# ATP6V0A2 notes

## 2026-06-03 PN review

ATP6V0A2 is the human V-ATPase 116 kDa a2 subunit, a V0-sector membrane subunit of the V-ATPase. UniProt describes it as a "Subunit of the V0 complex of vacuolar(H+)-ATPase" and states that V-ATPase acidifies intracellular compartments [file:human/ATP6V0A2/ATP6V0A2-uniprot.txt "Subunit of the V0 complex of vacuolar(H+)-ATPase"; "V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments"].

The strongest direct ATP6V0A2 literature support is endosomal. Hurtado-Lorenzo et al. reported that "The a2-isoform is targeted to early endosomes" and that it "interacts with ARNO in an intra-endosomal acidification-dependent manner"; they also found that "Inhibition of endosomal acidification abrogates protein trafficking" [PMID:16415858 "The a2-isoform is targeted to early endosomes"; "interacts with ARNO in an intra-endosomal acidification-dependent manner"; "Inhibition of endosomal acidification abrogates protein trafficking"]. This supports endosome membrane, proton transport/acidification, and pH-sensing trafficking context. It does not justify retaining generic protein binding as an informative MF annotation.

The human V-ATPase structural paper supports the general complex architecture and the endosome/lysosome acidification role: V-ATPases are "ATP-driven proton pumps" with a membrane Vo complex for proton transfer, and organellar V-ATPases establish pH homeostasis of endosomes and lysosomes [PMID:33065002 "V-ATPases are ATP-driven proton pumps"; "homeostasis of endosomes and lysosomes"]. The 2020 V-ATPase review similarly states that V-ATPases are the "primary source of organellar acidification" [PMID:32001091 "V-ATPases are the primary source of organellar acidification in all eukaryotes"].

The PN projection has two ATP6V0A2 candidate additions: GO:0007042 lysosomal lumen acidification and GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain [file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv "ATP6V0A2"; "GO:0007042"; "GO:0046610"]. The mapping audit requires manual gene-level review for lysosomal acidification propagation [file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv "manual_gene_level_review_required_before_gene_review_change"]. I accepted both PN-projected additions because they are supported by gene-level V0 subunit identity plus lysosomal membrane evidence, but I did not promote the broader PN autophagy/nutrient-sensing context into GO beyond these terms.

Lysosomal membrane support comes from lysosomal membrane proteomics that found "17 polypeptides comprising or associated with the vacuolar adenosine triphosphatase" in purified placental lysosomal membranes [PMID:17897319 "17 polypeptides comprising or associated with the vacuolar adenosine"]. This is enough to support lysosomal membrane and the PN lysosomal V0-domain addition when combined with ATP6V0A2 V0-subunit identity.

The HIF/iron paper found ATP6V0A2 among V-ATPase subunits enriched in a HIF1A reporter screen and concluded that V-ATPase disruption causes "intracellular iron depletion" [PMID:28296633 "ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1"; "disrupting the V-ATPase results in intracellular iron depletion"]. This supports keeping intracellular iron ion homeostasis as non-core, but the broader oxygen-response term is over-annotated relative to the mechanism.

The macroautophagy and immune-response annotations should be treated conservatively. The lipofuscin paper says "both the autophagosomes and the lysosomal system are not mandatory" for lipofuscin formation [PMID:22982048 "both the autophagosomes and the lysosomal system are not mandatory"], which is weak support for ATP6V0A2 as a macroautophagy regulator. The old J6B7/T-cell cDNA paper frames the clone as having a "putative immune regulatory role" [PMID:2247090 "putative immune regulatory role"], but this does not support a modern core ATP6V0A2 immune-response annotation.