Affinage

ATP6V1B2

V-type proton ATPase subunit B, brain isoform · UniProt P21281

Length
511 aa
Mass
56.5 kDa
Annotated
2026-06-09
20 papers in source corpus 11 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2015 Medium

    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

    PMID:25915598

    Open questions at the time
    • No in vitro reconstitution or direct biochemical assembly assay
    • Mechanistic consequence of the variant inferred from structure, not measured
  2. 2019 Medium

    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

    PMID:31257146

    Open questions at the time
    • Quantitative effect on proton pump output not directly measured
    • Link from weakened interaction to cognitive phenotype is correlative
  3. 2019 High

    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

    PMID:30720463

    Open questions at the time
    • Structural basis of how mutations alter pump assembly not resolved
    • Direct measurement of lysosomal pH change not reported
  4. 2021 Medium

    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

    PMID:34746137

    Open questions at the time
    • Paralog compensation by Atp6v1b1 in hair cells not mechanistically explained
    • Single lab model
  5. 2023 Medium

    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

    PMID:37628590

    Open questions at the time
    • Cellular circuit basis of epileptogenesis not defined
    • Does not link seizures to a specific lysosomal defect
  6. 2024 Medium

    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

    PMID:39210597

    Open questions at the time
    • Structural mechanism of constitutive activation unresolved
    • Link between altered acidification and cilium defect not mechanistically traced
  7. 2024 Medium

    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

    PMID:39075926

    Open questions at the time
    • Ortholog phenotype may not fully model human variant effects
    • No lysosomal readout in the fly model
  8. 2025 High

    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

    PMID:39757940

    Open questions at the time
    • Upstream signals activating ABL1 toward ATP6V1B2 not fully defined
    • Structural mechanism of Y68 phosphorylation on assembly not resolved
  9. 2025 Medium

    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

    PMID:40068100

    Open questions at the time
    • Molecular link from lysosomal failure to hair cell death not detailed
    • Single lab
  10. 2026 Medium

    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

    PMID:41637881

    Open questions at the time
    • Direct structural confirmation of conformational restriction limited to simulation
    • Enzymatic machinery adding/removing lactylation not identified
  11. 2026 Medium

    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

    PMID:41876447

    Open questions at the time
    • Whether FASN is degraded via autophagy or direct lysosomal targeting not distinguished
    • In vivo relevance not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How non-canonical cell-surface localization of ATP6V1B2 in senescent cells mediates altered pH and apoptosis resistance remains unresolved.
  • Preprint, no direct mechanistic test of how cell-surface V1B2 confers resistance
  • No reciprocal validation of surface localization mechanism

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005764 lysosome 4
Pathway
R-HSA-1643685 Disease 3 R-HSA-9612973 Autophagy 3 R-HSA-382551 Transport of small molecules 2
Partners
ABL1ATP6V1DATP6V1E1
Complex memberships
V-ATPase

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 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. Human genetics (sequencing), structural analysis Nature genetics Medium 25915598
2019 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. Co-immunoprecipitation, western blot, immunofluorescence, knockin mouse model, behavioral tests, resting-state fMRI EBioMedicine Medium 31257146
2019 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. Engineered lymphoma cell lines, primary FL B cells, S. cerevisiae complementary experiments, autophagy inhibitor treatment, mTOR activity assays The Journal of clinical investigation High 30720463
2021 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. Knockin mouse model (Atp6v1b2 c.1516C>T), immunostaining, western blotting, RNAscope, ABR/DPOAE testing, pharmacological rescue Frontiers in cell and developmental biology Medium 34746137
2024 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. Cell-based assays for lysosomal acidification and morphology, autophagic flux assays, cilium biogenesis assays, functional characterization of ATP6V1B2/ATP6V1C1 variants HGG advances Medium 39210597
2025 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. 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 Autophagy High 39757940
2024 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. Drosophila Vha55 knockdown model, behavioral seizure assays, climbing assays Clinical genetics Medium 39075926
2023 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. Knockin mouse model, behavioral tests, EEG analysis, pentylenetetrazol seizure threshold assay Genes Medium 37628590
2025 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. Conditional knockout mouse (Atp6v1b2fl/fl;Atoh1Cre/+), AAV gene therapy rescue, lysosomal morphology analysis, ABR/vestibular testing Advanced science Medium 40068100
2026 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. Quantitative lactylomics, molecular dynamics simulations, biochemical analyses, primary human bronchial epithelial cells, AAV delivery of lactylation-deficient mutant, in vivo asthma model Redox biology Medium 41637881
2026 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. ATP6V1B2 knockdown in liver cell lines, lipid accumulation assays, lysosomal pH measurement, autophagic flux assay, FASN protein level quantification Cell death discovery Medium 41876447
2025 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. 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 bioRxivpreprint Low

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nature genetics 177 25915598
2019 A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability. EBioMedicine 34 31257146
2019 Follicular lymphoma-associated mutations in vacuolar ATPase ATP6V1B2 activate autophagic flux and mTOR. The Journal of clinical investigation 29 30720463
2017 Dominant deafness-onychodystrophy syndrome caused by an ATP6V1B2 mutation. Clinical case reports 27 28396750
2020 DOORS syndrome and a recurrent truncating ATP6V1B2 variant. Genetics in medicine : official journal of the American College of Medical Genetics 25 32873933
2019 EXOME REPORT: Novel mutation in ATP6V1B2 segregating with autosomal dominant epilepsy, intellectual disability and mild gingival and nail abnormalities. European journal of medical genetics 16 31655144
2020 ATP6V1B2-related epileptic encephalopathy. Epileptic disorders : international epilepsy journal with videotape 13 32597767
2021 Syndromic Deafness Gene ATP6V1B2 Controls Degeneration of Spiral Ganglion Neurons Through Modulating Proton Flux. Frontiers in cell and developmental biology 12 34746137
2020 Clinicopathological Relationships in an Aged Case of DOORS Syndrome With a p.Arg506X Mutation in the ATP6V1B2 Gene. Frontiers in neurology 12 32849222
2016 Association of ATP6V1B2 rs1106634 with lifetime risk of depression and hippocampal neurocognitive deficits: possible novel mechanisms in the etiopathology of depression. Translational psychiatry 11 27824360
2024 Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function. HGG advances 10 39210597
2025 Nonreceptor tyrosine kinase ABL1 regulates lysosomal acidification by phosphorylating the ATP6V1B2 subunit of the vacuolar-type H+-ATPase. Autophagy 9 39757940
2022 A novel pathogenic ATP6V1B2 variant: Widening the genotypic spectrum of the epileptic neurodevelopmental phenotype. American journal of medical genetics. Part A 8 36135319
2025 Single Administration of AAV-mAtp6v1b2 Gene Therapy Rescues Hearing and Vestibular Disorders Caused by Atp6v1b2-Induced Lysosomal Dysfunction in Hair Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 40068100
2023 The ATP6V1B2 DDOD/DOORS-Associated p.Arg506* Variant Causes Hyperactivity and Seizures in Mice. Genes 5 37628590
2020 Establishment of human induced pluripotent stem cell line (CPGHi002-A) from a 10-month-old female patient with DDOD syndrome carrying a heterozygous c.1516 C > T mutation in ATP6V1B2. Stem cell research 4 32961450
2021 Generation of a gene corrected human isogenic iPSC line (CPGHi002-A-1) from a DDOD patient with heterozygous c.1516 C>T mutation in the ATP6V1B2 gene. Stem cell research 1 33714068
2026 Lactate-driven ATP6V1B2 lactylation triggers asthmatic inflammation by linking lysosomal dysfunction to mitochondrial ROS-dependent pyroptosis. Redox biology 0 41637881
2026 ATP6V1B2 alleviates hepatic steatosis by promoting lysosomal acidification in hepatocytes. Cell death discovery 0 41876447
2024 Epilepsy due to potential loss of ATP6V1B2 function with mechanistic insight by a Drosophila Vha55 model. Clinical genetics 0 39075926

Missed literature

Know a paper Affinage missed for ATP6V1B2? Flag it for the maintainers and the community.

No submissions yet.