ATP6V0A2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IBA GO_REF:0000033	ACCEPT	Summary: ATP6V0A2 is an integral V0 subunit of the V-type proton pump. Reason: V0 a2 is an integral subunit of the V-type proton pump. The PAINT assertion at PTN000179505 is consistent with the target UniProt record and conserved V0 architecture. The a1-containing structure in PMID:33065002 supplies family context, not a direct a2 structure; the PAINT tree and MSA were not independently reconstructed.
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IBA GO_REF:0000033	ACCEPT	Summary: The a2 subunit contributes to the assembled ATP-driven rotary proton pump. Reason: The existing contributes_to assertion correctly assigns a2 a role in the assembled rotational proton pump. V1 performs ATP hydrolysis and the V0 sector supplies proton translocation; this is not autonomous ATP hydrolysis by isolated a2. Retain the PAINT source and original qualifier.
GO:0005886 plasma membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Plasma-membrane localization is supported in particular human cell contexts. Reason: Retain the PAINT plasma-membrane location as a context-dependent location. The immutable UniProt record and current HPA supported plasma-membrane observations in A-431, U-251 MG and U2OS corroborate this location; the principal mechanistic synthesis emphasizes endosome/Golgi membranes. The target in the PTN000907964 descendant evidence is legitimate grounding, not circularity.
GO:0007035 vacuolar acidification	IBA GO_REF:0000033	ACCEPT	Summary: V0 a2 contributes directly to organelle acidification through proton translocation. Reason: Organelle acidification is a direct contribution of the V0 proton-translocation machinery and an appropriate broad inherited process. Retain the PAINT assertion. This does not require adding a lysosome-specific child term or using the project projection as independent evidence.
GO:0051117 ATPase binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: ATPase binding describes an assembly-associated interaction within the pump. Reason: The PAINT ATPase-binding assertion is compatible with the conserved V0 subunit interface in the assembled pump. Retain this assembly-associated binding context rather than rejecting it merely for being less informative. The core is the contribution to proton-pumping activity; no target-specific binding kinetics or complete PAINT-node reconstruction is claimed.
GO:0000220 vacuolar proton-transporting V-type ATPase, V0 domain	IEA GO_REF:0000002	ACCEPT	Summary: The a2 subunit belongs to the membrane-embedded V0 sector. Reason: The InterPro IPR026028 mapping agrees with the a2 protein being a membrane-sector V0 subunit. Preserve the machine-sourced vacuolar V0 term and do not add a lysosome-specific child solely to narrow it.
GO:0005886 plasma membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: The curated plasma-membrane location is a secondary, cell-dependent context. Reason: The UniProt subcellular-location mapping SL-0039 is corroborated by current human HPA plasma-membrane observations. Retain it as a cell-context location, secondary to the endosome/Golgi emphasis of the core.
GO:0010008 endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: The a2-containing pump localizes to early-endosome membranes. Reason: The UniProt endosome-membrane mapping SL-0100 agrees with PMID:16415858 a2 early-endosome localization and acidification-dependent ARNO recruitment. Species and construct details of individual assays remain as recorded in the primary consultation; this is not an isolated a2 transport assay.
GO:0033179 proton-transporting V-type ATPase, V0 domain	IEA GO_REF:0000120	ACCEPT	Summary: The combined domain and orthology mapping correctly places a2 in the V0 sector. Reason: The combined orthology/domain mapping to the V0 sector agrees with the curated a2 identity and conserved membrane-sector function. Preserve the exact GO_REF:0000120 source, including its P15920/Ensembl and IPR002490 provenance; it is not a PAINT annotation.
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000002	ACCEPT	Summary: Rotational proton-pumping activity belongs to the assembled complex, to which a2 contributes. Reason: The InterPro rotational proton-pump mapping identifies the correct complex activity. Interpret a2 as a contributing V0 subunit. A proposed replacement with the identical GO term is not a term correction; remove that review-level replacement while preserving the original source qualifier unchanged.
GO:1902600 proton transmembrane transport	IEA GO_REF:0000002	ACCEPT	Summary: The V0 a2 subunit contributes to proton movement across organelle membranes. Reason: The IPR002490 mapping to proton transmembrane transport agrees with the proton-transfer role of the V0 a subunit within V-ATPase. The protein contributes to the transport step itself rather than merely being a substrate of another process.
GO:0005515 protein binding	IPI PMID:16415858 V-ATPase interacts with ARNO and Arf6 in early endosomes and...	KEEP AS NON CORE	Summary: The a2 cytoplasmic region associates with ARNO/PSCD2; the study assigns Arf6 binding to subunit c. Reason: PMID:16415858 supports the specific a2–ARNO/PSCD2 association, including the human-cell vesicle co-IP and recombinant-tail assays read by the independent core consultant. Arf6 binds subunit c in that study, not directly a2. The tail donor species was not resolved in those selected Methods. Keep the verified association without claiming autonomous GEF activity or removing a correct interaction merely because GO:0005515 is generic. Supporting Evidence: PMID:16415858 ARNO with the a2-isoform of V-ATPase.
GO:0001669 acrosomal vesicle	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Mouse acrosomal a2 localization supports a specialized reproductive-cell context for the orthology transfer. Reason: The source is mouse-to-human Ensembl transfer from P15920/ENSMUSP00000039737. The actual MGI donor assertion cites PMID:11872743, whose complete official abstract explicitly reports a2 immunolocalization in developing and mature mouse acrosomes. Retain the specialized reproductive-cell location; it is not a direct human assay. Current HPA sperm-tail annotations are not used as proof of acrosomal localization. Supporting Evidence: PMID:11872743 with E1 and a2 isoforms is located specifically in developing acrosomes of spermatids and acrosomes in mature sperm.
GO:0015078 proton transmembrane transporter activity	IEA GO_REF:0000107	ACCEPT	Summary: The a2 subunit contributes to proton transport as part of V-ATPase. Reason: The mouse orthology transfer assigns a contribution to proton transmembrane transporter activity, consistent with conserved V0 function and the existing contributes_to qualifier. Retain the source and describe the assembled pump, not an isolated a2 transporter.
GO:0033176 proton-transporting V-type ATPase complex	IEA GO_REF:0000107	ACCEPT	Summary: V-type ATPase complex membership is consistent with the conserved a2 subunit. Reason: The Ensembl transfer of V-type ATPase complex membership is consistent with a2 subunit identity and curated human complex membership. Preserve this original broader component annotation alongside the original V0 annotations.
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Mouse macrophage a2 staining supports a perinuclear localization context. Reason: The Ensembl source traces to mouse P15920 and MGI IDA PMID:19549681. The actual original Results and Fig1 caption describe a2-specific antibody staining in mouse peritoneal macrophages, with a2 concentrated in the perinuclear region. Retain this broader spatial location as context, not a direct human experiment or a separate organelle identity.
GO:0005886 plasma membrane	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Human Protein Atlas observations support plasma-membrane localization in selected cell lines. Reason: The HPA IDA plasma-membrane observation is corroborated by the current target page and cell-line annotations. Retain the experimentally observed location as context-dependent; no image-pixel reanalysis or claim of a universal plasma-membrane pump role is made.
GO:0000139 Golgi membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: The Golgi membrane is a central location of the a2-containing pump. Reason: Golgi membrane is a central a2 location. PMID:32001091 supplies review context. PMID:39680136 Fig. 1B and viral-expression Methods identify human ATP6V0A2-V5 constructs in HeLa cells, with wildtype and R755Q co-localizing with TGN46. PMID:38396846 separately tests the isolated human N-terminal domain in HEK293 cells; this fragment experiment supports a targeting mechanism, not an additional full-length localization assay.
GO:0033176 proton-transporting V-type ATPase complex	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: V-ATPase complex membership is supported; the cited human structure contains a1 rather than a2. Reason: V-type ATPase complex membership is correct for a2. PMID:33065002 establishes the human a1-containing complex and conserved architecture; it must not be described as directly resolving a2. Retain the existing NAS assertion using independent a2 identity and complex evidence for interpretation.
GO:0061795 Golgi lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: The a2-containing pump contributes to Golgi lumen acidification. Reason: Golgi lumen acidification is a direct transport role of the a2-containing pump. PMID:32001091 supplies review context. PMID:39680136 Fig. 3 and Methods measure calibrated trans-Golgi pH in immortalized mouse MEFs: wildtype mean 5.80, knockout 6.52 and R755Q 6.25, with ionophore and bafilomycin controls. These are mouse functional measurements; the same paper separately establishes human a2 Golgi localization. The existing human NAS assertion and its original reference remain unchanged; no human pH IDA annotation is manufactured. Supporting Evidence: PMID:39680136 Atp6v0a2−/− cells showed a clearly elevated pH
GO:1902600 proton transmembrane transport	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: V0 a2 contributes to the proton-translocation machinery of V-ATPase. Reason: Proton transmembrane transport is a direct V0 function. Retain the existing NAS assertion while distinguishing family mechanism from the a1-containing human structural preparation in PMID:33065002; no autonomous a2 ATP-hydrolysis claim follows.
GO:0006879 intracellular iron ion homeostasis	IMP PMID:28296633 The vacuolar-ATPase complex and assembly factors, TMEM199 an...	KEEP AS NON CORE	Summary: ATP6V0A2 loss perturbs the iron-dependent HIF pathway in human cells. Reason: PMID:28296633 includes human ATP6V0A2 CRISPR validation of HIF reporter and endogenous HIF stabilization under aerobic culture. Its detailed iron-rescue experiments target the pump/assembly pathway and selected other subunits, not an a2-specific rescue in Fig8. Retain the curated iron-homeostasis consequence with this boundary; it is downstream context, not a second molecular core. Supporting Evidence: PMID:28296633 Depletion of the V-ATPase subunits also increased endogenous HIF1α
GO:0036295 cellular response to increased oxygen levels	IMP PMID:28296633 The vacuolar-ATPase complex and assembly factors, TMEM199 an...	UNDECIDED	Summary: Aerobic HIF stabilization does not by itself resolve the specific increased-oxygen stimulus annotation. Reason: PMID:28296633 directly tests ATP6V0A2 loss and aerobic HIF stabilization, but the inspected target Results/Fig1 and Methods do not establish a response following an increase in oxygen concentration. GO:0036295 specifically requires that stimulus. Preserve the IMP assertion pending the precise oxygen-response evidence; do not equate constitutive aerobic HIF turnover with a verified oxygen step-up assay or reject it solely as indirect.
GO:0016241 regulation of macroautophagy	NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	UNDECIDED	Summary: An ATP6V0A2-specific regulatory role in macroautophagy remains unresolved from the accessible evidence. Reason: The complete PMID:22982048 abstract distinguishes lipofuscin formation from macroautophagic uptake, so its title does not contradict macroautophagy involvement. Publisher introductory text identifies ATP6V0A1 siRNA, while an a2-specific regulatory assertion has not been verified in the full paper. Preserve the NAS source pending that target-level evidence; no confident wrong-paralog or REMOVE claim is made from incomplete text.
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	UNDECIDED	Summary: The exact a2 identification in the lysosomal-membrane proteomic dataset remains unverified. Reason: The existing HDA source PMID:17897319 is a placental lysosomal-membrane proteomic survey, but its exact Q9Y487/a2 target table was not accessible in this assessment. The study-wide V-ATPase count does not resolve that target. Preserve the experimental assertion without refuting it; defer a positive target-level adjudication and do not use it to manufacture additional lysosome-specific annotations.
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-1222516	UNDECIDED	Summary: Transfer of phagocytic-vesicle membrane localization to human a2 remains uncertain. Reason: Reactome:R-HSA-1222516 assigns the human V-ATPase complex to phagocytic-vesicle membrane. In contrast, the directly inspected PMID:19549681 Results/Fig1 reports a2 remaining perinuclear and essentially absent from bacterial phagosomes in mouse peritoneal macrophages, where a3 is recruited. That restricted mouse comparison is not a universal human negation, but it makes unqualified transfer of the complex location to human a2 uncertain.
GO:0010008 endosome membrane	TAS Reactome:R-HSA-5252133	ACCEPT	Summary: The Reactome complex event is consistent with a2 early-endosome membrane localization. Reason: The complete cached R-HSA-5252133 event places V-ATPase/ATP6AP1 interaction at endosome membranes. Retain the location with independent a2 early-endosome support from PMID:16415858; do not turn this Reactome complex event into a new direct a2–ATP6AP1 binding assay.
GO:0010008 endosome membrane	TAS Reactome:R-HSA-74723	ACCEPT	Summary: Endosome acidification is consistent with a2-containing V-ATPase at the endosome membrane. Reason: The complete R-HSA-74723 summary describes endosomal proton entry, consistent with a2 early-endosome localization and participation in the V0 pump. Retain the endosome-membrane source assertion without assigning independent catalysis to a2.
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917841	ACCEPT	Summary: The structured Reactome event places its catalyst at the endosome membrane. Reason: R-HSA-917841 has an endosome-membrane catalyst and endosomal transferrin-receptor acidification context, concordant with a2 early-endosome evidence. Its generic summary includes borrowed phagosome wording; use the actual structured compartment rather than that wording to interpret the original endosome annotation.
GO:0006955 immune response	TAS PMID:2247090 Cloning of a cDNA for a T cell produced molecule with a puta...	UNDECIDED	Summary: Human a2 N-terminal-fragment cytokine effects provide immune context, while the original TAS assertion remains incompletely resolved. Reason: PMID:2247090 reports dose-dependent mixed-lymphocyte suppression by hybrid-selected, in-vitro-translated material; its putative title is not a reason to reject the result. The original mouse J6B7 model and complete assay specificity remain unresolved for transfer to human ATP6V0A2. Retain UNDECIDED for this original TAS row. Neither the breadth of the immune-response term nor incomplete access to the historical assay establishes that the annotation is wrong; a universal immune role for the intact human pump is also not established. The separate uncached follow-up paper and its failed normal retrieval are recorded only in the notes and are not used as machine-readable supporting evidence. Supporting Evidence: PMID:2247090 significant suppression of a mixed lymphocyte reaction (MLR)
GO:0070273 phosphatidylinositol-4-phosphate binding	IDA PMID:38396846 The Human Mutation K237_V238del in a Putative Lipid Binding ...	NEW	Summary: The isolated human a2 N-terminal domain directly binds PI4P-containing liposomes. Reason: Purified human ATP6V0A2 residues 1–400 were tested in liposome pull-down assays. K237A/V238A and K237_V238del reduced PI4P association without detectable gross secondary-structure alteration by CD. HEK293 fragment localization and acute Golgi PI4P depletion independently connect the binding site to Golgi retention. This supports the MF at the human gene-product level with the tested fragment explicitly recorded; it does not establish full-length pump activation, exclusive PI4P specificity, or a new biological-process annotation. Supporting Evidence: PMID:38396846 WT a2NT showed significantly higher binding to PI(4)P

Gene Description

Existing Annotations Review

Core Functions

Contributes proton translocation in the assembled V-ATPase, coupling the complex's ATP-driven rotary mechanism to endosomal and Golgi acidification. ATP hydrolysis occurs in the V1 sector rather than autonomously in a2.

Binds phosphatidylinositol 4-phosphate through the cytosolic N-terminal domain, helping target or retain a2 at Golgi membranes. Direct binding and localization experiments tested human a2 residues 1–400; the contribution to targeting of the full-length pump is a mechanistic inference.

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