Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IBA GO_REF:0000033	ACCEPT	Summary: ATP6V0A2 encodes the a2 isoform of the V0 membrane sector of the V-ATPase. Complex membership is a core cellular-component annotation supported by UniProt curation and human V-ATPase structural literature. Reason: The annotation correctly places ATP6V0A2 in the vacuolar proton-transporting V-type ATPase complex. The protein is a V0 a-subunit of a multisubunit proton pump, and the V0 sector is the membrane proton-translocation module of the complex. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IBA GO_REF:0000033	ACCEPT	Summary: ATP6V0A2 contributes to the rotational V-ATPase proton-pumping activity as a V0 membrane-sector subunit, but does not independently hydrolyze ATP outside the assembled complex. Reason: The contributes_to qualifier is appropriate for a subunit of the V-ATPase complex. The complex couples ATP hydrolysis in V1 to proton transfer through V0, and ATP6V0A2 is a V0 a-subunit. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
GO:0005886 plasma membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Plasma-membrane localization is plausible for V-ATPase a-subunits in some cell contexts, but ATP6V0A2 is better established in endosomal, Golgi, and lysosomal/vesicular membranes. Reason: UniProt includes cell-membrane localization and the GOA contains HPA plasma-membrane evidence, so the annotation is not rejected. It should not be treated as the main proteostasis-relevant location for ATP6V0A2, whose strongest mechanistic evidence is in intracellular acidic compartments. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Cell membrane; Multi-pass membrane protein. PMID:16415858 The a2-isoform is targeted to early endosomes
GO:0007035 vacuolar acidification	IBA GO_REF:0000033	ACCEPT	Summary: Vacuolar acidification is a correct broad biological-process annotation for ATP6V0A2 as a V-ATPase V0 subunit involved in acidification of acidic intracellular compartments. Reason: The term captures the core acidification role of the V-ATPase. For the PN batch, lysosomal lumen acidification is added separately as a more specific supported annotation, but the existing broad annotation remains biologically sound. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:32001091 V-ATPases are the primary source of organellar acidification in all eukaryotes PMID:33065002 organellar V-ATPases are essential in establishing and maintaining the pH
GO:0051117 ATPase binding	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: ATPase binding is much less informative than the complex-membership and contributes_to V-ATPase activity annotations already present for ATP6V0A2. Reason: ATP6V0A2 functions as an integral V0-sector subunit. Treating ATPase binding as a gene-level molecular function risks reducing complex assembly/participation to a vague binding annotation; the more informative annotations are V-ATPase complex/V0-domain membership and contribution to proton-pumping ATPase activity. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
GO:0000220 vacuolar proton-transporting V-type ATPase, V0 domain	IEA GO_REF:0000002	ACCEPT	Summary: The vacuolar V-ATPase V0-domain annotation matches ATP6V0A2 family/domain evidence and its role as an integral membrane V0 a-subunit. Reason: ATP6V0A2 is a member of the V-ATPase 116 kDa subunit family and is curated as a V0-complex subunit. The broader V0-domain annotation is correct; the PN-derived lysosomal V0-domain annotation is added separately where lysosomal localization is supported. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Belongs to the V-ATPase 116 kDa subunit family.
GO:0005886 plasma membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Plasma-membrane localization is supported by UniProt/HPA-derived evidence but is secondary to the intracellular organelle acidification role. Reason: The location is plausible and appears in curated resources, but the literature most directly supporting ATP6V0A2 function emphasizes early endosomes, Golgi function, and endolysosomal acidification rather than a primary plasma-membrane role. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Cell membrane; Multi-pass membrane protein. PMID:16415858 The a2-isoform is targeted to early endosomes
GO:0010008 endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: ATP6V0A2 is well supported at the endosome membrane, especially early endosomes, where a2-containing V-ATPase contributes to pH sensing and endocytic trafficking. Reason: The UniProt-derived IEA annotation is consistent with direct literature showing the a2 isoform is targeted to early endosomes and participates in intra-endosomal acidification-dependent ARNO recruitment and endocytic trafficking. Supporting Evidence: PMID:16415858 The a2-isoform is targeted to early endosomes PMID:16415858 interacts with ARNO in an intra-endosomal acidification-dependent manner file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Essential component of the endosomal pH-sensing machinery
GO:0033179 proton-transporting V-type ATPase, V0 domain	IEA GO_REF:0000120	ACCEPT	Summary: The V0-domain annotation is a core cellular-component annotation for ATP6V0A2. Reason: ATP6V0A2 is the a2 isoform of the V-ATPase 116 kDa a-subunit and belongs to the V0 membrane proton-transfer sector. This term is already aligned with the PN V0 component projection, although PN also supports a lysosomal-specific child term. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000002	MODIFY	Summary: The V-ATPase rotational proton-pump activity is correct for the assembled ATP6V0A2-containing complex. ATP6V0A2 should be interpreted as contributing to this activity as a V0 subunit rather than acting as an independent ATPase. Reason: The term is biologically appropriate for ATP6V0A2-containing V-ATPase complexes, but the GOA qualifier should be changed from enables to contributes_to. The contributes_to IBA qualifier is the clearest representation of a single V0 subunit's contribution to the assembled proton pump. Proposed replacements: proton-transporting ATPase activity, rotational mechanism Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
GO:1902600 proton transmembrane transport	IEA GO_REF:0000002	ACCEPT	Summary: ATP6V0A2 participates in proton transmembrane transport as part of the V-ATPase proton-translocation machinery. Reason: The V0 sector transfers protons across organelle membranes as part of the V-ATPase. ATP6V0A2 is a V0 a-subunit in this machinery, so the process annotation is appropriate. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
GO:0005515 protein binding	IPI PMID:16415858 V-ATPase interacts with ARNO and Arf6 in early endosomes and...	REMOVE	Summary: PMID:16415858 supports a specific ARNO interaction with the a2 isoform, but GO:0005515 protein binding is too generic to retain as useful functional annotation. Reason: The interaction evidence is real, but generic protein binding is uninformative and is explicitly discouraged in this review workflow. The functional meaning of the interaction is better captured in the review text as endosomal pH-sensing/trafficking, not as GO:0005515. Supporting Evidence: PMID:16415858 interacts with ARNO in an intra-endosomal acidification-dependent manner PMID:16415858 Inhibition of endosomal acidification abrogates protein trafficking between
GO:0001669 acrosomal vesicle	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Acrosomal-vesicle localization is plausible by orthology for V-ATPase a-subunits but is not part of the core ATP6V0A2 proteostasis role reviewed here. Reason: The annotation comes from Ensembl orthology transfer rather than direct ATP6V0A2 literature in this review. It is retained as a possible specialized reproductive-cell location, but the main supported locations are endosome, Golgi, lysosomal, and other acidic-vesicle membranes. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt GO; GO:0001669; C:acrosomal vesicle; IEA:Ensembl.
GO:0015078 proton transmembrane transporter activity	IEA GO_REF:0000107	ACCEPT	Summary: ATP6V0A2 contributes to proton transmembrane transporter activity as a V0 membrane-sector component of the assembled V-ATPase. Reason: The contributes_to qualifier is appropriate for ATP6V0A2 because proton translocation is performed by the assembled V-ATPase/V0 machinery rather than by the isolated subunit. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
GO:0033176 proton-transporting V-type ATPase complex	IEA GO_REF:0000107	ACCEPT	Summary: The broader proton-transporting V-type ATPase complex annotation is correct for ATP6V0A2. Reason: ATP6V0A2 is an integral V0-sector subunit of the V-ATPase. The annotation is less specific than the V0-domain annotations but remains valid complex membership. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Perinuclear-region localization is compatible with Golgi/endosomal distribution but is not the most informative cellular-component annotation for ATP6V0A2. Reason: The annotation is retained as a broad localization transferred by Ensembl, but more precise experimentally supported locations include endosome membrane, Golgi membrane, and lysosomal membrane. Supporting Evidence: PMID:16415858 The a2-isoform is targeted to early endosomes file:human/ATP6V0A2/ATP6V0A2-uniprot.txt May play a role in maintaining the Golgi functions
GO:0005886 plasma membrane	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: HPA reports ATP6V0A2 at the plasma membrane, but this is a secondary location relative to intracellular acidic compartments. Reason: The IDA evidence supports retaining the localization, but the core functional literature for ATP6V0A2 centers on endosomal/Golgi/lysosomal acidification and V-ATPase complex function. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt GO; GO:0005886; C:plasma membrane; IDA:HPA.
GO:0000139 Golgi membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: Golgi membrane localization is consistent with ATP6V0A2 disease biology and Golgi acidification/glycosylation functions. Reason: ATP6V0A2 is implicated in maintaining Golgi pH-dependent functions, including glycosylation maturation. ComplexPortal and review evidence support Golgi-membrane assignment for the ATP6V0A2-containing V-ATPase variant. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt May play a role in maintaining the Golgi functions, such as glycosylation maturation, by controlling the Golgi pH PMID:32001091 V-ATPases are the primary source of organellar acidification in all eukaryotes
GO:0033176 proton-transporting V-type ATPase complex	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: Human V-ATPase structural literature supports ATP6V0A2 as part of a proton-transporting V-type ATPase complex. Reason: The annotation captures the assembled complex in which ATP6V0A2 acts. Human V-ATPase structures define a V1 ATP-hydrolysis complex and a Vo proton-transfer complex. Supporting Evidence: PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase
GO:0061795 Golgi lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: Golgi lumen acidification is a supported ATP6V0A2-associated process and explains the glycosylation defects seen when ATP6V0A2 is disrupted. Reason: UniProt and review evidence support ATP6V0A2 involvement in Golgi pH control and glycosylation maturation. This is a meaningful organelle-specific acidification annotation, not merely a broad proteostasis projection. Supporting Evidence: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt May play a role in maintaining the Golgi functions, such as glycosylation maturation, by controlling the Golgi pH PMID:32001091 V-ATPases are the primary source of organellar acidification in all eukaryotes
GO:1902600 proton transmembrane transport	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: Proton transmembrane transport is the fundamental transport process mediated by the assembled V-ATPase containing ATP6V0A2. Reason: The human V-ATPase is an ATP-driven proton pump with a Vo membrane complex for proton transfer, and ATP6V0A2 is one of the Vo a-subunits. Supporting Evidence: PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. file:human/ATP6V0A2/ATP6V0A2-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
GO:0006879 intracellular iron ion homeostasis	IMP PMID:28296633 The vacuolar-ATPase complex and assembly factors, TMEM199 an...	KEEP AS NON CORE	Summary: ATP6V0A2 disruption was identified in a V-ATPase/HIF screen, and the study supports a non-core role for V-ATPase function in intracellular iron availability and HIF prolyl hydroxylation. Reason: The evidence is direct enough to retain the annotation, but intracellular iron homeostasis is downstream of the core V-ATPase acidification role rather than the primary evolved function of ATP6V0A2. Supporting Evidence: PMID:28296633 ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1 PMID:28296633 disrupting the V-ATPase results in intracellular iron depletion
GO:0036295 cellular response to increased oxygen levels	IMP PMID:28296633 The vacuolar-ATPase complex and assembly factors, TMEM199 an...	MARK AS OVER ANNOTATED	Summary: The PMID:28296633 evidence supports V-ATPase effects on HIF stability under aerobic conditions through iron/PHD activity, but the GO term frames this too broadly as a response to increased oxygen levels. Reason: ATP6V0A2 depletion affects HIF1A regulation indirectly through V-ATPase-dependent iron homeostasis. The paper explicitly argues against a lysosomal-degradation mechanism and focuses on PHD activity; the broad oxygen-response term should not be treated as a core ATP6V0A2 function. Supporting Evidence: PMID:28296633 ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1 PMID:28296633 disrupting the V-ATPase results in intracellular iron depletion PMID:28296633 Rather than preventing the lysosomal degradation of HIF1α, the V-ATPase inhibition stabilised HIF1α by decreasing PHD enzymatic activity.
GO:0016241 regulation of macroautophagy	NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	MARK AS OVER ANNOTATED	Summary: The macroautophagy annotation is too broad for ATP6V0A2. V-ATPase acidification supports lysosomal degradation/autophagic flux, but PMID:22982048 does not establish ATP6V0A2 as a specific regulator of macroautophagy. Reason: The supporting paper discusses lipofuscin, autophagy, and lysosomal activity rather than ATP6V0A2-specific regulation of macroautophagy. For the PN batch, ATP6V0A2 should be represented by lysosomal acidification/V-ATPase component terms, not by a generic macroautophagy regulation term. Supporting Evidence: PMID:22982048 both the autophagosomes and the lysosomal system are not mandatory
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	ACCEPT	Summary: Lysosomal membrane localization is supported by lysosomal membrane proteomics and is important for the PN lysosomal V-ATPase projection. Reason: ATP6V0A2 is part of the V-ATPase system, and lysosomal membrane proteomics detected vacuolar ATPase-associated polypeptides in purified lysosomal membranes. This supports retaining the lysosomal membrane annotation and adding lysosomal V0-domain specificity. Supporting Evidence: PMID:17897319 17 polypeptides comprising or associated with the vacuolar adenosine file:human/ATP6V0A2/ATP6V0A2-deep-research-manual.md Both projected terms are accepted conservatively in the review because they are supported by ATP6V0A2 V0-subunit identity, lysosomal membrane evidence, and the broader human V-ATPase endosome/lysosome acidification literature. file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-1222516	KEEP AS NON CORE	Summary: Phagocytic vesicle membrane localization is supported by Reactome V-ATPase phagosome acidification context but is a context-specific location rather than ATP6V0A2 core identity. Reason: The V-ATPase acidifies phagosomes, but ATP6V0A2-specific evidence is indirect through Reactome complex membership. Retain as a specialized acidic-vesicle context, not as a main gene function. Supporting Evidence: Reactome:R-HSA-1222516 movement of three protons into the phagosome
GO:0010008 endosome membrane	TAS Reactome:R-HSA-5252133	ACCEPT	Summary: Reactome places ATP6V0A2-containing V-ATPase context at endosome membranes during ATP6AP1/V-ATPase binding and acidification-related events. Reason: Endosome membrane localization is well supported by both primary literature and Reactome event context; ATP6V0A2 is targeted to early endosomes and participates in pH-dependent trafficking. Supporting Evidence: Reactome:R-HSA-5252133 Vacuolar-type H+-ATPases (V-ATPases) are proton pumps that acidify intracellular cargos PMID:16415858 The a2-isoform is targeted to early endosomes
GO:0010008 endosome membrane	TAS Reactome:R-HSA-74723	ACCEPT	Summary: Endosome membrane localization is supported by the Reactome endosome acidification event and direct early-endosome literature for the a2 isoform. Reason: The annotation matches ATP6V0A2 involvement in endosomal acidification and pH-dependent endocytic trafficking. Supporting Evidence: Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome. PMID:16415858 The a2-isoform is targeted to early endosomes PMID:16415858 Inhibition of endosomal acidification abrogates protein trafficking between
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917841	ACCEPT	Summary: Endosome membrane localization is supported by Reactome transferrin-receptor endosome acidification context and by direct literature on the a2 isoform in early endosomes. Reason: ATP6V0A2-containing V-ATPase participates in acidifying endosomal compartments, including transferrin-receptor recycling/endosome contexts in Reactome. Supporting Evidence: Reactome:R-HSA-917841 When pumping, ATP hydrolysis drives a 120 degree rotation of the rotor which leads to movement of three protons PMID:16415858 The a2-isoform is targeted to early endosomes
GO:0006955 immune response	TAS PMID:2247090 Cloning of a cDNA for a T cell produced molecule with a puta...	MARK AS OVER ANNOTATED	Summary: The old immune-response annotation is not a precise ATP6V0A2 functional annotation. The cited cloning paper reports a putative immune regulatory protein but does not establish the modern V-ATPase a2 mechanism as immune response. Reason: ATP6V0A2/V-ATPase activity can affect immune-cell and MHC degradation contexts indirectly, but GO:0006955 is too broad and weakly supported by PMID:2247090 for this gene. It should not be considered a core proteostasis annotation. Supporting Evidence: PMID:2247090 putative immune regulatory role file:human/ATP6V0A2/ATP6V0A2-uniprot.txt the in vivo relevance of this observation needs to be confirmed
GO:0007042 lysosomal lumen acidification	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	NEW	Summary: The PN projection proposes lysosomal lumen acidification as a more specific term than existing vacuolar acidification. This is accepted conservatively because ATP6V0A2 is a V0 V-ATPase subunit with lysosomal membrane evidence and broad human V-ATPase evidence for endosome/lysosome pH homeostasis. Reason: The PN source node is manually mapped to lysosomal lumen acidification and the gene is one of the V0 lysosomal V-ATPase pump components in the projection. Independent literature supports V-ATPase-dependent pH homeostasis of endosomes and lysosomes, and ATP6V0A2 has lysosomal membrane support. The annotation is added as a specific lysosomal acidification term, while broader autophagy/process claims are not promoted. Supporting Evidence: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv ATP6V0A2 Autophagy-Lysosome Pathway\|Lysosomal catabolism\|Regulation of lysosomal environment\|Lysosomal acidification\|V0 lysosomal v-ATPase proton pump component PMID:33065002 organellar V-ATPases are essential in establishing and maintaining the pH PMID:17897319 17 polypeptides comprising or associated with the vacuolar adenosine file:human/ATP6V0A2/ATP6V0A2-deep-research-manual.md Both projected terms are accepted conservatively in the review because they are supported by ATP6V0A2 V0-subunit identity, lysosomal membrane evidence, and the broader human V-ATPase endosome/lysosome acidification literature.
GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	NEW	Summary: The PN projection proposes the lysosomal V0-domain component term. This is accepted because ATP6V0A2 is a V0 a-subunit, GOA already supports V0-domain membership, and lysosomal membrane evidence supports the lysosomal-specific component term. Reason: The existing GOA captures the broader V0 domain but lacks the lysosomal V0-domain component term. PN mapping and gene-level evidence together support the lysosomal-specific child term without requiring any broader autophagy-process assertion. Supporting Evidence: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain file:human/ATP6V0A2/ATP6V0A2-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase PMID:17897319 17 polypeptides comprising or associated with the vacuolar adenosine

Core Functions

ATP6V0A2 is a V0-sector a-subunit of the V-ATPase and contributes to ATP-driven proton transmembrane transport that acidifies endosomal, lysosomal, and Golgi compartments. This organelle acidification is the core proteostasis-relevant function, supporting endocytic trafficking, lysosomal degradation, and Golgi pH-dependent glycosylation.

Directly Involved In:

proton transmembrane transport lysosomal lumen acidification Golgi lumen acidification

Cellular Locations:

endosome membrane lysosomal membrane Golgi membrane

Supporting Evidence:

file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
Subunit of the V0 complex of vacuolar(H+)-ATPase
PMID:16415858
The a2-isoform is targeted to early endosomes
PMID:33065002
V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
ATP6V0A2 Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

InterPro-derived V0-domain and proton-pump terms are mostly correct, but independent enables activity is over-stated for a single subunit.

GO_REF:0000033

Annotation inferences using phylogenetic trees

IBA supports conserved V-ATPase complex membership and contributes_to proton-pump activity.

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

UniProt subcellular-location mappings for endosome and plasma membrane are compatible with the reviewed literature.

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

HPA plasma-membrane localization is retained as non-core context.

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

Orthology-transferred acrosomal/perinuclear locations are retained as non-core context.

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

Automated V0-domain annotation is consistent with ATP6V0A2 subunit identity.

PMID:16415858

V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway.

ATP6V0A2/a2 is targeted to early endosomes, binds ARNO/PSCD2 in an acidification-dependent manner, and supports endocytic degradative trafficking.

PMID:17897319

Integral and associated lysosomal membrane proteins.

Lysosomal membrane proteomics detected vacuolar ATPase-associated polypeptides in purified lysosomal membranes.

PMID:2247090

Cloning of a cDNA for a T cell produced molecule with a putative immune regulatory role.

The old T-cell cDNA study supports only a broad putative immune-regulatory context and is not sufficient for a core immune-response function.

PMID:22982048

Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.

The lipofuscin study does not establish ATP6V0A2-specific regulation of macroautophagy.

PMID:28296633

The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels.

ATP6V0A2 appeared in a V-ATPase/HIF screen; V-ATPase disruption affected intracellular iron and PHD-dependent HIF regulation.

PMID:32001091

Structure and Roles of V-type ATPases.

V-ATPase review supports ATP-driven organelle acidification and differentially localized mammalian isoforms.

PMID:33065002

Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.

Human V-ATPase structures support the V1 ATP-hydrolysis and Vo proton-transfer architecture and endosome/lysosome pH homeostasis.

Reactome:R-HSA-1222516

Intraphagosomal pH is lowered to 5 by V-ATPase

Reactome supports phagosomal V-ATPase acidification context.

Reactome:R-HSA-5252133

ATP6AP1 binds V-ATPase

Reactome supports V-ATPase acidification of intracellular cargos and ATP6AP1/V-ATPase context.

Reactome:R-HSA-74723

Endosome acidification

Reactome supports endosome lumen acidification by proton pump activity.

Reactome:R-HSA-917841

Acidification of Tf:TfR1 containing endosome

Reactome supports transferrin-receptor endosome acidification by V-type proton pumping ATPase.

file:human/ATP6V0A2/ATP6V0A2-uniprot.txt

UniProtKB ATP6V0A2 record Q9Y487

Curates ATP6V0A2 as a V0 V-ATPase a-subunit involved in organelle acidification, endosomal pH sensing, Golgi pH/glycosylation, and iron/HIF effects.

file:human/ATP6V0A2/ATP6V0A2-deep-research-manual.md

Manual deep research fallback for ATP6V0A2

Falcon deep research timed out and the configured fallback failed with quota error; this manual file summarizes the local UniProt, publication, Reactome, and PN evidence used for review.

file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv

Proteostasis PN projected annotations for ATP6V0A2

Projects ATP6V0A2 to lysosomal lumen acidification and lysosomal proton-transporting V-type ATPase V0 domain, both requiring gene-level review.

file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Proteostasis PN mapping scrutiny report

Flags lysosomal acidification mapping as requiring manual gene-level review before changing gene reviews.

Suggested Experiments

Experiment: Use endogenous tagging or isoform-specific antibodies to quantify ATP6V0A2 localization across Golgi, early endosome, late endosome, lysosome, plasma membrane, phagosome, and sperm/acrosomal compartments in relevant human cell types.

Hypothesis: ATP6V0A2 has a compartment-biased distribution that explains which lysosomal, Golgi, endosomal, and plasma-membrane GO cellular-component annotations should be core versus context-specific.

Experiment: Measure organelle pH and lysosomal proteolysis after ATP6V0A2-specific knockout or rescue, separating lysosomal lumen acidification from broader vacuolar/endosomal acidification and from other a-subunit compensation.

Hypothesis: ATP6V0A2 makes a measurable gene-specific contribution to lysosomal lumen acidification beyond general V-ATPase family membership.

Experiment: Test whether ATP6V0A2 loss alters mTORC1 recruitment/signaling at lysosomes independently of bulk organelle acidification defects.

Hypothesis: The PN nutrient-sensing placement reflects a V0-sector scaffolding or signaling role that can be experimentally separated from proton transport.

Deep Research

Manual

(ATP6V0A2-deep-research-manual.md)

ATP6V0A2 manual deep research fallback Manual

ATP6V0A2 manual deep research fallback

Falcon deep research was attempted on 2026-06-03 with just deep-research-falcon human ATP6V0A2 --fallback perplexity-lite. Falcon timed out after 600 seconds, and the configured Perplexity fallback returned an insufficient-quota 401. This manual fallback summarizes the local evidence used for the review.

Core function

ATP6V0A2 encodes the a2 isoform of the V-type proton ATPase 116 kDa a-subunit. UniProt curates ATP6V0A2 as a "Subunit of the V0 complex of vacuolar(H+)-ATPase" and describes V-ATPase as the enzyme responsible for acidifying intracellular compartments [file:human/ATP6V0A2/ATP6V0A2-uniprot.txt].

Human V-ATPase structural and review literature supports the complex-level function. Wang et al. describe V-ATPases as ATP-driven proton pumps with a cytoplasmic V1 ATP-hydrolysis module and membrane Vo proton-transfer module, and state that organellar V-ATPases maintain pH homeostasis of endosomes and lysosomes PMID:33065002. Vasanthakumar and Rubinstein describe V-ATPases as the primary source of organellar acidification in eukaryotes PMID:32001091.

Endosomal acidification and trafficking

The strongest direct ATP6V0A2/a2 evidence is the early endosome paper by Hurtado-Lorenzo et al. They report that the a2 isoform is targeted to early endosomes, interacts with ARNO/PSCD2 in an intra-endosomal acidification-dependent manner, and that inhibiting endosomal acidification disrupts protein trafficking between early and late endosomal compartments PMID:16415858. This supports endosome membrane localization, V-ATPase-dependent proton transport/acidification, and mechanistic text about pH sensing. It does not make GO:0005515 protein binding an informative retained molecular-function annotation.

Lysosomal and Golgi context

Lysosomal membrane evidence comes from lysosomal membrane proteomics, which identified polypeptides comprising or associated with vacuolar ATPase in purified placental lysosomal membranes PMID:17897319. Together with ATP6V0A2 V0-subunit identity, this supports the PN-projected lysosomal V0-domain annotation.

Golgi context is supported by UniProt's statement that ATP6V0A2 may maintain Golgi functions such as glycosylation maturation by controlling Golgi pH, consistent with the glycosylation defects seen in ATP6V0A2 disease [file:human/ATP6V0A2/ATP6V0A2-uniprot.txt].

HIF and iron

Miles et al. identified ATP6V0A2 among V-ATPase subunits enriched in a HIF1A reporter screen. Their mechanism is not direct oxygen sensing; V-ATPase disruption leads to intracellular iron depletion, impaired PHD activity, and HIF activation PMID:28296633. This supports retaining intracellular iron ion homeostasis as a non-core downstream role and treating the broad "cellular response to increased oxygen levels" annotation as over-annotated.

PN projection assessment

The Proteostasis PN projection proposes two ATP6V0A2 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]. The PN mapping audit flags lysosomal acidification mappings for manual gene-level review before review changes [file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv].

Both projected terms are accepted conservatively in the review because they are supported by ATP6V0A2 V0-subunit identity, lysosomal membrane evidence, and the broader human V-ATPase endosome/lysosome acidification literature. Broader ALP/nutrient-sensing context was not converted into additional GO terms.

Conservative removals and non-core calls

GO:0005515 protein binding is removed because the ARNO interaction is better represented as mechanistic context for endosomal pH sensing and trafficking. Regulation of macroautophagy is marked over-annotated because the supporting lipofuscin paper does not establish ATP6V0A2-specific macroautophagy regulation PMID:22982048. Immune response is marked over-annotated because the old cDNA paper only supports a putative immune-regulatory context and does not establish ATP6V0A2's modern V-ATPase function as a direct immune-response role PMID:2247090.

📚 Additional Documentation

Notes

(ATP6V0A2-notes.md)

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.

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. 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, 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, but this does not support a modern core ATP6V0A2 immune-response annotation.

Pn Notes

(ATP6V0A2-pn-notes.md)

ATP6V0A2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9Y487
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1388)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V0A2/ATP6V0A2-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V0A2/ATP6V0A2-ai-review.html
Gene notes: present - genes/human/ATP6V0A2/ATP6V0A2-notes.md
GOA TSV: present - genes/human/ATP6V0A2/ATP6V0A2-goa.tsv
UniProt record: present - genes/human/ATP6V0A2/ATP6V0A2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V0A2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V0A2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/ATP6V0A2/ATP6V0A2-deep-research-manual.md

AIGR Review Snapshot

Description: ATP6V0A2 encodes the a2 isoform of the V-type proton ATPase 116 kDa a-subunit, an integral membrane component of the V0 proton-translocation sector of the V-ATPase. The protein helps assemble and position V-ATPase activity in acidic intracellular compartments, especially early endosomes and Golgi/endolysosomal membranes, where the complex acidifies organelle lumens to support membrane trafficking, protein degradation, lysosomal function, and Golgi-dependent glycosylation. ATP6V0A2 also participates in endosomal pH-sensing through an acidification-dependent interaction with ARNO/PSCD2, and disruption of V-ATPase function affects intracellular iron availability and HIF prolyl hydroxylation. Biallelic ATP6V0A2 variants cause autosomal recessive cutis laxa type 2A and wrinkly skin syndrome with glycosylation defects.
Existing/core annotation action counts: ACCEPT: 17; KEEP_AS_NON_CORE: 7; MARK_AS_OVER_ANNOTATED: 4; MODIFY: 1; NEW: 2; REMOVE: 1

PN Consistency Summary

Consistency: Consistent. Notes, review, PN row, and PN-node mapping all converge on the V0-sector lysosomal V-ATPase identity. The review adds exactly the three projected terms at their mapped levels and explicitly declines to promote the broader nutrient-sensing/autophagy context. No contradictions.
PN story / NEW pressure: The lysosomal-specific terms were genuinely absent from ATP6V0A2 GOA (which had only broader GO:0007035 vacuolar acidification and GO:0033179/GO:0000220 V0-domain). Review adds GO:0007042 lysosomal lumen acidification (NEW) and GO:0046610 lysosomal V0 domain (NEW). I verified both are real, non-obsolete GO terms via OLS. These are defensible ADDs (more specific children of existing annotations), supported by V0-subunit identity plus lysosomal-membrane proteomics (PMID:17897319). The PN nutrient-sensing/mTORC1 story correctly does NOT generate a NEW term — review leaves it as a suggested_question/experiment only.
Evidence alignment: Divergent by design. PN cites review-article titles (mTORC1, SEA/GATOR, V-ATPase structure, neurodegeneration); the review's load-bearing PMIDs are independent primary/structural sources (16415858 ARNO endosome, 33065002 human V-ATPase cryo-EM, 32001091, 17897319 lysosomal proteomics, 28296633 iron/HIF). Only the V-ATPase-structure theme overlaps conceptually.
Verdict: Consistent; both lysosomal NEW terms are verified real, defensible ADDs; PN nutrient-sensing context correctly not propagated. No edits required.

Full Consistency Review

UniProt: Q9Y487 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
PN placement: two ALP rows — ALP|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V0 lysosomal v-ATPase proton pump component and ALP|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component ; PN-node mapping: V0 subtype leaves mapped/ok_for_propagation → GO:0046610 (lysosomal V0 domain) and GO:0033179 (V0 domain); Lysosomal-acidification type mapped/ok_for_propagation → GO:0007042; mTORC1/nutrient-sensing ancestors no_mapping; Pre-initiation class context_only/too_broad (GO:0010506).
Consistency: Consistent. Notes, review, PN row, and PN-node mapping all converge on the V0-sector lysosomal V-ATPase identity. The review adds exactly the three projected terms at their mapped levels and explicitly declines to promote the broader nutrient-sensing/autophagy context. No contradictions.
PN story / NEW pressure: The lysosomal-specific terms were genuinely absent from ATP6V0A2 GOA (which had only broader GO:0007035 vacuolar acidification and GO:0033179/GO:0000220 V0-domain). Review adds GO:0007042 lysosomal lumen acidification (NEW) and GO:0046610 lysosomal V0 domain (NEW). I verified both are real, non-obsolete GO terms via OLS. These are defensible ADDs (more specific children of existing annotations), supported by V0-subunit identity plus lysosomal-membrane proteomics (PMID:17897319). The PN nutrient-sensing/mTORC1 story correctly does NOT generate a NEW term — review leaves it as a suggested_question/experiment only.
Mapping strategy: No change warranted. Subtype-level ok_for_propagation and the conservative no_mapping/context_only ancestors are right; broad mTORC1 container is correctly not propagated (matches TOMM20/HSPA8 "too broad" precedent).
Evidence alignment: Divergent by design. PN cites review-article titles (mTORC1, SEA/GATOR, V-ATPase structure, neurodegeneration); the review's load-bearing PMIDs are independent primary/structural sources (16415858 ARNO endosome, 33065002 human V-ATPase cryo-EM, 32001091, 17897319 lysosomal proteomics, 28296633 iron/HIF). Only the V-ATPase-structure theme overlaps conceptually.
Verdict: Consistent; both lysosomal NEW terms are verified real, defensible ADDs; PN nutrient-sensing context correctly not propagated. No edits required.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ATP6V0A2/ATP6V0A2-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V0 lysosomal v-ATPase proton pump component

UniProt: Q9Y487
In branches: ALP
Notes: Subunit of the V0 (lysosomal membrane bound) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V0 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain]
  rationale: This PN leaf is restricted to V0-sector lysosomal V-ATPase components. The GO lysosomal V0-domain component term is the direct target.
- [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
  status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
  rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Lysosomal catabolism | Regulation of lysosomal environment | Lysosomal acidification | V0 lysosomal v-ATPase proton pump component

UniProt: Q9Y487
In branches: ALP
Notes: Subunit of the V0 (lysosomal membrane bound) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0033179 proton-transporting V-type ATPase, V0 domain]
  rationale: This PN subtype denotes the V0-sector component of the lysosomal V-type ATPase. The GO V0-domain component term is the appropriate propagation target.
- [type] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0007042 lysosomal lumen acidification]
  rationale: This PN group directly names the lysosomal acidification mechanism. Propagation to the GO lysosomal lumen acidification term is an exact mechanistic match.
- [group] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Lysosomal catabolism
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad lysosomal-degradation container. The subtree includes carbohydrate, lipid, protein, nuclease, phosphatase, sulfatase, and environment-regulation roles, so mapping should occur at the enzyme or process subtype level.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V0 lysosomal v-ATPase proton pump component
GO:0007042 lysosomal lumen acidification | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
GO:0033179 proton-transporting V-type ATPase, V0 domain | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q9Y487
gene_symbol: ATP6V0A2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ATP6V0A2 encodes the a2 isoform of the V-type proton ATPase 116 kDa a-subunit, an integral membrane component of the V0 proton-translocation sector of the V-ATPase. The protein helps assemble and position V-ATPase activity in acidic intracellular compartments, especially early endosomes and Golgi/endolysosomal membranes, where the complex acidifies organelle lumens to support membrane trafficking, protein degradation, lysosomal function, and Golgi-dependent glycosylation. ATP6V0A2 also participates in endosomal pH-sensing through an acidification-dependent interaction with ARNO/PSCD2, and disruption of V-ATPase function affects intracellular iron availability and HIF prolyl hydroxylation. Biallelic ATP6V0A2 variants cause autosomal recessive cutis laxa type 2A and wrinkly skin syndrome with glycosylation defects.
existing_annotations:
- term:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: ATP6V0A2 encodes the a2 isoform of the V0 membrane sector of the V-ATPase. Complex membership is a core cellular-component annotation supported by UniProt curation and human V-ATPase structural literature.
    action: ACCEPT
    reason: The annotation correctly places ATP6V0A2 in the vacuolar proton-transporting V-type ATPase complex. The protein is a V0 a-subunit of a multisubunit proton pump, and the V0 sector is the membrane proton-translocation module of the complex.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase
    - reference_id: PMID:33065002
      supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: ATP6V0A2 contributes to the rotational V-ATPase proton-pumping activity as a V0 membrane-sector subunit, but does not independently hydrolyze ATP outside the assembled complex.
    action: ACCEPT
    reason: The contributes_to qualifier is appropriate for a subunit of the V-ATPase complex. The complex couples ATP hydrolysis in V1 to proton transfer through V0, and ATP6V0A2 is a V0 a-subunit.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase
    - reference_id: PMID:33065002
      supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Plasma-membrane localization is plausible for V-ATPase a-subunits in some cell contexts, but ATP6V0A2 is better established in endosomal, Golgi, and lysosomal/vesicular membranes.
    action: KEEP_AS_NON_CORE
    reason: UniProt includes cell-membrane localization and the GOA contains HPA plasma-membrane evidence, so the annotation is not rejected. It should not be treated as the main proteostasis-relevant location for ATP6V0A2, whose strongest mechanistic evidence is in intracellular acidic compartments.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Cell membrane; Multi-pass membrane protein.
    - reference_id: PMID:16415858
      supporting_text: The a2-isoform is targeted to early endosomes
- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Vacuolar acidification is a correct broad biological-process annotation for ATP6V0A2 as a V-ATPase V0 subunit involved in acidification of acidic intracellular compartments.
    action: ACCEPT
    reason: The term captures the core acidification role of the V-ATPase. For the PN batch, lysosomal lumen acidification is added separately as a more specific supported annotation, but the existing broad annotation remains biologically sound.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are the primary source of organellar acidification in all eukaryotes
    - reference_id: PMID:33065002
      supporting_text: organellar V-ATPases are essential in establishing and maintaining the pH
    additional_reference_ids:
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: ATPase binding is much less informative than the complex-membership and contributes_to V-ATPase activity annotations already present for ATP6V0A2.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATP6V0A2 functions as an integral V0-sector subunit. Treating ATPase binding as a gene-level molecular function risks reducing complex assembly/participation to a vague binding annotation; the more informative annotations are V-ATPase complex/V0-domain membership and contribution to proton-pumping ATPase activity.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase
    - reference_id: PMID:33065002
      supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
- term:
    id: GO:0000220
    label: vacuolar proton-transporting V-type ATPase, V0 domain
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: The vacuolar V-ATPase V0-domain annotation matches ATP6V0A2 family/domain evidence and its role as an integral membrane V0 a-subunit.
    action: ACCEPT
    reason: ATP6V0A2 is a member of the V-ATPase 116 kDa subunit family and is curated as a V0-complex subunit. The broader V0-domain annotation is correct; the PN-derived lysosomal V0-domain annotation is added separately where lysosomal localization is supported.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Belongs to the V-ATPase 116 kDa subunit family.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Plasma-membrane localization is supported by UniProt/HPA-derived evidence but is secondary to the intracellular organelle acidification role.
    action: KEEP_AS_NON_CORE
    reason: The location is plausible and appears in curated resources, but the literature most directly supporting ATP6V0A2 function emphasizes early endosomes, Golgi function, and endolysosomal acidification rather than a primary plasma-membrane role.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Cell membrane; Multi-pass membrane protein.
    - reference_id: PMID:16415858
      supporting_text: The a2-isoform is targeted to early endosomes
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ATP6V0A2 is well supported at the endosome membrane, especially early endosomes, where a2-containing V-ATPase contributes to pH sensing and endocytic trafficking.
    action: ACCEPT
    reason: The UniProt-derived IEA annotation is consistent with direct literature showing the a2 isoform is targeted to early endosomes and participates in intra-endosomal acidification-dependent ARNO recruitment and endocytic trafficking.
    supported_by:
    - reference_id: PMID:16415858
      supporting_text: The a2-isoform is targeted to early endosomes
    - reference_id: PMID:16415858
      supporting_text: interacts with ARNO in an intra-endosomal acidification-dependent manner
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Essential component of the endosomal pH-sensing machinery
- term:
    id: GO:0033179
    label: proton-transporting V-type ATPase, V0 domain
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: The V0-domain annotation is a core cellular-component annotation for ATP6V0A2.
    action: ACCEPT
    reason: ATP6V0A2 is the a2 isoform of the V-ATPase 116 kDa a-subunit and belongs to the V0 membrane proton-transfer sector. This term is already aligned with the PN V0 component projection, although PN also supports a lysosomal-specific child term.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase
    - reference_id: PMID:33065002
      supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: The V-ATPase rotational proton-pump activity is correct for the assembled ATP6V0A2-containing complex. ATP6V0A2 should be interpreted as contributing to this activity as a V0 subunit rather than acting as an independent ATPase.
    action: MODIFY
    reason: The term is biologically appropriate for ATP6V0A2-containing V-ATPase complexes, but the GOA qualifier should be changed from enables to contributes_to. The contributes_to IBA qualifier is the clearest representation of a single V0 subunit's contribution to the assembled proton pump.
    proposed_replacement_terms:
    - id: GO:0046961
      label: proton-transporting ATPase activity, rotational mechanism
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase
    - reference_id: PMID:33065002
      supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: ATP6V0A2 participates in proton transmembrane transport as part of the V-ATPase proton-translocation machinery.
    action: ACCEPT
    reason: The V0 sector transfers protons across organelle membranes as part of the V-ATPase. ATP6V0A2 is a V0 a-subunit in this machinery, so the process annotation is appropriate.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
    - reference_id: PMID:33065002
      supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16415858
  qualifier: enables
  review:
    summary: PMID:16415858 supports a specific ARNO interaction with the a2 isoform, but GO:0005515 protein binding is too generic to retain as useful functional annotation.
    action: REMOVE
    reason: The interaction evidence is real, but generic protein binding is uninformative and is explicitly discouraged in this review workflow. The functional meaning of the interaction is better captured in the review text as endosomal pH-sensing/trafficking, not as GO:0005515.
    supported_by:
    - reference_id: PMID:16415858
      supporting_text: interacts with ARNO in an intra-endosomal acidification-dependent manner
    - reference_id: PMID:16415858
      supporting_text: Inhibition of endosomal acidification abrogates protein trafficking between
- term:
    id: GO:0001669
    label: acrosomal vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Acrosomal-vesicle localization is plausible by orthology for V-ATPase a-subunits but is not part of the core ATP6V0A2 proteostasis role reviewed here.
    action: KEEP_AS_NON_CORE
    reason: The annotation comes from Ensembl orthology transfer rather than direct ATP6V0A2 literature in this review. It is retained as a possible specialized reproductive-cell location, but the main supported locations are endosome, Golgi, lysosomal, and other acidic-vesicle membranes.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: GO; GO:0001669; C:acrosomal vesicle; IEA:Ensembl.
- term:
    id: GO:0015078
    label: proton transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: contributes_to
  review:
    summary: ATP6V0A2 contributes to proton transmembrane transporter activity as a V0 membrane-sector component of the assembled V-ATPase.
    action: ACCEPT
    reason: The contributes_to qualifier is appropriate for ATP6V0A2 because proton translocation is performed by the assembled V-ATPase/V0 machinery rather than by the isolated subunit.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase
    - reference_id: PMID:33065002
      supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: The broader proton-transporting V-type ATPase complex annotation is correct for ATP6V0A2.
    action: ACCEPT
    reason: ATP6V0A2 is an integral V0-sector subunit of the V-ATPase. The annotation is less specific than the V0-domain annotations but remains valid complex membership.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase
    - reference_id: PMID:33065002
      supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Perinuclear-region localization is compatible with Golgi/endosomal distribution but is not the most informative cellular-component annotation for ATP6V0A2.
    action: KEEP_AS_NON_CORE
    reason: The annotation is retained as a broad localization transferred by Ensembl, but more precise experimentally supported locations include endosome membrane, Golgi membrane, and lysosomal membrane.
    supported_by:
    - reference_id: PMID:16415858
      supporting_text: The a2-isoform is targeted to early endosomes
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: May play a role in maintaining the Golgi functions
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA reports ATP6V0A2 at the plasma membrane, but this is a secondary location relative to intracellular acidic compartments.
    action: KEEP_AS_NON_CORE
    reason: The IDA evidence supports retaining the localization, but the core functional literature for ATP6V0A2 centers on endosomal/Golgi/lysosomal acidification and V-ATPase complex function.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: GO; GO:0005886; C:plasma membrane; IDA:HPA.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: Golgi membrane localization is consistent with ATP6V0A2 disease biology and Golgi acidification/glycosylation functions.
    action: ACCEPT
    reason: ATP6V0A2 is implicated in maintaining Golgi pH-dependent functions, including glycosylation maturation. ComplexPortal and review evidence support Golgi-membrane assignment for the ATP6V0A2-containing V-ATPase variant.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: May play a role in maintaining the Golgi functions, such as glycosylation maturation, by controlling the Golgi pH
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are the primary source of organellar acidification in all eukaryotes
- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: part_of
  review:
    summary: Human V-ATPase structural literature supports ATP6V0A2 as part of a proton-transporting V-type ATPase complex.
    action: ACCEPT
    reason: The annotation captures the assembled complex in which ATP6V0A2 acts. Human V-ATPase structures define a V1 ATP-hydrolysis complex and a Vo proton-transfer complex.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase
- term:
    id: GO:0061795
    label: Golgi lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Golgi lumen acidification is a supported ATP6V0A2-associated process and explains the glycosylation defects seen when ATP6V0A2 is disrupted.
    action: ACCEPT
    reason: UniProt and review evidence support ATP6V0A2 involvement in Golgi pH control and glycosylation maturation. This is a meaningful organelle-specific acidification annotation, not merely a broad proteostasis projection.
    supported_by:
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: May play a role in maintaining the Golgi functions, such as glycosylation maturation, by controlling the Golgi pH
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are the primary source of organellar acidification in all eukaryotes
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: Proton transmembrane transport is the fundamental transport process mediated by the assembled V-ATPase containing ATP6V0A2.
    action: ACCEPT
    reason: The human V-ATPase is an ATP-driven proton pump with a Vo membrane complex for proton transfer, and ATP6V0A2 is one of the Vo a-subunits.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
- term:
    id: GO:0006879
    label: intracellular iron ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:28296633
  qualifier: involved_in
  review:
    summary: ATP6V0A2 disruption was identified in a V-ATPase/HIF screen, and the study supports a non-core role for V-ATPase function in intracellular iron availability and HIF prolyl hydroxylation.
    action: KEEP_AS_NON_CORE
    reason: The evidence is direct enough to retain the annotation, but intracellular iron homeostasis is downstream of the core V-ATPase acidification role rather than the primary evolved function of ATP6V0A2.
    supported_by:
    - reference_id: PMID:28296633
      supporting_text: ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1
    - reference_id: PMID:28296633
      supporting_text: disrupting the V-ATPase results in intracellular iron depletion
- term:
    id: GO:0036295
    label: cellular response to increased oxygen levels
  evidence_type: IMP
  original_reference_id: PMID:28296633
  qualifier: involved_in
  review:
    summary: The PMID:28296633 evidence supports V-ATPase effects on HIF stability under aerobic conditions through iron/PHD activity, but the GO term frames this too broadly as a response to increased oxygen levels.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATP6V0A2 depletion affects HIF1A regulation indirectly through V-ATPase-dependent iron homeostasis. The paper explicitly argues against a lysosomal-degradation mechanism and focuses on PHD activity; the broad oxygen-response term should not be treated as a core ATP6V0A2 function.
    supported_by:
    - reference_id: PMID:28296633
      supporting_text: ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1
    - reference_id: PMID:28296633
      supporting_text: disrupting the V-ATPase results in intracellular iron depletion
    - reference_id: PMID:28296633
      supporting_text: Rather than preventing the lysosomal degradation of HIF1α, the V-ATPase inhibition stabilised HIF1α by decreasing PHD enzymatic activity.
- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: NAS
  original_reference_id: PMID:22982048
  qualifier: involved_in
  review:
    summary: The macroautophagy annotation is too broad for ATP6V0A2. V-ATPase acidification supports lysosomal degradation/autophagic flux, but PMID:22982048 does not establish ATP6V0A2 as a specific regulator of macroautophagy.
    action: MARK_AS_OVER_ANNOTATED
    reason: The supporting paper discusses lipofuscin, autophagy, and lysosomal activity rather than ATP6V0A2-specific regulation of macroautophagy. For the PN batch, ATP6V0A2 should be represented by lysosomal acidification/V-ATPase component terms, not by a generic macroautophagy regulation term.
    supported_by:
    - reference_id: PMID:22982048
      supporting_text: both the autophagosomes and the lysosomal system are not mandatory
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: HDA
  original_reference_id: PMID:17897319
  qualifier: located_in
  review:
    summary: Lysosomal membrane localization is supported by lysosomal membrane proteomics and is important for the PN lysosomal V-ATPase projection.
    action: ACCEPT
    reason: ATP6V0A2 is part of the V-ATPase system, and lysosomal membrane proteomics detected vacuolar ATPase-associated polypeptides in purified lysosomal membranes. This supports retaining the lysosomal membrane annotation and adding lysosomal V0-domain specificity.
    supported_by:
    - reference_id: PMID:17897319
      supporting_text: 17 polypeptides comprising or associated with the vacuolar adenosine
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-deep-research-manual.md
      supporting_text: Both projected terms are accepted conservatively in the review because they are supported by ATP6V0A2 V0-subunit identity, lysosomal membrane evidence, and the broader human V-ATPase endosome/lysosome acidification literature.
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase
- term:
    id: GO:0030670
    label: phagocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1222516
  qualifier: located_in
  review:
    summary: Phagocytic vesicle membrane localization is supported by Reactome V-ATPase phagosome acidification context but is a context-specific location rather than ATP6V0A2 core identity.
    action: KEEP_AS_NON_CORE
    reason: The V-ATPase acidifies phagosomes, but ATP6V0A2-specific evidence is indirect through Reactome complex membership. Retain as a specialized acidic-vesicle context, not as a main gene function.
    supported_by:
    - reference_id: Reactome:R-HSA-1222516
      supporting_text: movement of three protons into the phagosome
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252133
  qualifier: located_in
  review:
    summary: Reactome places ATP6V0A2-containing V-ATPase context at endosome membranes during ATP6AP1/V-ATPase binding and acidification-related events.
    action: ACCEPT
    reason: Endosome membrane localization is well supported by both primary literature and Reactome event context; ATP6V0A2 is targeted to early endosomes and participates in pH-dependent trafficking.
    supported_by:
    - reference_id: Reactome:R-HSA-5252133
      supporting_text: Vacuolar-type H+-ATPases (V-ATPases) are proton pumps that acidify intracellular cargos
    - reference_id: PMID:16415858
      supporting_text: The a2-isoform is targeted to early endosomes
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74723
  qualifier: located_in
  review:
    summary: Endosome membrane localization is supported by the Reactome endosome acidification event and direct early-endosome literature for the a2 isoform.
    action: ACCEPT
    reason: The annotation matches ATP6V0A2 involvement in endosomal acidification and pH-dependent endocytic trafficking.
    supported_by:
    - reference_id: Reactome:R-HSA-74723
      supporting_text: The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome.
    - reference_id: PMID:16415858
      supporting_text: The a2-isoform is targeted to early endosomes
    - reference_id: PMID:16415858
      supporting_text: Inhibition of endosomal acidification abrogates protein trafficking between
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917841
  qualifier: located_in
  review:
    summary: Endosome membrane localization is supported by Reactome transferrin-receptor endosome acidification context and by direct literature on the a2 isoform in early endosomes.
    action: ACCEPT
    reason: ATP6V0A2-containing V-ATPase participates in acidifying endosomal compartments, including transferrin-receptor recycling/endosome contexts in Reactome.
    supported_by:
    - reference_id: Reactome:R-HSA-917841
      supporting_text: When pumping, ATP hydrolysis drives a 120 degree rotation of the rotor which leads to movement of three protons
    - reference_id: PMID:16415858
      supporting_text: The a2-isoform is targeted to early endosomes
- term:
    id: GO:0006955
    label: immune response
  evidence_type: TAS
  original_reference_id: PMID:2247090
  qualifier: involved_in
  review:
    summary: The old immune-response annotation is not a precise ATP6V0A2 functional annotation. The cited cloning paper reports a putative immune regulatory protein but does not establish the modern V-ATPase a2 mechanism as immune response.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATP6V0A2/V-ATPase activity can affect immune-cell and MHC degradation contexts indirectly, but GO:0006955 is too broad and weakly supported by PMID:2247090 for this gene. It should not be considered a core proteostasis annotation.
    supported_by:
    - reference_id: PMID:2247090
      supporting_text: putative immune regulatory role
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: the in vivo relevance of this observation needs to be confirmed
- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: The PN projection proposes lysosomal lumen acidification as a more specific term than existing vacuolar acidification. This is accepted conservatively because ATP6V0A2 is a V0 V-ATPase subunit with lysosomal membrane evidence and broad human V-ATPase evidence for endosome/lysosome pH homeostasis.
    action: NEW
    reason: The PN source node is manually mapped to lysosomal lumen acidification and the gene is one of the V0 lysosomal V-ATPase pump components in the projection. Independent literature supports V-ATPase-dependent pH homeostasis of endosomes and lysosomes, and ATP6V0A2 has lysosomal membrane support. The annotation is added as a specific lysosomal acidification term, while broader autophagy/process claims are not promoted.
    additional_reference_ids:
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
    - PMID:17897319
    - PMID:32001091
    supported_by:
    - reference_id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
      supporting_text: "ATP6V0A2\t\tAutophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component"
    - reference_id: PMID:33065002
      supporting_text: organellar V-ATPases are essential in establishing and maintaining the pH
    - reference_id: PMID:17897319
      supporting_text: 17 polypeptides comprising or associated with the vacuolar adenosine
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-deep-research-manual.md
      supporting_text: Both projected terms are accepted conservatively in the review because they are supported by ATP6V0A2 V0-subunit identity, lysosomal membrane evidence, and the broader human V-ATPase endosome/lysosome acidification literature.
- term:
    id: GO:0046610
    label: lysosomal proton-transporting V-type ATPase, V0 domain
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: part_of
  review:
    summary: The PN projection proposes the lysosomal V0-domain component term. This is accepted because ATP6V0A2 is a V0 a-subunit, GOA already supports V0-domain membership, and lysosomal membrane evidence supports the lysosomal-specific component term.
    action: NEW
    reason: The existing GOA captures the broader V0 domain but lacks the lysosomal V0-domain component term. PN mapping and gene-level evidence together support the lysosomal-specific child term without requiring any broader autophagy-process assertion.
    additional_reference_ids:
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
    - PMID:17897319
    - file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
    supported_by:
    - reference_id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
      supporting_text: "GO:0046610\tlysosomal proton-transporting V-type ATPase, V0 domain"
    - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
      supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase
    - reference_id: PMID:17897319
      supporting_text: 17 polypeptides comprising or associated with the vacuolar adenosine
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings:
  - statement: InterPro-derived V0-domain and proton-pump terms are mostly correct, but independent enables activity is over-stated for a single subunit.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: IBA supports conserved V-ATPase complex membership and contributes_to proton-pump activity.
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings:
  - statement: UniProt subcellular-location mappings for endosome and plasma membrane are compatible with the reviewed literature.
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings:
  - statement: HPA plasma-membrane localization is retained as non-core context.
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings:
  - statement: Orthology-transferred acrosomal/perinuclear locations are retained as non-core context.
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings:
  - statement: Automated V0-domain annotation is consistent with ATP6V0A2 subunit identity.
- id: PMID:16415858
  title: V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway.
  findings:
  - statement: ATP6V0A2/a2 is targeted to early endosomes, binds ARNO/PSCD2 in an acidification-dependent manner, and supports endocytic degradative trafficking.
- id: PMID:17897319
  title: Integral and associated lysosomal membrane proteins.
  findings:
  - statement: Lysosomal membrane proteomics detected vacuolar ATPase-associated polypeptides in purified lysosomal membranes.
- id: PMID:2247090
  title: Cloning of a cDNA for a T cell produced molecule with a putative immune regulatory role.
  findings:
  - statement: The old T-cell cDNA study supports only a broad putative immune-regulatory context and is not sufficient for a core immune-response function.
- id: PMID:22982048
  title: Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.
  findings:
  - statement: The lipofuscin study does not establish ATP6V0A2-specific regulation of macroautophagy.
- id: PMID:28296633
  title: The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels.
  findings:
  - statement: ATP6V0A2 appeared in a V-ATPase/HIF screen; V-ATPase disruption affected intracellular iron and PHD-dependent HIF regulation.
- id: PMID:32001091
  title: Structure and Roles of V-type ATPases.
  findings:
  - statement: V-ATPase review supports ATP-driven organelle acidification and differentially localized mammalian isoforms.
- id: PMID:33065002
  title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.
  findings:
  - statement: Human V-ATPase structures support the V1 ATP-hydrolysis and Vo proton-transfer architecture and endosome/lysosome pH homeostasis.
- id: Reactome:R-HSA-1222516
  title: Intraphagosomal pH is lowered to 5 by V-ATPase
  findings:
  - statement: Reactome supports phagosomal V-ATPase acidification context.
- id: Reactome:R-HSA-5252133
  title: ATP6AP1 binds V-ATPase
  findings:
  - statement: Reactome supports V-ATPase acidification of intracellular cargos and ATP6AP1/V-ATPase context.
- id: Reactome:R-HSA-74723
  title: Endosome acidification
  findings:
  - statement: Reactome supports endosome lumen acidification by proton pump activity.
- id: Reactome:R-HSA-917841
  title: Acidification of Tf:TfR1 containing endosome
  findings:
  - statement: Reactome supports transferrin-receptor endosome acidification by V-type proton pumping ATPase.
- id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
  title: UniProtKB ATP6V0A2 record Q9Y487
  findings:
  - statement: Curates ATP6V0A2 as a V0 V-ATPase a-subunit involved in organelle acidification, endosomal pH sensing, Golgi pH/glycosylation, and iron/HIF effects.
- id: file:human/ATP6V0A2/ATP6V0A2-deep-research-manual.md
  title: Manual deep research fallback for ATP6V0A2
  findings:
  - statement: Falcon deep research timed out and the configured fallback failed with quota error; this manual file summarizes the local UniProt, publication, Reactome, and PN evidence used for review.
- id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
  title: Proteostasis PN projected annotations for ATP6V0A2
  findings:
  - statement: Projects ATP6V0A2 to lysosomal lumen acidification and lysosomal proton-transporting V-type ATPase V0 domain, both requiring gene-level review.
- id: file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv
  title: Proteostasis PN mapping scrutiny report
  findings:
  - statement: Flags lysosomal acidification mapping as requiring manual gene-level review before changing gene reviews.
core_functions:
- description: ATP6V0A2 is a V0-sector a-subunit of the V-ATPase and contributes to ATP-driven proton transmembrane transport that acidifies endosomal, lysosomal, and Golgi compartments. This organelle acidification is the core proteostasis-relevant function, supporting endocytic trafficking, lysosomal degradation, and Golgi pH-dependent glycosylation.
  contributes_to_molecular_function:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  directly_involved_in:
  - id: GO:1902600
    label: proton transmembrane transport
  - id: GO:0007042
    label: lysosomal lumen acidification
  - id: GO:0061795
    label: Golgi lumen acidification
  locations:
  - id: GO:0010008
    label: endosome membrane
  - id: GO:0005765
    label: lysosomal membrane
  - id: GO:0000139
    label: Golgi membrane
  supported_by:
  - reference_id: file:human/ATP6V0A2/ATP6V0A2-uniprot.txt
    supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase
  - reference_id: PMID:16415858
    supporting_text: The a2-isoform is targeted to early endosomes
  - reference_id: PMID:33065002
    supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
  - reference_id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
    supporting_text: "ATP6V0A2\t\tAutophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component"
proposed_new_terms: []
suggested_questions:
- question: For ATP6V0A2-containing V-ATPase complexes, which cell types and organelles carry the a2 isoform versus other a-subunit isoforms, and should any GO annotations be isoform- or tissue-context restricted?
- question: Does ATP6V0A2 have a direct lysosomal mTORC1 nutrient-sensing role distinct from its general V0-sector contribution to V-ATPase acidification?
- question: Can the ATP6V0A2-ARNO/PSCD2 interaction be represented with a more informative GO molecular-function term than generic protein binding, or should it remain as mechanistic annotation text only?
suggested_experiments:
- description: Use endogenous tagging or isoform-specific antibodies to quantify ATP6V0A2 localization across Golgi, early endosome, late endosome, lysosome, plasma membrane, phagosome, and sperm/acrosomal compartments in relevant human cell types.
  hypothesis: ATP6V0A2 has a compartment-biased distribution that explains which lysosomal, Golgi, endosomal, and plasma-membrane GO cellular-component annotations should be core versus context-specific.
- description: Measure organelle pH and lysosomal proteolysis after ATP6V0A2-specific knockout or rescue, separating lysosomal lumen acidification from broader vacuolar/endosomal acidification and from other a-subunit compensation.
  hypothesis: ATP6V0A2 makes a measurable gene-specific contribution to lysosomal lumen acidification beyond general V-ATPase family membership.
- description: Test whether ATP6V0A2 loss alters mTORC1 recruitment/signaling at lysosomes independently of bulk organelle acidification defects.
  hypothesis: The PN nutrient-sensing placement reflects a V0-sector scaffolding or signaling role that can be experimentally separated from proton transport.

ATP6V0A2

Gene Description