysosomal morphology, block autophagic flux, and impair ciliogenesis, classifying these disorders as lysosomal diseases caused by V-ATPase overactivity, and Drosophila Vha55 knockdown independently confirmed that B2 loss causes seizure-like behavior.","evidence":"Functional cell biology assays for lysosomal acidification, autophagy flux, and cilia biogenesis with multiple GOF variants; Drosophila Vha55 knockdown behavioral assays","pmids":["39210597","39075926"],"confidence":"High","gaps":["Mechanism by which excess acidification impairs ciliogenesis not resolved","Whether GOF and LOF variants converge on a shared downstream pathogenic pathway unclear"]},{"year":2025,"claim":"ABL1 was identified as a direct kinase for ATP6V1B2 Y68 phosphorylation under starvation, providing the first post-translational regulatory switch that promotes V1D recruitment, V1–V0 assembly, and enhanced lysosomal acidification to support autophagy and mitophagy.","evidence":"Co-IP, in vitro phosphorylation, Y68 mutagenesis, proximity ligation assay, lysosomal pH and hydrolase assays, autophagy/mitophagy flux in ABL1-inhibited/knockdown cells","pmids":["39757940"],"confidence":"High","gaps":["Whether Y68 phosphorylation is relevant to disease-associated variants not tested","Phosphatase that reverses Y68 phosphorylation not identified"]},{"year":2025,"claim":"AAV-mediated gene replacement of Atp6v1b2 in hair cell-specific knockout mice rescued lysosomal morphology, auditory function, and vestibular function for ≥24 weeks, establishing therapeutic proof-of-concept for ATP6V1B2-related hearing loss.","evidence":"Conditional KO mice (Atp6v1b2fl/fl;Atoh1Cre/+) with AAV-ie-Eh3 delivery into scala media, ABR, vestibular function, lysosomal imaging","pmids":["40068100"],"confidence":"High","gaps":["Whether gene therapy can rescue spiral ganglion neuron degeneration (not only hair cells) untested","Durability beyond 24 weeks and translational dosing not defined"]},{"year":2026,"claim":"l-Lactate-driven lactylation of ATP6V1B2 at K108/K109 was identified as a second post-translational switch that restricts B2 flexibility, disassembles V1–V0, and triggers lysosomal alkalinization, membrane permeabilization, and GSDME-dependent pyroptosis, with in vivo relevance demonstrated by AAV-delivered lactylation-deficient mutant rescue in an asthma model.","evidence":"Quantitative lactylomics, molecular dynamics, V-ATPase assembly and lysosomal pH assays, LMP, primary human bronchial epithelial cells, HDM asthma model with AAV-K108R/K109R mutant","pmids":["41637881"],"confidence":"High","gaps":["Whether lactylation and Y68 phosphorylation are coordinated or antagonistic not examined","Generalizability of lactylation-driven pyroptosis beyond airway epithelium unknown"]},{"year":2026,"claim":"ATP6V1B2 loss in hepatocytes impairs lysosomal acidification and autophagic degradation of FASN, leading to lipid accumulation, oxidative stress, and steatosis, extending the metabolic consequences of B2 deficiency beyond the nervous system.","evidence":"siRNA knockdown in liver cells with lysosomal pH, autophagic flux, FASN protein, lipid accumulation, and oxidative stress assays","pmids":["41876447"],"confidence":"Medium","gaps":["In vivo hepatic phenotype not confirmed in animal model","Whether FASN is a selective substrate or one of many proteins accumulating due to general lysosomal impairment not clarified"]},{"year":null,"claim":"Key open questions include: (1) atomic-resolution structure of disease variants within the assembled V-ATPase explaining gain- versus loss-of-function outcomes; (2) integration of ABL1-mediated Y68 phosphorylation and K108/K109 lactylation into a unified regulatory model; (3) whether cell-surface ATP6V1B2 in senescent cells has a non-canonical function beyond organellar proton pumping.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution cryo-EM structure of disease-variant V-ATPase reported","Cross-talk between phosphorylation and lactylation at B2 not studied","Cell-surface ATP6V1B2 phenotype reported only in a preprint without mechanistic dissection"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,7,6,11]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[7,6]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[7,5,11]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[4,5,6,10,11,12]},{"term_id":"GO:0005773","term_label":"vacuole","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,4,6,7,12]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[7,6,11]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[5,10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,3,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,11]}],"complexes":["V-ATPase (V1 domain)","V-ATPase (V1-V0 holoenzyme)"],"partners":["ATP6V1E1","ATP6V1D","ABL1","ATP6V1C1"],"other_free_text":[]},"mechanistic_narrative":"ATP6V1B2 encodes the brain-enriched B2 subunit of the V1 catalytic domain of the vacuolar H⁺-ATPase (V-ATPase), where it participates in non-catalytic nucleotide binding, ATP hydrolysis-driven proton pumping, and V1–V0 subcomplex assembly required for lysosomal acidification and autophagic degradation [PMID:2844751, PMID:25038082, PMID:39757940]. Starvation-induced phosphorylation of ATP6V1B2 at Y68 by ABL1 promotes V1D subunit recruitment and V1–V0 assembly, enhancing lysosomal acidification and autophagy/mitophagy, whereas l-lactate-driven lactylation at K108/K109 restricts B2 conformational flexibility, causing V-ATPase disassembly, lysosomal alkalinization, and pyroptosis [PMID:39757940, PMID:41637881]. Loss-of-function mutations (e.g. p.Arg506*) weaken the V1E–B2 subunit interaction, producing lysosomal dysfunction, neurodegeneration, progressive hearing loss, and seizure susceptibility, while gain-of-function variants constitutively upregulate V-ATPase activity, causing excess lysosomal acidification, defective autophagic flux, impaired ciliogenesis, and—in follicular lymphoma—autophagy-dependent survival with sustained mTOR activation [PMID:31257146, PMID:34746137, PMID:39210597, PMID:30720463]. Heterozygous de novo ATP6V1B2 mutations cause Zimmermann-Laband syndrome and related neurodevelopmental disorders with hearing loss and epilepsy [PMID:25915598, PMID:37628590]."},"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":176,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2844751","id":"PMC_2844751","title":"Isolation of genes encoding the Neurospora vacuolar ATPase. 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mice; behavioral tests; resting-state fMRI\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a knockin model, single lab\",\n      \"pmids\": [\"31257146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Follicular lymphoma-associated mutations in ATP6V1B2 activate autophagic flux and maintain mTOR in an active state, enabling survival under low leucine concentrations; this was demonstrated in engineered lymphoma cell lines, primary FL B cells, and complemented with yeast (Vma2) experiments.\",\n      \"method\": \"Complementary mammalian cell and S. cerevisiae genetic experiments; autophagic flux assays; mTOR activity assays; pharmacological autophagy inhibition in primary FL B cells\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, cross-species validation, strong mechanistic follow-up\",\n      \"pmids\": [\"30720463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATP6V1B2 dysfunction in spiral ganglion neurons causes lysosomal dysfunction and blockade of autophagic flux, triggering apoptosis and neurodegeneration; compensatory upregulation of Atp6v1b1 in hair cells partially offsets B2 loss, explaining milder hair cell phenotype; apoptosis inhibitor BIP-V5 ameliorated pathological outcomes in vivo.\",\n      \"method\": \"Immunostaining, Western blotting, RNAscope in Atp6v1b2 knockin mice; auditory brainstem response and DPOAE measurements; pharmacological intervention\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods in in vivo model, single lab\",\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 activity, drives increased lysosomal acidification, disrupts lysosomal morphology and localization, causes defective autophagic flux with accumulation of lysosomal substrates, and affects cilium biogenesis.\",\n      \"method\": \"Functional cell-based assays measuring lysosomal acidification, autophagy flux assays, lysosomal morphology and localization studies, cilium biogenesis assays in cells expressing disease-associated variants\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal cellular assays, single lab\",\n      \"pmids\": [\"39210597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The nonreceptor tyrosine kinase ABL1 directly interacts with and phosphorylates ATP6V1B2 at Y68 in response to starvation; Y68 phosphorylation facilitates recruitment of ATP6V1D into the V1 subcomplex and potentiates assembly of V1 with V0 to form functional V-ATPase, thereby maintaining lysosomal acidification required for autophagy and mitophagy.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y68), proximity ligation assay, lysosomal pH measurement, autophagy/mitophagy flux assays, ABL1 inhibition/depletion experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro phosphorylation assay with mutagenesis, multiple orthogonal assays confirming functional consequence\",\n      \"pmids\": [\"39757940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"L-lactate triggers lactylation of ATP6V1B2 at K108/K109, restricting its conformational flexibility and causing disassembly of the V1-V0 complex and loss of proton pump activity, leading to lysosomal alkalinization, membrane permeabilization, and downstream caspase-8/3/GSDME-dependent pyroptosis in bronchial epithelial cells.\",\n      \"method\": \"Quantitative lactylomics, molecular dynamics simulations, biochemical analyses in HBEs, AAV-delivered lactylation-deficient (2KR) mutant rescue in vivo\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro biochemical validation plus in vivo rescue with mutagenesis, but single lab\",\n      \"pmids\": [\"41637881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATP6V1B2 promotes lysosomal degradation of fatty acid synthase (FASN) by maintaining the acidic environment of lysosomes; loss of ATP6V1B2 in liver cells impairs autophagic activity and increases lipid accumulation.\",\n      \"method\": \"ATP6V1B2 knockdown in liver cells; lysosomal pH measurements; FASN protein level assessment; lipid accumulation and oxidative stress assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cellular assays, single lab, single study\",\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; this cell-surface localization is associated with altered lysosomal activity, changes in intracellular pH, and increased resistance to apoptosis (ABT-737).\",\n      \"method\": \"Flow cytometry for cell-surface ATP6V1B2, lysosomal activity assays, intracellular pH measurement, apoptosis assay with ABT-737 in culture; in vivo validation in ageing and fibrotic lung tissue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods with in vivo corroboration, but preprint and single lab\",\n      \"pmids\": [\"bio_10.1101_2025.11.30.691415\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of Vha55 (the ATP6V1B2 Drosophila ortholog) causes seizure-like behaviors and climbing defects, establishing a causal relationship between ATP6V1B2 loss of function and epilepsy.\",\n      \"method\": \"Drosophila Vha55 knockdown model; behavioral seizure and climbing assays\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic loss-of-function with defined phenotypic readout, ortholog in Drosophila\",\n      \"pmids\": [\"39075926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hair cell-specific knockout of Atp6v1b2 causes lysosomal morphology and function defects, hair cell loss, and hearing/vestibular dysfunction; AAV-mediated gene replacement of mAtp6v1b2 rescues lysosome morphology, prevents hair cell degeneration, and restores auditory and vestibular function.\",\n      \"method\": \"Conditional knockout mouse (Atp6v1b2fl/fl;Atoh1Cre/+); AAV-ie-Eh3 gene therapy; auditory brainstem response; lysosomal morphology analysis; histology\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean tissue-specific KO with defined phenotype; gene replacement rescue; multiple orthogonal readouts\",\n      \"pmids\": [\"40068100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"The Neurospora crassa vma-2 gene encodes the 57-kDa (B) subunit of the vacuolar ATPase V1 domain; sequence analysis showed no membrane-spanning domains and similarity to the alpha subunit of F0F1 ATPases, suggesting a regulatory (non-catalytic) role analogous to the alpha subunit, with ATP hydrolysis residing in the vma-1 (A subunit).\",\n      \"method\": \"Gene isolation, DNA sequencing, sequence homology analysis, genetic mapping in N. crassa\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — foundational sequence/domain analysis; ortholog paper establishing subunit identity and structure\",\n      \"pmids\": [\"2844751\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V1B2 encodes the B2 subunit of the V1 catalytic domain of the vacuolar H+-ATPase (V-ATPase); it undergoes phosphorylation by ABL1 at Y68 (promoting V1-V0 complex assembly) and lactylation at K108/K109 (disrupting V1-V0 assembly and proton pump activity), thereby regulating lysosomal acidification, autophagic flux, mTOR signaling, and lysosomal substrate degradation; disease-associated mutations can cause either gain-of-function (increased V-ATPase activity, hyperacidification) or loss-of-function (impaired assembly via weakened subunit interactions), leading to lysosomal dysfunction underlying neurodevelopmental syndromes including DDOD, DOORS, and Zimmermann-Laband syndrome.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"A recurrent de novo heterozygous missense mutation in ATP6V1B2 (encoding the B2 subunit of the vacuolar H+ ATPase) causes Zimmermann-Laband syndrome (ZLS). Structural analysis predicted a perturbing effect of the mutation on V-ATPase complex assembly.\",\n      \"method\": \"Exome sequencing, structural modeling\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human genetic discovery with structural modeling, single study\",\n      \"pmids\": [\"25915598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"The Neurospora crassa vma-2 gene encodes the 57-kDa B subunit of the vacuolar ATPase (ortholog of ATP6V1B2). The polypeptide has no membrane-spanning domains, shows ~25% amino acid identity with both the vma-1 (A subunit) gene product and the alpha/beta subunits of F0F1 ATPases, suggesting it evolved from a common ancestor and likely fulfills a function analogous to the alpha subunit of F0F1 ATPases (non-catalytic nucleotide binding).\",\n      \"method\": \"Gene isolation, DNA sequencing, sequence analysis, genetic mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — foundational biochemical/sequence analysis in fungal ortholog, single study\",\n      \"pmids\": [\"2844751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mutations in ATP6V1B2 found in follicular lymphoma activate autophagic flux and maintain mTOR in an active state, enabling survival under low leucine conditions. Engineered lymphoma cell lines and primary FL B cells with mutated ATP6V1B2 were addicted to autophagy for survival, demonstrating that recurrent hotspot mutations in ATP6V1B2 constitutively upregulate autophagic flux as an adaptive mechanism in lymphoma pathogenesis.\",\n      \"method\": \"Engineered lymphoma cell lines, primary FL B cells, yeast complementation (S. cerevisiae), autophagy inhibitor treatment, leucine starvation assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in mammalian cells and yeast, mechanistic pathway placement\",\n      \"pmids\": [\"30720463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The ATP6V1B2 c.1516C>T (p.Arg506X) mutation causes cognitive defects in knockin mice via impaired hippocampal CA1 region function. Co-immunoprecipitation demonstrated a weaker interaction between the V1E and B2 subunits in Atp6v1b2 Arg506X/Arg506X mice, although overall V-ATPase assembly was not abolished, indicating the molecular mechanism involves weakened inter-subunit interactions rather than complete complex disassembly.\",\n      \"method\": \"Knockin mice (Atp6v1b2 c.1516C>T), behavioral tests, resting-state fMRI, immunofluorescence, Western blot, co-immunoprecipitation, zebrafish atp6v1b2 knockdown\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockin model with multiple orthogonal methods including co-IP demonstrating specific subunit interaction defect\",\n      \"pmids\": [\"31257146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Atp6v1b2 Arg506X knockin mice, lysosomal dysfunction and blockade of autophagic flux in spiral ganglion neurons leads to apoptosis and neurodegeneration, causing progressive hearing loss. Atp6v1b1 transcription was upregulated in hair cells as genetic compensation, explaining milder hearing impairment in hair cells. Intraperitoneal administration of apoptosis inhibitor BIP-V5 improved phenotypic and pathological outcomes.\",\n      \"method\": \"Transgenic knockin mice, ABR, DPOAE, immunostaining, Western blotting, RNAscope, apoptosis inhibitor treatment\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model with multiple methods, pharmacological rescue experiment confirming mechanism\",\n      \"pmids\": [\"34746137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Disease-associated gain-of-function variants in ATP6V1B2 (and ATP6V1C1) upregulate V-ATPase proton-pumping activity, resulting in increased lysosomal acidification, disrupted lysosomal morphology and localization, defective autophagic flux, accumulation of lysosomal substrates, and impaired cilium biogenesis. This classifies these disorders as lysosomal diseases caused by V-ATPase gain-of-function.\",\n      \"method\": \"Functional cell biology assays, lysosomal acidification measurements, autophagy flux assays, lysosomal morphology/localization imaging, cilia biogenesis assays\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays demonstrating gain-of-function mechanism with multiple variants\",\n      \"pmids\": [\"39210597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In response to starvation, the nonreceptor tyrosine kinase ABL1 directly interacts with ATP6V1B2 and phosphorylates it at tyrosine 68 (Y68). This phosphorylation facilitates recruitment of the ATP6V1D subunit into the V1 subcomplex and potentiates assembly of the V1 subcomplex with the membrane-embedded V0 subcomplex to form functional V-ATPase, thereby enhancing lysosomal acidification and supporting autophagic/mitophagic degradation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphorylation assay, site-directed mutagenesis (Y68), proximity ligation assay, lysosomal pH measurement, lysosomal hydrolase activity assay, autophagy/mitophagy flux assays, ABL1 inhibition/knockdown\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro phosphorylation assay with mutagenesis (Y68) combined with multiple functional readouts in cells\",\n      \"pmids\": [\"39757940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Candida albicans (ortholog VMA2/V1B subunit), the V1B subunit is required for V-ATPase assembly at the vacuolar membrane, proton transport activity, and ATPase-specific activity. Repression of VMA2 caused vacuolar alkalinization, abnormal vacuolar morphology, impaired filamentation and virulence, defective autophagy under nitrogen starvation, and increased osmotic stress susceptibility.\",\n      \"method\": \"Tetracycline-regulatable VMA2 mutant, proton transport assay, ATPase activity assay, vacuolar morphology imaging, filamentation assays, C. elegans infection model\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct enzymatic assays (proton transport, ATPase activity) combined with multiple functional phenotypic readouts in fungal ortholog\",\n      \"pmids\": [\"25038082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Atp6v1b2 Arg506* heterozygous knockin mice display locomotor hyperactivity, reduced anxiety, interictal epileptic activity on EEG, and reduced seizure threshold to pentylenetetrazol, confirming that the ATP6V1B2 p.Arg506* variant causes seizure susceptibility in vivo.\",\n      \"method\": \"IMPC phenotyping pipeline, EEG recording, pentylenetetrazol seizure threshold assay, behavioral tests\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo heterozygous knockin mouse model with EEG and pharmacological seizure challenge, single study\",\n      \"pmids\": [\"37628590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of Vha55 (the Drosophila ortholog of ATP6V1B2) in flies causes seizure-like behaviors and climbing defects, establishing a causal relationship between ATP6V1B2 loss-of-function and epilepsy phenotypes.\",\n      \"method\": \"Drosophila Vha55 knockdown model, seizure-like behavior assay, climbing assay, NMD analysis\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo ortholog knockdown in Drosophila with functional behavioral readouts, single study\",\n      \"pmids\": [\"39075926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AAV-mediated delivery of wild-type Atp6v1b2 into the scala media of hair cell-specific Atp6v1b2 knockout mice (Atp6v1b2fl/fl;Atoh1Cre/+) prevented hair cell degeneration, restored lysosomal morphology, and rescued auditory and vestibular function for at least 24 weeks, establishing that Atp6v1b2 is critical for lysosomal function in hair cells and that its loss drives hair cell degeneration and hearing loss.\",\n      \"method\": \"Hair cell-specific conditional knockout mice, AAV-ie-Eh3 gene delivery, ABR, vestibular function tests, lysosomal morphology imaging\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO model plus rescue by gene therapy with multiple functional readouts, single study\",\n      \"pmids\": [\"40068100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"l-Lactate-driven lactylation of ATP6V1B2 at K108/K109 restricts its conformational flexibility, causing disassembly of the V1-V0 complex and loss of proton pump activity, leading to lysosomal alkalinization and membrane permeabilization. This triggers cathepsin B leakage, mitochondrial ROS, and Caspase-8/3/GSDME-dependent pyroptosis. AAV delivery of a lactylation-deficient ATP6V1B2 (K108R/K109R) mutant attenuated airway inflammation in an asthma model.\",\n      \"method\": \"Quantitative lactylomics, molecular dynamics simulations, biochemical assays, V-ATPase assembly assay, lysosomal pH measurement, LMP assay, primary HBEs, HDM asthma model, AAV-delivered 2KR mutant\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods including structural simulations, enzymatic activity, site-specific mutant rescue in vivo\",\n      \"pmids\": [\"41637881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATP6V1B2 promotes lysosomal degradation of fatty acid synthase (FASN) by maintaining the acidic environment of lysosomes; loss of ATP6V1B2 in hepatocytes impairs lysosomal acidification and autophagic activity, leading to FASN accumulation and increased lipid deposition, oxidative stress, and hepatic steatosis.\",\n      \"method\": \"ATP6V1B2 siRNA knockdown in liver cells, lipid accumulation assays, oxidative stress assays, autophagic flux assays, lysosomal pH measurement, FASN protein level analysis\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in cell model with multiple readouts linking ATP6V1B2 to lysosomal acidification and FASN degradation, single study\",\n      \"pmids\": [\"41876447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In response to DNA damage, a subset of senescent cells upregulates ATP6V1B2 (V1B2) on the cell surface (csV1B2). This surface localization is associated with altered lysosomal activity and changes in intracellular pH. Cells expressing csV1B2 show increased resistance to ABT-737-induced apoptosis and a transcriptional signature of DNA repair and apoptosis resistance.\",\n      \"method\": \"Flow cytometry, live-cell imaging, transcriptional profiling, in vitro apoptosis resistance assay, analysis of naturally occurring senescent cells in ageing and fibrotic lungs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single study, correlative link between surface localization and apoptosis resistance without direct mechanistic dissection\",\n      \"pmids\": [\"bio_10.1101_2025.11.30.691415\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ATP6V1B2 encodes the B2 subunit of the vacuolar H+-ATPase (V-ATPase) V1 domain, where it contributes to ATP hydrolysis and complex assembly; it is phosphorylated at Y68 by ABL1 upon starvation to promote V1-V0 subcomplex assembly and lysosomal acidification, and can be inactivated by l-lactate-driven lactylation at K108/K109, leading to V-ATPase disassembly and lysosomal dysfunction; disease-associated mutations cause either loss-of-function (weakened V1E–B2 subunit interactions, lysosomal dysfunction, and neurodegeneration/hearing loss) or gain-of-function (upregulated V-ATPase activity, increased lysosomal acidification, defective autophagic flux, and mTOR activation) depending on the specific variant, collectively classifying ATP6V1B2-related disorders as lysosomal diseases.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATP6V1B2 encodes the B2 (non-catalytic) subunit of the V1 catalytic domain of the vacuolar H⁺-ATPase (V-ATPase), functioning as a central regulatory hub that controls V1–V0 holoenzyme assembly and thereby governs lysosomal acidification, autophagic flux, and substrate degradation across diverse cell types. ABL1 phosphorylates ATP6V1B2 at Y68 under starvation to promote V1D recruitment and V1–V0 assembly, sustaining lysosomal pH for autophagy and mitophagy, whereas lactylation at K108/K109 restricts B2 conformational flexibility, triggers V1–V0 disassembly, and leads to lysosomal alkalinization and pyroptosis [PMID:39757940, PMID:41637881]. Loss of ATP6V1B2 in hair cells and spiral ganglion neurons causes lysosomal dysfunction, blocked autophagic flux, and cell degeneration that can be rescued by AAV-mediated gene replacement [PMID:40068100, PMID:34746137]. Heterozygous missense mutations cause Zimmermann-Laband syndrome and DDOD syndrome through altered V-ATPase complex assembly, while gain-of-function variants hyperacidify lysosomes and disrupt cilium biogenesis [PMID:25915598, PMID:31257146, PMID:39210597].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Identification of the V-ATPase B subunit as a non-catalytic regulatory component homologous to the F1-ATPase α subunit established the molecular identity and predicted function of what would become ATP6V1B2.\",\n      \"evidence\": \"Gene isolation, sequencing, and homology analysis of vma-2 in Neurospora crassa\",\n      \"pmids\": [\"2844751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulatory function inferred from sequence homology only, not from biochemical assay\", \"No mammalian B2 isoform characterized at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The discovery that heterozygous ATP6V1B2 missense mutations cause Zimmermann-Laband syndrome linked the B2 subunit to human neurodevelopmental disease and implicated disrupted V-ATPase complex assembly as the pathogenic mechanism.\",\n      \"evidence\": \"Exome sequencing of affected individuals with structural modeling of mutation impact on V-ATPase assembly\",\n      \"pmids\": [\"25915598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural modeling only; no direct biochemical demonstration of impaired assembly\", \"Functional consequence of mutation not tested in cells\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that the DDOD-associated R506* truncation weakens V1E–B2 interaction without abolishing complex assembly, coupled with hippocampal dysfunction in knockin mice, established that partial loss of V-ATPase integrity suffices to cause neurodegeneration and cognitive defects.\",\n      \"evidence\": \"Co-immunoprecipitation and Western blot in Atp6v1b2 knockin mice; behavioral and fMRI analysis\",\n      \"pmids\": [\"31257146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lysosomal pH and autophagic flux not directly measured in this model\", \"Mechanism of selective hippocampal vulnerability unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Follicular lymphoma-associated ATP6V1B2 mutations were shown to be gain-of-function: they activate autophagic flux while sustaining mTOR activity, enabling cancer cell survival under amino acid deprivation — revealing that B2 alterations can rewire nutrient sensing.\",\n      \"evidence\": \"Engineered mammalian lymphoma cells, primary FL B cells, and cross-species validation in yeast vma2 mutants; autophagy and mTOR activity assays\",\n      \"pmids\": [\"30720463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise structural mechanism by which mutations increase V-ATPase activity not defined\", \"Whether mTOR activation is direct or secondary to enhanced lysosomal function unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ATP6V1B2 dysfunction in spiral ganglion neurons was shown to block autophagic flux and trigger apoptotic neurodegeneration, while compensatory Atp6v1b1 upregulation in hair cells explained their relative resilience — establishing cell-type-specific vulnerability to B2 loss.\",\n      \"evidence\": \"Immunostaining, Western blot, RNAscope in Atp6v1b2 knockin mice; ABR measurements; apoptosis inhibitor rescue\",\n      \"pmids\": [\"34746137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of B1 compensatory upregulation not defined\", \"Single knockin model, single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Systematic characterization of dominant disease variants showed that gain-of-function ATP6V1B2 mutations hyperacidify lysosomes, disrupt lysosomal morphology, impair autophagic flux, and compromise cilium biogenesis, broadening the phenotypic spectrum beyond simple loss-of-function.\",\n      \"evidence\": \"Cell-based assays for lysosomal pH, autophagy, lysosomal morphology, and ciliogenesis in cells expressing patient variants\",\n      \"pmids\": [\"39210597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking hyperacidification to cilium biogenesis defects not defined\", \"In vivo confirmation of gain-of-function mechanism needed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Knockdown of the Drosophila ortholog Vha55 caused seizure-like behaviors, establishing a causal link between ATP6V1B2 loss-of-function and epilepsy in an invertebrate model.\",\n      \"evidence\": \"Drosophila Vha55 knockdown; behavioral seizure and climbing assays\",\n      \"pmids\": [\"39075926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog-based inference; mammalian epilepsy phenotype not demonstrated by direct knockout\", \"Lysosomal or neuronal mechanism underlying seizures not characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The identification of ABL1 as a kinase that phosphorylates ATP6V1B2 at Y68 to promote V1D recruitment and V1–V0 assembly under starvation provided the first upstream regulatory mechanism controlling V-ATPase holoenzyme formation through B2 modification.\",\n      \"evidence\": \"In vitro kinase assay, co-IP, site-directed mutagenesis (Y68F/E), proximity ligation assay, lysosomal pH and autophagy flux measurements, ABL1 inhibition/depletion\",\n      \"pmids\": [\"39757940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other kinases also phosphorylate Y68 is unknown\", \"Structural basis for how Y68 phosphorylation promotes V1D binding not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Hair cell-specific Atp6v1b2 knockout demonstrated that B2 is essential for lysosomal integrity and hair cell survival, and AAV-mediated gene replacement fully rescued auditory and vestibular function, establishing proof-of-concept for gene therapy.\",\n      \"evidence\": \"Conditional knockout mouse (Atp6v1b2fl/fl;Atoh1Cre/+); AAV-ie-Eh3 gene therapy; ABR; lysosomal morphology; histology\",\n      \"pmids\": [\"40068100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term durability of gene therapy not assessed\", \"Whether rescue extends to spiral ganglion neuron pathology not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Lactylation of ATP6V1B2 at K108/K109 was identified as a post-translational modification that opposes V1–V0 assembly, providing a metabolite-driven switch that links lactate metabolism to lysosomal integrity and cell death via pyroptosis.\",\n      \"evidence\": \"Quantitative lactylomics, molecular dynamics simulations, biochemical assays in bronchial epithelial cells, AAV-delivered lactylation-deficient mutant (2KR) rescue in vivo\",\n      \"pmids\": [\"41637881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; independent replication needed\", \"Whether lactylation at K108/K109 occurs in cell types beyond bronchial epithelium unclear\", \"Interplay between Y68 phosphorylation and K108/K109 lactylation not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"ATP6V1B2 was shown to promote lysosomal degradation of FASN by maintaining acidic lysosomal pH; its loss in hepatocytes impairs autophagic flux and increases lipid accumulation, linking V-ATPase B2 function to hepatic lipid metabolism.\",\n      \"evidence\": \"ATP6V1B2 knockdown in liver cells; lysosomal pH, FASN protein levels, lipid accumulation, and oxidative stress assays\",\n      \"pmids\": [\"41876447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Knockdown only; no knockout or rescue to confirm specificity\", \"In vivo hepatic phenotype not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of how post-translational modifications at Y68, K108, and K109 coordinately regulate V1–V0 assembly, whether tissue-specific B1/B2 isoform compensation is transcriptionally regulated, and what explains the divergent outcomes (gain vs. loss of function) of different disease-associated variants at the atomic level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of mammalian B2 with post-translational modifications\", \"Coordinated regulation of Y68 phosphorylation and K108/K109 lactylation untested\", \"Structural basis distinguishing gain-of-function from loss-of-function variants unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 5, 6, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [3, 4, 5, 6, 7, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 3, 5, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [5, 6, 11]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"complexes\": [\n      \"V-ATPase (V1 domain)\",\n      \"V-ATPase holoenzyme (V1-V0)\"\n    ],\n    \"partners\": [\n      \"ABL1\",\n      \"ATP6V1E1\",\n      \"ATP6V1D\",\n      \"FASN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ATP6V1B2 encodes the brain-enriched B2 subunit of the V1 catalytic domain of the vacuolar H⁺-ATPase (V-ATPase), where it participates in non-catalytic nucleotide binding, ATP hydrolysis-driven proton pumping, and V1–V0 subcomplex assembly required for lysosomal acidification and autophagic degradation [PMID:2844751, PMID:25038082, PMID:39757940]. Starvation-induced phosphorylation of ATP6V1B2 at Y68 by ABL1 promotes V1D subunit recruitment and V1–V0 assembly, enhancing lysosomal acidification and autophagy/mitophagy, whereas l-lactate-driven lactylation at K108/K109 restricts B2 conformational flexibility, causing V-ATPase disassembly, lysosomal alkalinization, and pyroptosis [PMID:39757940, PMID:41637881]. Loss-of-function mutations (e.g. p.Arg506*) weaken the V1E–B2 subunit interaction, producing lysosomal dysfunction, neurodegeneration, progressive hearing loss, and seizure susceptibility, while gain-of-function variants constitutively upregulate V-ATPase activity, causing excess lysosomal acidification, defective autophagic flux, impaired ciliogenesis, and—in follicular lymphoma—autophagy-dependent survival with sustained mTOR activation [PMID:31257146, PMID:34746137, PMID:39210597, PMID:30720463]. Heterozygous de novo ATP6V1B2 mutations cause Zimmermann-Laband syndrome and related neurodevelopmental disorders with hearing loss and epilepsy [PMID:25915598, PMID:37628590].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Identification of the V-ATPase B subunit as a soluble, non-membrane-spanning polypeptide homologous to F₁F₀-ATPase α/β subunits established that V-ATPase B functions in non-catalytic nucleotide binding rather than as a membrane pore component.\",\n      \"evidence\": \"Gene isolation, sequencing, and sequence comparison of Neurospora crassa vma-2 (B subunit ortholog)\",\n      \"pmids\": [\"2844751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic versus regulatory nucleotide-binding roles of B versus A subunits not yet resolved in mammalian V-ATPase\", \"No structural data for the B subunit at this time\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration that the V1B subunit is required for V-ATPase membrane assembly, proton transport, and ATPase activity established its essential role in vacuolar acidification and downstream processes including autophagy and stress resistance.\",\n      \"evidence\": \"Regulatable VMA2 mutant in C. albicans with proton transport and ATPase activity assays, vacuolar morphology, and nitrogen-starvation autophagy\",\n      \"pmids\": [\"25038082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Findings in fungal ortholog; mammalian-specific regulatory mechanisms unexplored\", \"No post-translational regulatory input identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that recurrent de novo ATP6V1B2 missense mutations cause Zimmermann-Laband syndrome linked human disease to predicted disruption of V-ATPase complex assembly.\",\n      \"evidence\": \"Exome sequencing of ZLS patients with structural modeling of variant impact on V-ATPase\",\n      \"pmids\": [\"25915598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural prediction only; functional consequence of the ZLS variant on V-ATPase activity not directly measured\", \"Gain- versus loss-of-function not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two independent studies distinguished loss-of-function from gain-of-function mechanisms: the p.Arg506* variant weakens V1E–B2 interaction causing lysosomal dysfunction and cognitive impairment, while follicular lymphoma hotspot mutations constitutively activate autophagic flux and sustain mTOR, creating autophagy dependence.\",\n      \"evidence\": \"Knockin mice (Arg506*) with co-IP showing weakened V1E–B2 interaction, behavioral/fMRI readouts; engineered lymphoma lines and primary FL B cells with autophagy inhibition and leucine-starvation assays, yeast complementation\",\n      \"pmids\": [\"31257146\", \"30720463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how specific variants produce opposite functional outcomes unknown\", \"Whether mTOR activation is a direct consequence of enhanced V-ATPase activity or an indirect effect of altered amino acid sensing not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The p.Arg506* variant was shown to cause progressive hearing loss through lysosomal dysfunction and autophagic flux blockade leading to spiral ganglion neuron apoptosis, while compensatory Atp6v1b1 upregulation in hair cells explained milder cochlear phenotypes.\",\n      \"evidence\": \"Knockin mouse ABR/DPOAE, immunostaining, RNAscope for Atp6v1b1, and BIP-V5 apoptosis inhibitor rescue\",\n      \"pmids\": [\"34746137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether B1 compensation occurs in human cochlear hair cells not tested\", \"Long-term therapeutic window for apoptosis inhibition not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Heterozygous Arg506* knockin mice displayed seizure susceptibility and epileptic EEG activity, confirming that partial ATP6V1B2 loss of function is sufficient to cause neuronal hyperexcitability in vivo.\",\n      \"evidence\": \"EEG recording and pentylenetetrazol seizure threshold assay in heterozygous knockin mice\",\n      \"pmids\": [\"37628590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular mechanism connecting lysosomal dysfunction to neuronal hyperexcitability not dissected\", \"Single mutation tested; generalizability to other LOF variants unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Gain-of-function ATP6V1B2 variants were shown to hyperacidify lysosomes, disrupt lysosomal morphology, block autophagic flux, and impair ciliogenesis, classifying these disorders as lysosomal diseases caused by V-ATPase overactivity, and Drosophila Vha55 knockdown independently confirmed that B2 loss causes seizure-like behavior.\",\n      \"evidence\": \"Functional cell biology assays for lysosomal acidification, autophagy flux, and cilia biogenesis with multiple GOF variants; Drosophila Vha55 knockdown behavioral assays\",\n      \"pmids\": [\"39210597\", \"39075926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which excess acidification impairs ciliogenesis not resolved\", \"Whether GOF and LOF variants converge on a shared downstream pathogenic pathway unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ABL1 was identified as a direct kinase for ATP6V1B2 Y68 phosphorylation under starvation, providing the first post-translational regulatory switch that promotes V1D recruitment, V1–V0 assembly, and enhanced lysosomal acidification to support autophagy and mitophagy.\",\n      \"evidence\": \"Co-IP, in vitro phosphorylation, Y68 mutagenesis, proximity ligation assay, lysosomal pH and hydrolase assays, autophagy/mitophagy flux in ABL1-inhibited/knockdown cells\",\n      \"pmids\": [\"39757940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Y68 phosphorylation is relevant to disease-associated variants not tested\", \"Phosphatase that reverses Y68 phosphorylation not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"AAV-mediated gene replacement of Atp6v1b2 in hair cell-specific knockout mice rescued lysosomal morphology, auditory function, and vestibular function for ≥24 weeks, establishing therapeutic proof-of-concept for ATP6V1B2-related hearing loss.\",\n      \"evidence\": \"Conditional KO mice (Atp6v1b2fl/fl;Atoh1Cre/+) with AAV-ie-Eh3 delivery into scala media, ABR, vestibular function, lysosomal imaging\",\n      \"pmids\": [\"40068100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether gene therapy can rescue spiral ganglion neuron degeneration (not only hair cells) untested\", \"Durability beyond 24 weeks and translational dosing not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"l-Lactate-driven lactylation of ATP6V1B2 at K108/K109 was identified as a second post-translational switch that restricts B2 flexibility, disassembles V1–V0, and triggers lysosomal alkalinization, membrane permeabilization, and GSDME-dependent pyroptosis, with in vivo relevance demonstrated by AAV-delivered lactylation-deficient mutant rescue in an asthma model.\",\n      \"evidence\": \"Quantitative lactylomics, molecular dynamics, V-ATPase assembly and lysosomal pH assays, LMP, primary human bronchial epithelial cells, HDM asthma model with AAV-K108R/K109R mutant\",\n      \"pmids\": [\"41637881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether lactylation and Y68 phosphorylation are coordinated or antagonistic not examined\", \"Generalizability of lactylation-driven pyroptosis beyond airway epithelium unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"ATP6V1B2 loss in hepatocytes impairs lysosomal acidification and autophagic degradation of FASN, leading to lipid accumulation, oxidative stress, and steatosis, extending the metabolic consequences of B2 deficiency beyond the nervous system.\",\n      \"evidence\": \"siRNA knockdown in liver cells with lysosomal pH, autophagic flux, FASN protein, lipid accumulation, and oxidative stress assays\",\n      \"pmids\": [\"41876447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo hepatic phenotype not confirmed in animal model\", \"Whether FASN is a selective substrate or one of many proteins accumulating due to general lysosomal impairment not clarified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: (1) atomic-resolution structure of disease variants within the assembled V-ATPase explaining gain- versus loss-of-function outcomes; (2) integration of ABL1-mediated Y68 phosphorylation and K108/K109 lactylation into a unified regulatory model; (3) whether cell-surface ATP6V1B2 in senescent cells has a non-canonical function beyond organellar proton pumping.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution cryo-EM structure of disease-variant V-ATPase reported\", \"Cross-talk between phosphorylation and lactylation at B2 not studied\", \"Cell-surface ATP6V1B2 phenotype reported only in a preprint without mechanistic dissection\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 7, 6, 11]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [7, 6]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [7, 5, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [4, 5, 6, 10, 11, 12]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 4, 6, 7, 12]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [7, 6, 11]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [5, 10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 3, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 11]}\n    ],\n    \"complexes\": [\n      \"V-ATPase (V1 domain)\",\n      \"V-ATPase (V1-V0 holoenzyme)\"\n    ],\n    \"partners\": [\n      \"ATP6V1E1\",\n      \"ATP6V1D\",\n      \"ABL1\",\n      \"ATP6V1C1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}