ATP6V0C

ATP6V0C encodes the 16-kDa proteolipid c-subunit of the V0 sector of vacuolar H+-ATPase (V-ATPase), essential for complex assembly, proton translocation, and acidification of lysosomes, endosomes, and vacuoles, thereby governing autophagy-lysosome pathway flux, intracellular pH homeostasis, and neurotransmitter vesicle loading (PMID:2145283, PMID:24695574, PMID:16061667). Beyond its canonical role in proton pumping, ATP6V0C serves as a scaffold that bridges the SNARE proteins STX17 and VAMP8 to promote autophagosome–lysosome fusion independently of lysosomal acidification, and it directly binds and stabilizes HIF-1α by competing with VHL, participating in a positive transcriptional feedback loop in which HIF-1α reciprocally induces ATP6V0C expression (PMID:38481802, PMID:17178925, PMID:41738275). Heterozygous loss-of-function variants in ATP6V0C cause a neurodevelopmental syndrome with epilepsy, confirmed by impaired V-ATPase function in yeast complementation assays and seizure phenotypes in Drosophila and C. elegans disease models (PMID:36074901). ATP6V0C is also exploited by HIV-1 Vpu to redirect tetherin into intracellular compartments, facilitating viral release (PMID:32291285).

1. 1990 High

   Establishing that subunit c is indispensable for V-ATPase assembly and vacuolar function answered the foundational question of whether this small proteolipid is merely a structural repeat or a functional requirement for the holoenzyme.

   Evidence VMA3 gene disruption in S. cerevisiae with biochemical ATPase activity, vacuolar acidification, protein sorting, and endocytosis assays

   PMID:2145283

   Open questions at the time

   • Mammalian requirement not yet demonstrated
   • Stoichiometry of c-subunit ring not defined
   • No information on tissue-specific roles
2. 2002 High

   Defining the transcriptional control of ATP6V0C by Sp1/Oct1 on a GC-rich, TATA-less promoter established how basal expression of this housekeeping subunit is maintained and can be pharmacologically modulated.

   Evidence In vivo footprinting, promoter-reporter mutagenesis, EMSA, and drug treatment in human cells

   PMID:12133827

   Open questions at the time

   • Chromatin-level regulation not addressed
   • Tissue-specific transcription factors not explored
   • TFEB regulation not yet identified
3. 2005 High

   Demonstrating that ATP6V0C knockdown impairs proton secretion, intracellular pH recovery, MMP-2 activity, and in vivo tumor growth linked V-ATPase c-subunit function to cancer cell invasion and the tumor microenvironment.

   Evidence siRNA knockdown in hepatocellular carcinoma cells with pH measurement, zymography, and xenograft model

   PMID:16061667

   Open questions at the time

   • Whether effect is specific to ATP6V0C versus other V-ATPase subunits
   • Mechanism linking extracellular acidification to MMP activation not fully defined
4. 2006 Medium

   Identification of a direct ATP6V0C–HIF-1α interaction that competes with VHL binding revealed an unexpected non-canonical role for the c-subunit in oxygen-sensing signaling, independent of proton pumping.

   Evidence Co-immunoprecipitation, N-terminal deletion mapping, confocal colocalization, and siRNA knockdown

   PMID:17178925

   Open questions at the time

   • Single-lab observation at the time
   • Physiological context for nuclear translocation unclear
   • No in vivo validation
5. 2008 Medium

   Discovery that the E3 ligase RNF182 ubiquitinates ATP6V0C for proteasomal degradation established a post-translational regulatory axis controlling c-subunit abundance.

   Evidence Yeast two-hybrid confirmed by co-immunoprecipitation and in vitro ubiquitination assay

   PMID:18298843

   Open questions at the time

   • Physiological consequence of RNF182-mediated degradation on V-ATPase activity not tested
   • No in vivo confirmation
   • Ubiquitination sites on ATP6V0C not mapped
6. 2009 Medium

   Showing that ATP6V0C depletion raises lysosomal pH and redirects sequestered chemotherapeutics to the nucleus in drug-resistant cells mechanistically explained V-ATPase's role in multidrug resistance.

   Evidence siRNA knockdown in MCF-7/ADR cells with intracellular drug distribution and cytotoxicity assays

   PMID:19299075

   Open questions at the time

   • Contribution of ATP6V0C versus whole V-ATPase not dissected
   • Clinical relevance not established
7. 2014 Medium

   Demonstrating that ATP6V0C loss blocks autophagic flux at the lysosomal degradation step, with accumulation of α-synuclein and APP-CTFs, directly implicated the c-subunit in neurodegeneration-relevant proteostasis.

   Evidence siRNA knockdown in differentiated SH-SY5Y cells with LysoTracker, LC3-II flux assay, LC3/LAMP-1 colocalization

   PMID:24695574

   Open questions at the time

   • In vivo neuronal validation lacking
   • Whether partial loss mirrors disease conditions unknown
   • No rescue experiment
8. 2020 Medium

   Identifying ATP6V0C as a Vpu-binding partner that mediates tetherin sequestration into endo-lysosomes revealed how HIV-1 hijacks the V-ATPase c-subunit to counteract innate restriction.

   Evidence Yeast two-hybrid, siRNA knockdown, overexpression, HIV-1 release assay, and immunofluorescence colocalization

   PMID:32291285

   Open questions at the time

   • Structural basis of Vpu–ATP6V0C interaction not resolved
   • Relevance in primary T cells or in vivo not shown
   • ATP6V0C'' paralog specificity mechanism unclear
9. 2023 High

   Cross-species functional validation of heterozygous ATP6V0C variants as causative for a neurodevelopmental/epilepsy syndrome established ATP6V0C haploinsufficiency as a Mendelian disease gene.

   Evidence Yeast complementation (LysoSensor, CaCl2 growth), Drosophila seizure assay, C. elegans variant phenotyping, in silico structural modelling

   PMID:36074901

   Open questions at the time

   • Patient iPSC-derived neuronal model not yet reported
   • Genotype-phenotype correlation across variant types not fully resolved
   • Whether seizures arise from impaired acidification, fusion, or both is unknown
10. 2024 Medium

    Demonstrating that TFEB transcriptionally activates ATP6V0C and that ATP6V0C scaffolds STX17–VAMP8 for autophagosome–lysosome fusion uncovered a second, acidification-independent function in membrane fusion.

    Evidence CUT&Run-qPCR, luciferase reporter, co-immunoprecipitation of ATP6V0C with STX17/VAMP8, siRNA flux assays

    PMID:38481802

    Open questions at the time

    • Structural basis of the scaffold function not defined
    • Whether SNARE-bridging and proton-pumping roles are mutually exclusive or concurrent is unclear
    • Single-lab finding awaiting independent replication
11. 2026 High

    Conditional alveolar-specific ATP6V0C knockout attenuating lung injury and epistasis with HIF-1α knockout validated the ATP6V0C–HIF-1α positive feedback loop in vivo, resolving the physiological relevance of the 2006 binding observation.

    Evidence AT2-specific Cre conditional KO mice, Co-IP in injured lung, RNA-seq, AAV-mediated overexpression in HIF-1α KO background, LPS-induced ALI model

    PMID:41738275

    Open questions at the time

    • Whether the feedback loop operates in non-pulmonary tissues is untested
    • Molecular determinants governing V-ATPase-dependent vs HIF-1α-dependent ATP6V0C functions not separated
12. 2026 Medium

    AAV2-mediated ATP6V0C overexpression promoting axon regeneration after optic nerve crush revealed a neuroprotective gain-of-function linked to enhanced lysosomal clearance under ER stress.

    Evidence AAV2 transgene in retinal ganglion cells, optic nerve crush model, axon regeneration and RGC survival quantification

    PMID:42023031

    Open questions at the time

    • Mechanism connecting lysosomal acidification to axon regrowth signaling not delineated
    • Long-term efficacy and functional recovery not assessed
    • Single model system

• Key unresolved questions include the structural basis of ATP6V0C's dual role as a proton channel subunit and SNARE scaffold, whether its HIF-1α-stabilizing function is mechanistically separable from V-ATPase activity in vivo, and how disease-causing variants differentially impact acidification versus membrane fusion.
• No high-resolution structure of mammalian ATP6V0C in the assembled V0 ring with bound SNAREs
• Separation-of-function mutants distinguishing proton pumping from scaffold activity not generated
• Genotype-phenotype studies in patient-derived neurons for the epilepsy syndrome are lacking