Affinage

ATP6V0D1

V-type proton ATPase subunit d 1 · UniProt P61421

Audit flag: ungrounded claim
Length
351 aa
Mass
40.3 kDa
Annotated
2026-06-09
41 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP6V0D1 encodes the d1 subunit of the vacuolar H⁺-ATPase V0 sector and functions as a determinant of organellar acidification across diverse cellular contexts (PMID:33346633, PMID:36213534). Loss of ATP6V0D1 raises lysosomal pH and impairs V-ATPase-dependent functions, including lysosome-dependent coronavirus entry/replication and a parallel host-factor requirement for influenza A virus (PMID:18615018, PMID:33346633). The subunit is allosterically druggable: JTC801 stabilizes ATP6V0D1 and Schisandrol A binds cysteine-335 to drive a conformational change that activates V-ATPase-dependent lysosomal acidification (PMID:36640329, PMID:36213534). Through this activity ATP6V0D1 restrains alkaliptosis, a pH-dependent cell death; mechanistically it acts upstream of STAT3 (with which it physically interacts) and AKT to sustain lysosomal pH homeostasis, such that STAT3/AKT inhibition restores alkaliptosis sensitivity in ATP6V0D1-deficient pancreatic cancer cells (PMID:36640329, PMID:41019981). Its lysosomal acidifying role also underlies chemoresistance, sequestering drugs to limit cytotoxicity and modulating ABCB1 expression in a pH-dependent manner (PMID:40552114, PMID:38751020). ATP6V0D1 is delivered to lysosome-related organelle membranes for V-ATPase assembly by the BLOC-2 subunit HPS6, supporting Weibel-Palade body biogenesis (PMID:35252216), and assembly is regulated by Tmem9 in microglia (PMID:39871402). At the organismal level it is required for vertebrate eye development and melanosome biogenesis, and adipose-specific deletion in mice causes lipodystrophy and secondary cardiomyopathy through a myocardin–IRS-1–FoxO1 axis (PMID:18836173, PMID:38505620).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2000 Medium

    Establishing the gene structure and conservation of ATP6V0D1 provided the molecular foundation for studying the d1 subunit and distinguished its regulation from its genomic neighbor.

    Evidence Gene cloning, exon-intron mapping, and forskolin expression assays in JEG3 cells

    PMID:11118322

    Open questions at the time
    • Did not address subunit function within the V-ATPase complex
    • No protein-level activity characterized
  2. 2005 Low

    Tissue localization raised the possibility that the d1 subunit has functions beyond canonical proton transport, by appearing at the apical membrane without other V-ATPase subunits.

    Evidence Immunostaining of V-ATPase subunit isoforms in rat epididymis and vas deferens

    PMID:16192400

    Open questions at the time
    • Single localization study with no functional rescue or knockout
    • Putative complex-independent role never validated mechanistically
  3. 2008 Medium

    Functional genetics defined ATP6V0D1 as a specific influenza host factor and, separately, as essential for vertebrate eye, melanosome, and RPE development, linking the subunit to acidification-dependent organelle function in vivo.

    Evidence Genome-wide RNAi screen with human siRNA viral assays; loss-of-function zebrafish mutant with histology, BrdU, TUNEL, and EM

    PMID:18615018 PMID:18836173

    Open questions at the time
    • Molecular step in viral replication not pinpointed
    • Whether developmental phenotypes derive solely from acidification loss not isolated
  4. 2009 Medium

    Intronic sequences of ATP6V0D1 were shown to act as enhancers for the neighboring AgRP gene, a genomic-regulatory property distinct from the subunit's protein function.

    Evidence Enhancer screening and transgenic mouse reporter assays under dietary challenge

    PMID:19285986

    Open questions at the time
    • Concerns the locus rather than the ATP6V0D1 protein
    • No link to V-ATPase activity
  5. 2020 Medium

    Knockdown tied ATP6V0D1 directly to lysosomal pH and coronavirus replication, mechanistically connecting its acidifying activity to viral entry, and AP-MS placed the protein in physical contact with phosphorylated tau in disease tissue.

    Evidence siRNA knockdown with coronavirus cytopathic-effect and lysosomal pH assays; AP-MS from Alzheimer neurofibrillary tangles

    PMID:32812023 PMID:33346633

    Open questions at the time
    • Tau interaction lacks reciprocal validation or functional follow-up
    • Causal role of pH rise in blocking coronavirus not formally separated from off-target effects
  6. 2022 High

    ATP6V0D1 was established as a druggable, allosterically regulated acidification controller and a node restraining alkaliptosis, defining both a cysteine-335 ligand site and a STAT3-coupled pH-homeostasis mechanism.

    Evidence MS target ID, CETSA, cysteine-335 mutagenesis, Co-IP, knockout cell-death assays, xenografts; plus HPS6 Co-IP with parallel WPB knockdown phenotypes

    PMID:35252216 PMID:36213534 PMID:36640329

    Open questions at the time
    • Structural basis of allosteric activation not resolved
    • How HPS6 selects ATP6V0D1 cargo for delivery unknown
  7. 2024 High

    In vivo deletion and pH-manipulation studies expanded ATP6V0D1 from a lysosomal subunit to a regulator of adipogenesis/cardiac metabolism and of the alkaliptosis-ABCB1 chemoresistance axis.

    Evidence Adipose-specific knockout mice with RNA-seq, ChIP-qPCR, luciferase, and AAV rescue; ATP6V0D1 overexpression and intracellular pH manipulation in ovarian cancer cells

    PMID:38505620 PMID:38751020

    Open questions at the time
    • How an adipose lysosomal subunit controls myocardin transcriptionally is unresolved
    • Direct vs indirect control of ABCB1 by pH not fully separated
  8. 2025 Medium

    Recent work refined the downstream signaling and disease contexts, placing ATP6V0D1 upstream of STAT3/AKT in PDAC, implicating it in lysosomal drug sequestration in neuroblastoma, and connecting Tmem9-regulated V-ATPase assembly to microglial complement activity.

    Evidence Knockout transcriptomics/Western blot in PDAC; subunit-controlled siRNA with cell-cycle, migration, and lysosomal uptake assays; Tmem9 gain/loss in 5xFAD mice and BV2 cells

    PMID:39871402 PMID:40552114 PMID:41019981

    Open questions at the time
    • ATP6V0D1's precise step in the Tmem9→complement pathway inferred not directly tested
    • Single-lab observations awaiting independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single V0 subunit integrates lysosomal acidification with such diverse outcomes—alkaliptosis, adipogenesis, viral entry, and chemoresistance—and whether these reflect one acidification mechanism or distinct complex-independent activities remains unresolved.
  • No structure of ATP6V0D1 within the assembled V-ATPase
  • Complex-independent functions not mechanistically separated from canonical proton transport

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005764 lysosome 4 GO:0005886 plasma membrane 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-382551 Transport of small molecules 2 R-HSA-5357801 Programmed Cell Death 2
Partners
HPS6STAT3TMEM9
Complex memberships
vacuolar H+-ATPase (V-ATPase) V0 sector

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 RNAi knockdown of ATP6V0D1 (the human homologue of the Drosophila gene identified in a genome-wide screen) in HEK 293 cells significantly inhibited replication of H5N1 and H1N1 influenza A viruses but not vesicular stomatitis virus or vaccinia virus, establishing a specific host-factor role for ATP6V0D1 in influenza virus replication. Genome-wide RNAi screen in Drosophila followed by siRNA knockdown of human ATP6V0D1 in HEK 293 cells with influenza virus infection assay Nature Medium 18615018
2005 ATP6V0D1 (d1 subunit) was localized by immunostaining to the apical membrane of principal cells in the rat epididymis and vas deferens in the apparent absence of other V-ATPase subunits, suggesting a physiological function distinct from its role in proton transport via the complete V-ATPase complex. Immunohistochemistry/immunofluorescence localization of V-ATPase subunit isoforms in rat epididymis and vas deferens Biology of reproduction Low 16192400
2008 Zebrafish carrying a loss-of-function mutation in atp6v0d1 exhibited microphthalmic eyes, defective retinoblast cell cycle exit, elevated retinal apoptosis, abnormal photoreceptor outer segment morphology, RPE malformation with undigested outer segment material in vacuoles, and oculocutaneous albinism with melanosome biogenesis defects, demonstrating that ATP6V0D1 is required for v-ATPase complex function during vertebrate eye development. Genetic loss-of-function zebrafish mutant analysis with histology, BrdU incorporation, TUNEL assay, in situ hybridization, and electron microscopy Investigative ophthalmology & visual science Medium 18836173
2020 siRNA knockdown of ATP6V0D1 in LLC-MK2 cells blocked the cytopathic effect of HCoV-NL63 coronavirus, and ATP6V0D1 knockdown was associated with increased lysosomal pH, implicating the subunit in lysosome-dependent coronavirus entry/replication. siRNA knockdown of ATP6V0D1 with coronavirus cytopathic effect assay and lysosomal pH measurement ACS infectious diseases Medium 33346633
2022 ATP6V0D1 was identified as a direct molecular target of JTC801 (the alkaliptosis-inducing drug) using mass-spectrometry-based target identification and cellular thermal shift assay. JTC801-mediated stabilization of ATP6V0D1 protein increases its interaction with STAT3, leading to increased STAT3 expression and activity that sustains lysosomal pH homeostasis. Genetic or pharmacological inhibition of STAT3 restored alkaliptosis sensitivity in ATP6V0D1-deficient pancreatic ductal adenocarcinoma cells. Mass-spectrometry-based drug target ID, cellular thermal shift assay, point mutation, co-immunoprecipitation, siRNA/gene knockout with cell death assays, mouse xenograft models Cell reports High 36640329
2022 Schisandrol A (SolA) was shown to allosterically activate ATP6V0D1 by binding to cysteine 335, inducing a conformational change that activates V-ATPase-dependent lysosomal acidification. This lysosomal acidification selectively promoted mitochondrial BH3-only protein BIM degradation, preserving mitochondrial homeostasis and neuronal cell survival against AGEs-induced apoptosis. Drug target identification, cysteine-335 point mutation, lysosomal pH measurement, mitochondrial assays, cell survival assay Acta pharmaceutica Sinica. B High 36213534
2022 HPS6 (a BLOC-2 complex subunit) was shown to interact with ATP6V0D1 by co-immunoprecipitation. Knockdown of either HPS6 or ATP6V0D1 in HUVECs produced similar Weibel-Palade body defects (misshaped WPBs, decreased WPB number, impaired vWF tubulation), indicating that HPS6 transports ATP6V0D1 to the WPB limiting membrane for V-ATPase assembly and maintenance of acidic luminal pH required for WPB biogenesis. Co-immunoprecipitation, siRNA knockdown of HPS6 and ATP6V0D1, fluorescence microscopy of WPB morphology Frontiers in cell and developmental biology Medium 35252216
2024 Adipose-specific deletion of Atp6v0d1 in mice caused generalized lipodystrophy, identifying ATP6V0D1 as a master regulator of adipogenesis. The resulting Atp6v0d1AKO mice developed spontaneous cardiomyopathy with cardiac insulin resistance (decreased IRS-1/2 expression), lipid accumulation, and increased FoxO1. Myocardin was downregulated in these hearts and shown by RNAi, luciferase reporter, and ChIP-qPCR to directly regulate IRS-1 transcription; restoring cardiac myocardin expression reversed metabolic gene dysregulation and improved cardiac function. Adipose-specific Atp6v0d1 knockout mice, RNA-seq, RNAi, luciferase reporter assay, ChIP-qPCR, in vivo AAV-mediated gene delivery Theranostics High 38505620
2025 Knockdown of ATP6V0D1 (but not ATP6V1H) in neuroblastoma cells enhanced sensitivity to ellipticine, suppressed proliferation and migration, decreased lysosomal drug uptake, and induced G2/M arrest. ATP6V0D1 knockdown also suppressed ellipticine-induced cytoplasmic vacuolation (ER swelling), establishing a specific role for ATP6V0D1 in lysosomal drug sequestration-mediated chemoresistance. siRNA knockdown of ATP6V0D1 and ATP6V1H, cell viability assay, migration assay, flow cytometry (cell cycle), lysosomal uptake assay, EM for vacuolation characterization Molecular & cellular oncology Medium 40552114
2025 Microglial Tmem9 was shown to regulate V-ATPase assembly through ATP6V0D1. In an Alzheimer's disease mouse model (5xFAD), Tmem9 downregulation (by physical exercise) inhibited C1q complement activation and reduced microglial synapse engulfment; overexpression of Tmem9 promoted complement activation. The pathway was placed as Tmem9 → ATP6V0D1 (V-ATPase subunit) → V-ATPase assembly → complement activation. In vivo exercise intervention in 5xFAD mice, Tmem9 overexpression/knockdown in BV2 cells treated with oAβ, complement activation assay, synapse engulfment assay Aging cell Medium 39871402
2000 The human VPATPD (ATP6V0D1) gene was characterized: it spans 19 kb, consists of 8 exons, and encodes a protein 99.5% identical to mouse subunit D at the amino acid level. The gene is located on chromosome 16q22, transcribed from the complementary strand relative to HSD11B2, with their 3' ends only 0.5 kb apart. Forskolin upregulates HSD11B2 but not VPATPD in JEG3 cells, showing distinct regulatory control despite genomic proximity. Gene cloning, sequencing, exon-intron mapping, RT-PCR, comparative sequence analysis, cell-based reporter/expression assay with forskolin Biochemical and biophysical research communications Medium 11118322
2024 ATP6V0D1 overexpression or JTC801-mediated stabilization of ATP6V0D1 protein inhibited ABCB1 (multidrug resistance protein) upregulation in paclitaxel-resistant ovarian cancer cells, overcoming drug resistance via alkaliptosis. Increasing intracellular pH (pH 8.5 via NaOH) suppressed ABCB1 expression whereas acidification (pH 6.5 via HCl) amplified ABCB1, demonstrating that the ATP6V0D1-mediated alkaliptosis-ABCB1 axis mediates paclitaxel resistance. Gene transfection (ATP6V0D1 overexpression), JTC801 pharmacological treatment, intracellular pH manipulation, ABCB1 expression assay, cell growth inhibition assay Molecular carcinogenesis Medium 38751020
2009 Control elements located within the first intron of ATP6V0D1 were shown experimentally to function as enhancers that modulate expression of the neighboring AgRP gene with spatiotemporal specificity, demonstrating that intronic sequences of ATP6V0D1 can act in trans on adjacent gene promoters. In vitro enhancer screening, transgenic mouse reporter assays with dietary/fasting challenges, comparative sequence analysis Journal of molecular biology Medium 19285986
2020 Affinity purification-mass spectrometry using PHF1-immunoreactive phosphorylated tau as bait from Alzheimer's disease brain tissue identified ATP6V0D1 as a protein that directly interacts with phosphorylated tau in neurofibrillary tangles. Affinity purification-mass spectrometry from microdissected neurofibrillary tangles in human Alzheimer's disease brain Brain : a journal of neurology Low 32812023
2025 ATP6V0D1 deletion in PDAC cells led to compensatory overactivation of STAT3-mediated lysosomal pH regulation and AKT signaling. Inhibition of STAT3 or AKT pathways in ATP6V0D1-deficient cells restored sensitivity to alkaliptosis, placing ATP6V0D1 upstream of STAT3/AKT as a suppressor of these oncogenic pathways. Gene knockdown/knockout, transcriptomic analysis, Western blotting, CCK-8/PI cell death assays, macropinocytosis assay, DepMap database analysis Cancer drug resistance Medium 41019981

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Drosophila RNAi screen identifies host genes important for influenza virus replication. Nature 353 18615016
2020 Phosphorylated tau interactome in the human Alzheimer's disease brain. Brain : a journal of neurology 293 32812023
2005 Distinct expression patterns of different subunit isoforms of the V-ATPase in the rat epididymis. Biology of reproduction 141 16192400
2019 The macrophage-specific V-ATPase subunit ATP6V0D2 restricts inflammasome activation and bacterial infection by facilitating autophagosome-lysosome fusion. Autophagy 134 30681394
2009 Atp6v0d2 is an essential component of the osteoclast-specific proton pump that mediates extracellular acidification in bone resorption. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 115 19113919
2015 Critical role of CAV1/caveolin-1 in cell stress responses in human breast cancer cells via modulation of lysosomal function and autophagy. Autophagy 109 25945613
2008 The vacuolar-ATPase complex regulates retinoblast proliferation and survival, photoreceptor morphogenesis, and pigmentation in the zebrafish eye. Investigative ophthalmology & visual science 78 18836173
2020 The SARS-CoV-2 Cytopathic Effect Is Blocked by Lysosome Alkalizing Small Molecules. ACS infectious diseases 64 33346633
2020 KIF5A-dependent axonal transport deficiency disrupts autophagic flux in trimethyltin chloride-induced neurotoxicity. Autophagy 62 32160081
2022 ATP6V0D1 promotes alkaliptosis by blocking STAT3-mediated lysosomal pH homeostasis. Cell reports 60 36640329
2023 Mechanisms of alkaliptosis. Frontiers in cell and developmental biology 54 37601110
2014 High bone mass in mice lacking Cx37 because of defective osteoclast differentiation. The Journal of biological chemistry 54 24509854
2022 Schisandrol A protects AGEs-induced neuronal cells death by allosterically targeting ATP6V0d1 subunit of V-ATPase. Acta pharmaceutica Sinica. B 41 36213534
2016 Molecular Characterization of the Vacuolating Autotransporter Toxin in Uropathogenic Escherichia coli. Journal of bacteriology 34 26858103
2018 A Proteomics Survey of Junín Virus Interactions with Human Proteins Reveals Host Factors Required for Arenavirus Replication. Journal of virology 26 29187543
2022 The FACT complex facilitates expression of lysosomal and antioxidant genes through binding to TFEB and TFE3. Autophagy 23 35230915
2017 Systemic Analysis of miRNAs in PD Stress Condition: miR-5701 Modulates Mitochondrial-Lysosomal Cross Talk to Regulate Neuronal Death. Molecular neurobiology 22 28710704
2018 Impact of energy restriction during late gestation on the muscle and blood transcriptome of beef calves after preconditioning. BMC genomics 20 30253751
2018 Quantitative proteomic analysis of intracerebral hemorrhage in rats with a focus on brain energy metabolism. Brain and behavior 17 30307711
2023 Identification of Novel Senescent Markers in Small Extracellular Vesicles. International journal of molecular sciences 16 36768745
2022 HPS6 Regulates the Biogenesis of Weibel-Palade Body in Endothelial Cells Through Trafficking v-ATPase to Its Limiting Membrane. Frontiers in cell and developmental biology 14 35252216
2024 Alkaliptosis induction counteracts paclitaxel-resistant ovarian cancer cells via ATP6V0D1-mediated ABCB1 inhibition. Molecular carcinogenesis 10 38751020
2023 Thyroid hormone upregulates LAMP2 expression and lysosome activity. Biochemical and biophysical research communications 10 37099812
2025 Physical Exercise Decreases Complement-Mediated Synaptic Loss and Protects Against Cognitive Impairment by Inhibiting Microglial Tmem9-ATP6V0D1 in Alzheimer's Disease. Aging cell 8 39871402
2009 Control elements in the neighboring ATPase gene influence spatiotemporal expression of the human agouti-related protein. Journal of molecular biology 8 19285986
2000 Structure of the VPATPD gene encoding subunit D of the human vacuolar proton ATPase. Biochemical and biophysical research communications 6 11118322
2024 Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit. Theranostics 5 38505620
2023 Literature-Based Discovery to Elucidate the Biological Links between Resistant Hypertension and COVID-19. Biology 4 37759668
2022 A Novel Somatic Mutation Implicates ATP6V0D1 in Proinsulin Processing. Journal of the Endocrine Society 3 36694809
2023 Transcriptome analysis of skeletal muscle in dermatomyositis, polymyositis, and dysferlinopathy, using a bioinformatics approach. Frontiers in neurology 2 38125829
2026 Development of a Novel 11-Gene Signature Related to Immune Subtypes for Fibromyalgia. Endocrine, metabolic & immune disorders drug targets 1 40070065
2025 The Role of V-ATPase ATP6V0D1 Subunit in Chemoresistance and Ellipticine-Induced Cytoplasmic Vacuolation in Neuroblastoma Cells. Molecular & cellular oncology 1 40552114
2025 Identifying diagnostic biomarkers for glaucoma based on transcriptome combined with Mendelian randomization. Scientific reports 1 40593846
2024 Identifying Hub Genes for Glaucoma based on Bulk RNA Sequencing Data and Multi-machine Learning Models. Current medicinal chemistry 1 38362683
2026 Genomic Investigations Unveil the Genetic Underpinnings of Environmental Adaptation in African Goat Populations. Integrative zoology 0 41684133
2025 [Artificial light at night effects glucose metabolism in the developing jawbone by inhibiting melatonin secretion]. Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology 0 39848802
2025 The combination of PF-429242 and chloroquine triggers pH-dependent cell death in hepatocellular carcinoma cells. International journal of medical sciences 0 40520896
2025 Deacetylation of ATG16L1 is required for LC3-associated lysosomal microautophagy. Autophagy 0 40851277
2025 Blood transcriptome analysis reveals CTSB and ATP6V0D1 expression in circulating monocytes as potential biomarkers of sepsis. Shock (Augusta, Ga.) 0 40961380
2025 Cryptotanshinone differentially induces cell death in ATP6V0D1-deficient pancreatic cancer cells. Cancer drug resistance (Alhambra, Calif.) 0 41019981
2025 Pathways in the brain, heart and lung influenced by SARS-CoV-2 NSP6 and SARS-CoV-2 regulated miRNAs: an in silico study hinting cancer incidence. Cardio-oncology (London, England) 0 41126309

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