Affinage

ATP6V1C1

V-type proton ATPase subunit C 1 · UniProt P21283

Round 2 corrected
Length
382 aa
Mass
43.9 kDa
Annotated
2026-04-28
48 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP6V1C1 encodes the C1 subunit of the V1 peripheral sector of the vacuolar H⁺-ATPase (V-ATPase) and is essential for V1 domain assembly onto membranes and for proton pump catalytic activity, functioning as a critical determinant of organellar and extracellular acidification across eukaryotes (PMID:8416931, PMID:14961347). In osteoclasts, ATP6V1C1 localizes to the ruffled border, physically interacts with the a3 (ATP6V0A3) subunit, drives extracellular acid secretion required for bone resorption, and independently organizes the F-actin ring through co-localization with actin and microtubules (PMID:18657050); in cancer cells, it sustains lysosomal V-ATPase activity that activates mTORC1 signaling, suppresses autophagy, and promotes tumor growth and metastasis (PMID:24155661, PMID:28504970, PMID:33183740). Gain-of-function ATP6V1C1 variants increase lysosomal acidification, disrupt autophagic flux and ciliogenesis causing a DOORS-like neurodevelopmental syndrome, while conditional loss in hair cells produces sensorineural hearing loss through synaptic ribbon loss, autophagic failure, and apoptosis (PMID:39210597, PMID:41539473).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1993 High

    Establishing that the C subunit (VMA5) is structurally required for V1 sector assembly and vacuolar ATPase activity resolved the foundational question of whether this subunit is catalytic or architectural.

    Evidence VMA5 deletion in yeast abolished V-ATPase activity and prevented V1 membrane assembly (enzyme activity assay, membrane fractionation)

    PMID:8416931

    Open questions at the time
    • No structural information on how subunit C bridges V1 subunits
    • Mammalian isoform-specific functions not addressed
  2. 2001 Medium

    Cross-species complementation of yeast vma5 mutants with an ascidian C subunit demonstrated that the assembly/activity role of subunit C is conserved across metazoans, extending the yeast paradigm to animal biology.

    Evidence Heterologous expression of ascidian subunit C rescued yeast vma5 pH-sensitivity phenotype

    PMID:14961347

    Open questions at the time
    • Mammalian C1 vs C2 isoform specificity not tested
    • Mechanism of functional conservation at the structural level unknown
  3. 2009 High

    Identifying ATP6V1C1 as the sole C-subunit isoform in osteoclasts and demonstrating its interaction with a3, ruffled border localization, and independent role in F-actin ring formation established a tissue-specific function beyond generic acidification.

    Evidence RNAi knockdown in osteoclasts, co-IP of C1–a3 interaction, confocal co-localization with F-actin and microtubules, bone resorption pit and acidification assays

    PMID:18657050

    Open questions at the time
    • Structural basis of C1–a3 interaction not resolved
    • How C1 organizes F-actin independently of a3 remains mechanistically undefined
  4. 2013 High

    Demonstration that ATP6V1C1 knockdown impairs lysosomal acidification, cancer cell invasion, and in vivo tumor growth/metastasis revealed the subunit as a non-redundant driver of malignant phenotypes through V-ATPase-dependent mechanisms.

    Evidence shRNA knockdown in breast cancer cells, lysosomal pH assay, Matrigel invasion, 4T1 xenograft and bone metastasis models

    PMID:24155661

    Open questions at the time
    • Downstream signaling pathway not identified at this stage
    • Whether the effect is specific to C1 versus other V-ATPase subunits unclear
  5. 2017 High

    Linking ATP6V1C1-dependent V-ATPase activity to mTORC1 signaling in cancer cells answered the mechanistic question of how lysosomal acidification translates into a proliferative advantage, and showed selectivity for transformed over untransformed cells.

    Evidence shRNA knockdown in multiple breast cancer lines, V-ATPase activity assay, mTORC1 phosphorylation Western blot, orthotopic and intraosseous mouse tumor models

    PMID:28504970

    Open questions at the time
    • Whether mTORC1 activation is direct (via amino acid sensing on lysosome) or indirect not distinguished
    • Cancer-type generalizability beyond breast cancer not tested
  6. 2020 Medium

    Establishing that ATP6V1C1 activates mTOR to suppress autophagy and reduce radiosensitivity in esophageal cancer extended the mTORC1-autophagy axis to a second cancer type and revealed therapeutic vulnerability upon silencing.

    Evidence siRNA/overexpression, colony formation, autophagosome/autolysosome imaging, mTOR pathway Western blot, nude mouse xenograft with radiation

    PMID:33183740

    Open questions at the time
    • Whether autophagic effect is fully mTOR-dependent or involves parallel pathways not resolved
    • Direct radiosensitization mechanism versus autophagic cell death not distinguished
  7. 2024 High

    Discovery that gain-of-function ATP6V1C1 variants cause hyperacidification, disrupted autophagy, impaired ciliogenesis, and a DOORS-like neurodevelopmental phenotype established the first human Mendelian disease link and showed that excess V-ATPase activity is as pathogenic as deficiency.

    Evidence Patient variant analysis, lysosomal pH assay, autophagic flux (LC3/p62), ciliogenesis assay, comparison with ATP6V1B2 variants

    PMID:39210597

    Open questions at the time
    • Number of families limited; full phenotypic spectrum not defined
    • Structural basis of gain-of-function not determined
    • Contribution of ciliogenesis defect versus autophagy defect to neurological phenotype unclear
  8. 2024 Medium

    Showing that V-ATPase subunit C is released from vacuolar membranes during yeast replicative aging—regulated by the RAVE complex (assembly) and Oxr1 (disassembly)—linked reversible V-ATPase disassembly to aging and lifespan control.

    Evidence Yeast replicative aging model, fluorescence microscopy of Vma5 localization, vacuolar pH, genetic epistasis (rav1Δ, oxr1Δ), lifespan assays (preprint)

    PMID:bio_10.1101_2024.07.23.604825

    Open questions at the time
    • Preprint; not yet peer-reviewed
    • Whether RAVE-Oxr1 regulation is conserved in mammalian cells unknown
    • Signal triggering age-dependent disassembly not identified
  9. 2025 Medium

    Identification of ATP6V1C1 as the direct binding target of veratramine demonstrated that the C1 subunit is a druggable node whose pharmacological inhibition disrupts V-ATPase catalysis and the autophagic-lysosomal pathway.

    Evidence Thermal proteome profiling, thermal proximity co-aggregation, direct binding assay, V-ATPase activity and lysosomal acidification assays

    PMID:40384877

    Open questions at the time
    • Binding site on C1 not structurally defined
    • Selectivity over other V-ATPase subunits or off-target effects not fully characterized
  10. 2026 High

    Two discoveries in 2026 expanded the functional repertoire: (1) CAF-derived extracellular vesicles deliver ATP6V1C1 protein to lung adenocarcinoma cells where it suppresses ID1-IGFBP3 to amplify IGF1R/Akt/ERK-driven EMT, and (2) conditional hair cell knockout and a gain-of-function knock-in established that ATP6V1C1 controls ribbon synapse integrity, autophagic flux, and auditory/vestibular function.

    Evidence EV proteomic profiling, siRNA/overexpression with EMT/signaling readouts, in vivo metastasis model (lung cancer); conditional KO and R281P knock-in mice, ABR, electron microscopy of ribbon synapses, autophagic flux assays (hair cells)

    PMID:41539473 PMID:41548219

    Open questions at the time
    • Non-canonical transcriptional role (ID1/IGFBP3 suppression) mechanism unclear—whether V-ATPase-dependent or independent not distinguished
    • Whether EV-delivered C1 assembles into recipient-cell V-ATPase complexes unknown
    • Relative contributions of synaptic vs autophagic defects to hearing loss not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of ATP6V1C1's bridging role in V1-V0 assembly, the mechanism by which it organizes F-actin independently of other V-ATPase subunits, and whether the non-canonical transcriptional effects observed in cancer are V-ATPase-dependent remain unresolved.
  • No high-resolution structure of mammalian V-ATPase C1 in complex context
  • Mechanism linking C1 to F-actin organization unknown
  • Whether ID1/IGFBP3 regulation requires V-ATPase catalytic activity or is a moonlighting function is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0140657 ATP-dependent activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005764 lysosome 4 GO:0005773 vacuole 3 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-382551 Transport of small molecules 5 R-HSA-1643685 Disease 4 R-HSA-9612973 Autophagy 4 R-HSA-162582 Signal Transduction 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-5357801 Programmed Cell Death 1
Partners
ATP6V0A3ATP6V1B2ID1IGFBP3MTOR
Complex memberships
V-ATPase (V1 sector)V-ATPase holoenzyme (V1-V0)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 VMA5 (yeast ortholog of ATP6V1C1) encodes the 42-kDa peripheral subunit of the vacuolar H+-ATPase V1 sector, and is essential for assembly of the V1 domain onto the vacuolar membrane; deletion of VMA5 abolishes vacuolar ATPase enzyme activity and prevents V1 subunit assembly. Genetic deletion (vma5 mutant), vacuolar ATPase enzyme activity assay, membrane fractionation The Journal of biological chemistry High 8416931
2001 Subunit C of V-ATPase from the ascidian Ascidia sydneiensis samea (ortholog of ATP6V1C1) functionally complements yeast vma5 mutants, rescuing pH sensitivity, demonstrating that subunit C is responsible for V-ATPase assembly and activity regulation across metazoan species. Heterologous complementation of yeast vma5 mutant with ascidian cDNA under galactose-inducible promoter; pH sensitivity growth assay Marine biotechnology (New York, N.Y.) Medium 14961347
2009 Atp6v1c1 (C1) is the predominant C-subunit isoform expressed in osteoclasts (C2a and C2b are absent), is induced by RANKL during osteoclast differentiation, localizes to the ruffled border of activated osteoclasts, physically interacts with the a3 subunit (Atp6v0a3), is essential for osteoclast acidification activity and bone resorption, and is required for F-actin ring formation (unlike a3). C1 co-localizes with microtubules at the plasma membrane and with F-actin in mature osteoclasts. Lentivirus-mediated RNAi knockdown, immunoprecipitation (C1–a3 interaction), confocal immunofluorescence (co-localization with ruffled border, microtubules, F-actin), bone resorption pit assay, acidification assay The Biochemical journal High 18657050
2013 Silencing of Atp6v1c1 in breast cancer cells inhibits lysosomal acidification and impairs cell growth, migration, and invasion in vitro, and reduces tumor growth, metastasis, and osteolytic bone lesions in vivo, establishing that Atp6v1c1 promotes breast cancer growth and bone metastasis through regulation of lysosomal V-ATPase activity. Lentivirus-mediated shRNA knockdown, lysosomal acidification assay, Matrigel invasion assay, 4T1 xenograft mouse model, in vivo bone metastasis imaging International journal of biological sciences High 24155661
2014 Atp6v1c1 co-localizes with filamentous actin (F-actin) in breast cancer cells, and its depletion disrupts normal F-actin arrangement in 4T1, MDA-MB-231, and MDA-MB-435s cells, implicating Atp6v1c1 in actin cytoskeletal organization that facilitates cancer cell metastasis. shRNA knockdown, confocal immunofluorescence co-localization of Atp6v1c1 with F-actin (phalloidin staining), multiple human and mouse cancer cell lines PloS one Medium 24454753
2015 AAV-mediated shRNA knockdown of Atp6v1c1 in periodontal lesions protects against bone erosion (>85%) and gingival inflammation caused by P. gingivalis infection, reduces osteoclast numbers, inhibits infiltration of dendritic cells and macrophages, and suppresses expression of osteoclast-related genes and pro-inflammatory cytokine genes, revealing a dual role in osteoimmunology. AAV-shRNA gene knockdown in mouse periodontitis model, histomorphometry, immunohistochemistry for immune cell infiltration, qRT-PCR for cytokine/osteoclast gene expression PloS one Medium 26274612
2017 Lentiviral shRNA-mediated knockdown of Atp6v1c1 reduces V-ATPase activity, impairs mTORC1 pathway activation, reduces proliferation in human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-435s) but not in untransformed C3H10T1/2 cells, and reduces orthotopic/intraosseous tumor growth and bone metastasis in vivo, establishing that Atp6v1c1 enhances breast cancer growth partly through mTORC1 signaling downstream of V-ATPase activity. Lentiviral shRNA knockdown, V-ATPase activity assay, mTORC1 phosphorylation (Western blot), cell proliferation assay, orthotopic and intraosseous mouse tumor models, TCGA genomic analysis Oncotarget High 28504970
2017 Deletion of VMA5 (ATP6V1C1 ortholog) in Candida albicans leads to vacuolar dysfunction, disturbance of calcium homeostasis, inhibition of calcium-related oxidative stress response, defects in autophagy completion, impaired hyphal development, and attenuated virulence. PCR-mediated homologous recombination gene deletion, vacuolar acidification assay, calcium homeostasis measurement, autophagy flux assay, hyphal morphology, murine infection model Future microbiology Medium 28879785
2020 ATP6V1C1 inhibits autophagy and reduces radiosensitivity in esophageal squamous cell carcinoma (ESCC) cells; silencing ATP6V1C1 combined with ionizing radiation promotes autophagy, suppresses tumor growth, and increases apoptosis. The mechanism involves ATP6V1C1 activating mTOR signaling to suppress autophagy and thereby reduce radiosensitivity. siRNA knockdown and plasmid overexpression, colony formation assay, EdU proliferation assay, flow cytometry (apoptosis), γH2AX assay (DNA damage), immunofluorescence (autophagosomes/autolysosomes), transmission electron microscopy (autophagic ultrastructure), Western blot (mTOR pathway), nude mouse xenograft Gene Medium 33183740
2024 Dominantly acting gain-of-function variants in ATP6V1C1 (and ATP6V1B2) upregulate V-ATPase function, causing increased lysosomal acidification, disruption of lysosomal morphology and localization, defective autophagic flux with accumulation of lysosomal substrates, and impaired cilium biogenesis, resulting in a neurodevelopmental phenotype resembling DOORS syndrome. Patient-derived variant analysis, lysosomal pH assay, lysosomal morphology imaging (confocal), autophagic flux assay (LC3/p62 Western blot, immunofluorescence), ciliogenesis assay, functional comparison with ATP6V1B2 variants HGG advances High 39210597
2024 V-ATPase subunit C (Vma5, yeast ortholog of ATP6V1C1) is released from the lysosome-like vacuole into the cytosol during yeast replicative aging (after >5 cell divisions), reflecting V-ATPase disassembly into V1 and V0 subcomplexes, which causes vacuole alkalinization. Caloric restriction prevents this disassembly. The RAVE complex promotes V-ATPase reassembly (Rav2 levels decline with age), and Oxr1 promotes disassembly; rav1Δ shortens replicative lifespan while oxr1Δ extends it. Yeast replicative aging model, fluorescence microscopy of Vma5 (subunit C) localization, vacuolar pH measurement, caloric restriction experiments, genetic epistasis (rav1Δ, oxr1Δ), Rav2 overexpression, lifespan assays bioRxivpreprint Medium bio_10.1101_2024.07.23.604825
2025 ATP6V1C1 is the direct binding target of the natural compound veratramine (VAM); VAM directly binds ATP6V1C1, inhibits V-ATPase catalytic activity and lysosomal acidification, and disrupts the autophagic-lysosomal pathway essential for cancer cell survival. Thermal proteome profiling (TPP), thermal proximity co-aggregation (TPCA) to identify V-ATPase complex dissociation, direct binding assay, V-ATPase catalytic activity assay, lysosomal acidification assay, autophagic flux assay International journal of biological sciences Medium 40384877
2026 CAF-derived extracellular vesicles deliver ATP6V1C1 protein to lung adenocarcinoma cells, where it suppresses IGFBP3 expression by downregulating the transcriptional regulator ID1, inducing epithelial-mesenchymal transition and amplifying IGF1/IGF1R/Akt/ERK signaling, creating a feedforward metastatic loop. Quantitative proteomic profiling of CAF-derived EVs, EV uptake assays, siRNA/overexpression of ATP6V1C1, Western blot and qRT-PCR for ID1/IGFBP3/EMT markers, IGF1R/Akt/ERK signaling assays, in vivo metastasis mouse model Cell reports Medium 41548219
2026 Conditional knockout of Atp6v1c1 in mouse hair cells causes early-onset sensorineural hearing loss and vestibular malfunction, with synaptic defects in inner hair cells (loss of ribbon synapses, accumulation of endocytic compartments, absence of F-actin mesh at active zones), disrupted autophagic flux, and apoptosis. A gain-of-function p.R281P knock-in variant causes late-onset high-frequency hearing loss through disrupted autophagic flux and spiral ganglion neuron degeneration. Conditional knockout mouse (hair cell-specific), auditory brainstem response (ABR), confocal and electron microscopy (ribbon synapses, endocytic compartments, F-actin), autophagic flux assay, apoptosis assay, knock-in mouse model (p.R281P), linkage analysis and exome sequencing in human family Journal of genetics and genomics High 41539473

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2002 The vacuolar (H+)-ATPases--nature's most versatile proton pumps. Nature reviews. Molecular cell biology 961 11836511
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
1997 Structure, function and regulation of the vacuolar (H+)-ATPase. Annual review of cell and developmental biology 488 9442887
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2006 V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nature cell biology 396 16415858
1999 Vacuolar and plasma membrane proton-adenosinetriphosphatases. Physiological reviews 348 10221984
2007 Coupling of rotation and catalysis in F(1)-ATPase revealed by single-molecule imaging and manipulation. Cell 307 17662945
2001 Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver. Proceedings of the National Academy of Sciences of the United States of America 300 11752456
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
1999 Structure and properties of the vacuolar (H+)-ATPases. The Journal of biological chemistry 252 10224039
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
1999 Animal plasma membrane energization by proton-motive V-ATPases. BioEssays : news and reviews in molecular, cellular and developmental biology 206 10440860
1997 The vacuolar H+-ATPase: a universal proton pump of eukaryotes. The Biochemical journal 199 9210392
1986 Receptor-mediated endocytosis: the intracellular journey of transferrin and its receptor. Biochimie 169 2874839
2007 Integral and associated lysosomal membrane proteins. Traffic (Copenhagen, Denmark) 163 17897319
2013 Proteomic analysis of podocyte exosome-enriched fraction from normal human urine. Journal of proteomics 126 23376485
1993 Isolation of vacuolar membrane H(+)-ATPase-deficient yeast mutants; the VMA5 and VMA4 genes are essential for assembly and activity of the vacuolar H(+)-ATPase. The Journal of biological chemistry 112 8416931
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2021 Combinatorial CRISPR screen identifies fitness effects of gene paralogues. Nature communications 106 33637726
2009 Atp6v1c1 is an essential component of the osteoclast proton pump and in F-actin ring formation in osteoclasts. The Biochemical journal 74 18657050
1998 Characterization of a staphylococcal plasmid related to pUB110 and carrying two novel genes, vatC and vgbB, encoding resistance to streptogramins A and B and similar antibiotics. Antimicrobial agents and chemotherapy 58 9661023
2022 The chimeric gene atp6c confers cytoplasmic male sterility in maize by impairing the assembly of the mitochondrial ATP synthase complex. Molecular plant 41 35272047
2013 Silencing of atp6v1c1 prevents breast cancer growth and bone metastasis. International journal of biological sciences 39 24155661
2007 Intracellular pH regulation in oral squamous cell carcinoma is mediated by increased V-ATPase activity via over-expression of the ATP6V1C1 gene. Oral oncology 38 17467328
2017 Osteoclast proton pump regulator Atp6v1c1 enhances breast cancer growth by activating the mTORC1 pathway and bone metastasis by increasing V-ATPase activity. Oncotarget 36 28504970
2014 Atp6v1c1 may regulate filament actin arrangement in breast cancer cells. PloS one 29 24454753
2020 The ATPase subunit of ATP6V1C1 inhibits autophagy and enhances radiotherapy resistance in esophageal squamous cell carcinoma. Gene 15 33183740
2001 Subunit C of the vacuolar-type ATPase from the vanadium-rich ascidian Ascidia sydneiensis samea rescued the pH sensitivity of yeast vma5 mutants. Marine biotechnology (New York, N.Y.) 15 14961347
2024 Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function. HGG advances 10 39210597
2023 A P-type pentatricopeptide repeat protein ZmRF5 promotes 5' region partial cleavages of atp6c transcripts to restore the fertility of CMS-C maize by recruiting a splicing factor. Plant biotechnology journal 9 38073308
2015 Targeting Atp6v1c1 Prevents Inflammation and Bone Erosion Caused by Periodontitis and Reveals Its Critical Function in Osteoimmunology. PloS one 9 26274612
2017 Contribution of VMA5 to vacuolar function, stress response, ion homeostasis and autophagy in Candida albicans. Future microbiology 8 28879785
2016 Expression of ATP6V1C1 during oral carcinogenesis. Biotechnic & histochemistry : official publication of the Biological Stain Commission 5 26984774
2026 Cancer-associated fibroblast-derived extracellular vesicles deliver ATP6V1C1 to promote lung adenocarcinoma metastasis via the ID1-IGFBP3 axis. Cell reports 1 41548219
2025 Integrated thermal proteome and thermal proximity co-aggregation profiling identifies ATP6V1C1 as a novel anti-cancer drug target. International journal of biological sciences 1 40384877
2026 ATP6V1C1 deficiency impairs auditory and vestibular hair cell function and leads to sensorineural hearing loss in humans and mice. Journal of genetics and genomics = Yi chuan xue bao 0 41539473