ATP6AP1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0033176 proton-transporting V-type ATPase complex	IBA GO_REF:0000033	ACCEPT	Summary: Accept V-type ATPase complex membership. ATP6AP1/Ac45 is an accessory V0-associated subunit and structural hub of the mature human V-ATPase. Reason: IBA propagation is consistent with direct structural and disease-complementation evidence showing ATP6AP1 as a V0-associated accessory subunit required for V-ATPase assembly and function. The PAINT ancestral node and alignment were not replayed; support for the inherited complex role here comes from independent human structural evidence, not a claim of revalidated node placement. Supporting Evidence: PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring. PMID:27231034 Processed wild-type Ac45, but not its disease mutants, restored V-ATPase-dependent growth in Voa1 mutant yeast.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Accept ER membrane localization. Human hepatocyte immunostaining places Ac45 mainly in the ER and ERGIC. Reason: This UniProt-location-derived annotation is supported by direct immunostaining in human hepatocytes and by the Voa1 assembly-factor model in the ER. Supporting Evidence: PMID:27231034 The subcellular localization of Ac45 in hepatocytes was studied by immunostaining of IHH cells. Ac45 was found to be mainly localized to the ER, and ER-to-Golgi Intermediate Compartment (ERGIC), but not to the trans-Golgi network (TGN) or components of the endosomal system
GO:0012505 endomembrane system	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Broad endomembrane-system localization is true but non-specific for a single-pass accessory subunit acting in ER/ERGIC and endolysosomal V-ATPase compartments. Reason: ATP6AP1 is an endomembrane protein, but more informative reviewed locations include ER membrane, ERGIC membrane, endosome membrane, lysosomal membrane, and V-ATPase complex membership. Supporting Evidence: PMID:27231034 The subcellular localization of Ac45 in hepatocytes was studied by immunostaining of IHH cells. Ac45 was found to be mainly localized to the ER, and ER-to-Golgi Intermediate Compartment (ERGIC), but not to the trans-Golgi network (TGN) or components of the endosomal system PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:0030659 cytoplasmic vesicle membrane	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Cytoplasmic vesicle membrane localization is plausible for ATP6AP1-containing V-ATPase in secretory/endocytic vesicles, but is broader and less central than ER/ERGIC and endolysosomal locations. Reason: Ac45 guides V-ATPase into specialized subcellular compartments including regulated secretory vesicles; however this ARBA term is a non-core location compared with the better-supported ER/ERGIC and lysosomal/endosomal membrane terms. Supporting Evidence: PMID:27231034 This accessory subunit of the proton pump guides the V-ATPase into specialized subcellular compartments such as neuroendocrine regulated secretory vesicles1415 or the ruffled border of the osteoclast101617 thereby regulating its activity.
GO:0030665 clathrin-coated vesicle membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Clathrin-coated vesicle membrane localization is retained as a non-core location inferred from UniProt subcellular mapping and vesicle-trafficking context. Reason: The literature supports Ac45/V-ATPase roles in membrane trafficking and specialized vesicle targeting, but the evidence is not central enough to treat this particular vesicle class as a core ATP6AP1 location. The cached UniProt record explicitly uses ortholog-based evidence for specialized vesicle localization; brain expression alone is not localization proof, and this assessment does not claim a human synaptic-vesicle experiment. Supporting Evidence: PMID:27231034 This accessory subunit of the proton pump guides the V-ATPase into specialized subcellular compartments such as neuroendocrine regulated secretory vesicles1415 or the ruffled border of the osteoclast101617 thereby regulating its activity.
GO:0030672 synaptic vesicle membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Synaptic vesicle membrane localization is plausible by similarity and neuroendocrine vesicle biology, but should be non-core for the human gene review. Reason: ATP6AP1 is highly expressed in brain and Ac45 has neuroendocrine regulated secretory-vesicle biology, but the human review should emphasize the shared V-ATPase accessory/assembly role rather than tissue-specific synaptic-vesicle placement. The cached UniProt record explicitly uses ortholog-based evidence for specialized vesicle localization; brain expression alone is not localization proof, and this assessment does not claim a human synaptic-vesicle experiment. Supporting Evidence: PMID:27231034 This accessory subunit of the proton pump guides the V-ATPase into specialized subcellular compartments such as neuroendocrine regulated secretory vesicles1415 or the ruffled border of the osteoclast101617 thereby regulating its activity.
GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane	IEA GO_REF:0000044	ACCEPT	Summary: Accept ERGIC membrane localization. Human hepatocyte immunostaining directly localized Ac45 to ER and ERGIC. Reason: This is a directly supported early-secretory-pathway location and fits the V0 assembly-factor role of ATP6AP1/Ac45. Supporting Evidence: PMID:27231034 The subcellular localization of Ac45 in hepatocytes was studied by immunostaining of IHH cells. Ac45 was found to be mainly localized to the ER, and ER-to-Golgi Intermediate Compartment (ERGIC), but not to the trans-Golgi network (TGN) or components of the endosomal system
GO:0098588 bounding membrane of organelle	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: The broad membrane localization is correct and retained as non-core. Reason: The human protein has a membrane-spanning region and is structurally incorporated into the membrane V0 sector. More specific locations are more informative for synthesis, but breadth alone does not make this membrane assertion biologically over-annotated. Retain the original evidence and qualifier. Supporting Evidence: PMID:27231034 The subcellular localization of Ac45 in hepatocytes was studied by immunostaining of IHH cells. Ac45 was found to be mainly localized to the ER, and ER-to-Golgi Intermediate Compartment (ERGIC), but not to the trans-Golgi network (TGN) or components of the endosomal system PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:0005515 protein binding	IPI PMID:32353859 A SARS-CoV-2 protein interaction map reveals targets for dru...	UNDECIDED	Summary: The source-specific ATP6AP1 interaction remains unverified. Reason: The complete cached abstract for PMID:32353859 establishes the study context, but the exact ATP6AP1 partner, construct and pair-specific assay entry have not been inspected. Retain the experimental source assertion without treating the generic term or screen scale as evidence that the interaction is incorrect. Independently verified interactions from other papers do not verify this source-specific record.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	UNDECIDED	Summary: The source-specific ATP6AP1 interaction remains unverified. Reason: The complete cached abstract for PMID:32814053 establishes the study context, but the exact ATP6AP1 partner, construct and pair-specific assay entry have not been inspected. Retain the experimental source assertion without treating the generic term or screen scale as evidence that the interaction is incorrect. Independently verified interactions from other papers do not verify this source-specific record.
GO:0005515 protein binding	IPI PMID:33060197 Comparative host-coronavirus protein interaction networks re...	UNDECIDED	Summary: The source-specific ATP6AP1 interaction remains unverified. Reason: The complete cached abstract for PMID:33060197 establishes the study context, but the exact ATP6AP1 partner, construct and pair-specific assay entry have not been inspected. Retain the experimental source assertion without treating the generic term or screen scale as evidence that the interaction is incorrect. Independently verified interactions from other papers do not verify this source-specific record.
GO:0005515 protein binding	IPI PMID:33845483 Multilevel proteomics reveals host perturbations by SARS-CoV...	UNDECIDED	Summary: The source-specific ATP6AP1 interaction remains unverified. Reason: The complete cached abstract for PMID:33845483 establishes the study context, but the exact ATP6AP1 partner, construct and pair-specific assay entry have not been inspected. Retain the experimental source assertion without treating the generic term or screen scale as evidence that the interaction is incorrect. Independently verified interactions from other papers do not verify this source-specific record.
GO:0005515 protein binding	IPI PMID:34232536 Interactomes of SARS-CoV-2 and human coronaviruses reveal ho...	UNDECIDED	Summary: The source-specific ATP6AP1 interaction remains unverified. Reason: The complete cached abstract for PMID:34232536 establishes the study context, but the exact ATP6AP1 partner, construct and pair-specific assay entry have not been inspected. Retain the experimental source assertion without treating the generic term or screen scale as evidence that the interaction is incorrect. Independently verified interactions from other papers do not verify this source-specific record.
GO:0005515 protein binding	IPI PMID:34997207 SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent...	KEEP AS NON CORE	Summary: A verified viral NSP6–ATP6AP1 association is retained as non-core interaction context. Reason: PMID:34997207 Results and Fig. 5F describe reciprocal co-immunoprecipitation of His-tagged NSP6 and endogenous ATP6AP1 in four human lung epithelial cell lines. This verifies the association in those transfected-cell conditions, without establishing purified binary binding or making viral interaction a core ATP6AP1 molecular function. Supporting Evidence: PMID:34997207 Here, we validated NSP6-ATP6AP1 interaction by reciprocal co-immunoprecipitation in four human lung epithelial cell lines.
GO:0010008 endosome membrane	IEA GO_REF:0000107	ACCEPT	Summary: Accept endosome membrane activity context for ATP6AP1-containing V-ATPase. Reason: Endosomal V-ATPase activity acidifies endosomal lumen and supports membrane trafficking; ATP6AP1 is a V0 accessory subunit of the same complex. 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:33065002 Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation
GO:0031267 small GTPase binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Retain orthology-supported small GTPase binding in a specialized trafficking context. Reason: The actual GOA donor is mouse Ac45 UniProtKB:Q9R1Q9 (the IEA also names ENSMUSP00000019231). PMID:22467241 uses mouse Ac45 NM_018794 and primary mouse bone-marrow osteoclasts; Fig. 6 reports Ac45/Rab7 colocalization and co-IP with wild-type and Q67L Rab7, with Rac1 as a negative comparison. These assays support association, not a purified binary-binding mechanism. This supports the existing human orthology transfer without relabeling it human IDA. The negative Rag-subunit assay in PMID:22053050 does not refute Rab7 binding. Supporting Evidence: PMID:22467241 We found that Ac45 colocalized with Rab7 in resorbing osteoclasts cultured on bone slices (Fig. 6A).
GO:0036035 osteoclast development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Keep osteoclast development as a non-core, orthology-derived tissue context. Reason: PMID:22467241 experimentally links mouse Ac45 depletion to impaired osteoclast differentiation, lysosomal delivery to the ruffled border and cathepsin-K exocytosis. Retain the existing orthology-supported process as specialized, non-core biology; do not describe the mouse perturbation as a human direct assay or treat absence of a prominent human bone phenotype as contrary evidence. Supporting Evidence: PMID:27231034 This accessory subunit of the proton pump guides the V-ATPase into specialized subcellular compartments such as neuroendocrine regulated secretory vesicles1415 or the ruffled border of the osteoclast101617 thereby regulating its activity.
GO:0046611 lysosomal proton-transporting V-type ATPase complex	IEA GO_REF:0000107	ACCEPT	Summary: Accept lysosomal V-type ATPase complex membership. Reason: The biologically relevant function of ATP6AP1 is as an accessory/regulatory subunit of the endolysosomal V-ATPase; structural data define ATP6AP1 as a Vo assembly hub. Supporting Evidence: PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring. Reactome:R-HSA-5252133 V-type proton ATPase subunit S1 (ATP6AP1) is thought to function as an accessory subunit of the V0 subcomplex of V-ATPase, facilitating acidification
GO:0097401 synaptic vesicle lumen acidification	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Keep synaptic vesicle lumen acidification as a non-core, tissue-specific V-ATPase context. Reason: ATP6AP1/Ac45 guides V-ATPase into neuroendocrine regulated secretory vesicles and is highly expressed in brain, but the core conserved role is V-ATPase accessory/assembly and endolysosomal acidification. The cached UniProt record explicitly uses ortholog-based evidence for specialized vesicle localization; brain expression alone is not localization proof, and this assessment does not claim a human synaptic-vesicle experiment. Supporting Evidence: PMID:27231034 This accessory subunit of the proton pump guides the V-ATPase into specialized subcellular compartments such as neuroendocrine regulated secretory vesicles1415 or the ruffled border of the osteoclast101617 thereby regulating its activity.
GO:0099638 endosome to plasma membrane protein transport	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Keep endosome-to-plasma-membrane protein transport as a non-core trafficking consequence of ATP6AP1/V-ATPase function. Reason: PMID:22467241 experimentally links mouse Ac45 depletion to impaired osteoclast differentiation, lysosomal delivery to the ruffled border and cathepsin-K exocytosis. Retain the existing orthology-supported process as specialized, non-core biology; do not describe the mouse perturbation as a human direct assay or treat absence of a prominent human bone phenotype as contrary evidence. Supporting Evidence: PMID:27231034 This accessory subunit of the proton pump guides the V-ATPase into specialized subcellular compartments such as neuroendocrine regulated secretory vesicles1415 or the ruffled border of the osteoclast101617 thereby regulating its activity. PMID:33065002 Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation
GO:0140677 molecular function activator activity	IEA GO_REF:0000107	UNDECIDED	Summary: The mechanism underlying the transferred molecular-function activator assertion remains unresolved. Reason: The original assertion is GO:0140677 molecular function activator activity, not the narrower ATPase activator term. Its IEA source transfers from mouse Ac45 Q9R1Q9/ENSMUSP00000019231. The inspected human structural incorporation, processed human Ac45 complementation in yeast and mouse pump-trafficking/acidification data establish a functional pump-associated role but do not independently resolve the donor-specific binding-dependent activation mechanism. Preserve the original assertion without replacing it by independently enabled GO:0060590 or treating uncertainty as evidence of absence. The proposed pump-contribution core is a separate, qualified synthesis.
GO:1904263 positive regulation of TORC1 signaling	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Retain the curated V-ATPase-associated nutrient-signaling role as non-core. Reason: The V-ATPase is required for amino-acid signaling to mTORC1 and acts between lysosomal amino acids and Rag GTPase nucleotide loading. ATP6AP1 is a V-ATPase accessory subunit, so the process annotation is appropriate. This complex-associated nutrient-signaling role is retained as secondary to the synthesized ATP6AP1 assembly/acidification core. Its classification does not assert that the curated signaling evidence is false or that isolated ATP6AP1 has a demonstrated exchange-factor activity. Supporting Evidence: PMID:22053050 The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and the nucleotide loading of the Rag GTPases. PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:0005765 lysosomal membrane	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	ACCEPT	Summary: Accept lysosomal membrane as an activity location of ATP6AP1-containing V-ATPase. Reason: The mTORC1 amino-acid sensing machinery is lysosome-centered and requires V-ATPase. ATP6AP1 is a V-ATPase accessory subunit; lysosomal membrane is an appropriate activity context. The location also directly matches the independently supported proton-pump core; retaining it as ACCEPT does not make every signaling role described in this source a core function. Supporting Evidence: PMID:22053050 The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and the nucleotide loading of the Rag GTPases. PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:0046611 lysosomal proton-transporting V-type ATPase complex	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	ACCEPT	Summary: Accept lysosomal V-type ATPase complex membership. Reason: Although the 2011 mTORC1 paper discusses V-ATPase as a complex, later human structural evidence directly defines ATP6AP1 as a Vo assembly hub, supporting the complex-membership annotation. Supporting Evidence: PMID:22053050 The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and the nucleotide loading of the Rag GTPases. PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:0071230 cellular response to amino acid stimulus	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	KEEP AS NON CORE	Summary: Retain the curated V-ATPase-associated nutrient-signaling role as non-core. Reason: Amino acids regulate mTORC1 via lysosomal V-ATPase-Ragulator-Rag machinery. ATP6AP1 contributes as an accessory V-ATPase subunit rather than as a standalone amino-acid sensor. This complex-associated nutrient-signaling role is retained as secondary to the synthesized ATP6AP1 assembly/acidification core. Its classification does not assert that the curated signaling evidence is false or that isolated ATP6AP1 has a demonstrated exchange-factor activity. Supporting Evidence: PMID:22053050 The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and the nucleotide loading of the Rag GTPases. PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:0160124 guanyl nucleotide exchange factor activator activity	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	KEEP AS NON CORE	Summary: Retain the curated V-ATPase-associated nutrient-signaling role as non-core. Reason: The contributes_to qualifier is essential. PMID:22053050 places the V-ATPase upstream of Rag nucleotide loading and describes physical/functional coupling to Ragulator; the directly tested recombinant contacts are d1 with p18 and D with p18/p14. ATP6AP1 is not individually named in the accessible main text, and its supplemental assay was not replayed. Retain the curated complex-level contribution by deference to that evidence, supported by independent human V-ATPase membership, without claiming that isolated ATP6AP1 binds or directly activates a GEF. This complex-associated nutrient-signaling role is retained as secondary to the synthesized ATP6AP1 assembly/acidification core. Its classification does not assert that the curated signaling evidence is false or that isolated ATP6AP1 has a demonstrated exchange-factor activity. Supporting Evidence: PMID:22053050 The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and the nucleotide loading of the Rag GTPases. PMID:22053050 Ragulator provides a physical and functional link between the v-ATPase and the Rag GTPases.
GO:1904263 positive regulation of TORC1 signaling	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Retain the curated V-ATPase-associated nutrient-signaling role as non-core. Reason: This ISS annotation matches direct human V-ATPase evidence from the amino-acid sensing pathway and is consistent with ATP6AP1 complex membership. This complex-associated nutrient-signaling role is retained as secondary to the synthesized ATP6AP1 assembly/acidification core. Its classification does not assert that the curated signaling evidence is false or that isolated ATP6AP1 has a demonstrated exchange-factor activity. Supporting Evidence: PMID:22053050 The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and the nucleotide loading of the Rag GTPases. PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:1904263 positive regulation of TORC1 signaling	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	KEEP AS NON CORE	Summary: Retain the curated V-ATPase-associated nutrient-signaling role as non-core. Reason: The inspected study places the V-ATPase complex upstream of Rag GTPase nucleotide loading in amino-acid signaling to mTORC1. Retain this curated complex-associated role with the original evidence code; the ATP6AP1-specific supplemental assay has not been independently reconstructed. This complex-associated nutrient-signaling role is retained as secondary to the synthesized ATP6AP1 assembly/acidification core. Its classification does not assert that the curated signaling evidence is false or that isolated ATP6AP1 has a demonstrated exchange-factor activity. Supporting Evidence: PMID:22053050 The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and the nucleotide loading of the Rag GTPases. PMID:22053050 Ragulator provides a physical and functional link between the v-ATPase and the Rag GTPases.
GO:0000139 Golgi membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	UNDECIDED	Summary: Golgi membrane localization remains unresolved across cell types. Reason: The original NAS review is available here only as an abstract and its ATP6AP1-specific location discussion has not been read. The human IHH experiment in PMID:27231034 found ER/ERGIC and not TGN localization in that context; it does not exclude all Golgi residence in other tissues or conditions. Preserve the source assertion pending its specific support, rather than using that negative assay as a universal exclusion. Supporting Evidence: PMID:27231034 The subcellular localization of Ac45 in hepatocytes was studied by immunostaining of IHH cells. Ac45 was found to be mainly localized to the ER, and ER-to-Golgi Intermediate Compartment (ERGIC), but not to the trans-Golgi network (TGN) or components of the endosomal system PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps.
GO:0005765 lysosomal membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: Accept lysosomal membrane localization for ATP6AP1-containing V-ATPase. Reason: V-ATPases are central endolysosomal proton pumps, and ATP6AP1 is a structural V0-associated hub in human V-ATPase. Supporting Evidence: PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps. PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:0005886 plasma membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	KEEP AS NON CORE	Summary: Keep plasma membrane localization as a non-core specialized V-ATPase context. Reason: Plasma membrane V-ATPases function in specialized cells such as osteoclasts, and Ac45 guides V-ATPase to the ruffled border, but this is not the central shared ATP6AP1 role across tissues. Supporting Evidence: PMID:27231034 This accessory subunit of the proton pump guides the V-ATPase into specialized subcellular compartments such as neuroendocrine regulated secretory vesicles1415 or the ruffled border of the osteoclast101617 thereby regulating its activity. PMID:33065002 Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation
GO:0007035 vacuolar acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: Accept vacuolar acidification as the broad V-ATPase acidification process. Reason: ATP6AP1 is an accessory V-ATPase subunit. V-ATPases are ATP-driven proton pumps that acidify intracellular vesicles and organelles. Supporting Evidence: PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps. PMID:33065002 Vesicular- or vacuolar-type adenosine triphosphatases (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:0007042 lysosomal lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: Retain lysosomal lumen acidification through ATP6AP1 participation in the V-ATPase complex. Reason: The V-ATPase complex acidifies lysosomal lumina, and ATP6AP1 is incorporated into the human V0 sector. Structural and functional evidence supports this complex-level role without assigning autonomous proton transport to ATP6AP1. The original NAS review is cached as an abstract; this assessment relies on the independently inspected human structural evidence and retains the curated biological-process assertion. Supporting Evidence: PMID:33065002 Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:0007042 lysosomal lumen acidification	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: Accept lysosomal lumen acidification based on structural evidence for ATP6AP1 in human V-ATPase. Reason: The structural study defines ATP6AP1 as a Vo assembly hub in an ATP-driven proton pump that maintains lysosomal and endosomal pH. Supporting Evidence: PMID:33065002 Vesicular- or vacuolar-type adenosine triphosphatases (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. PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:0010008 endosome membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: Accept endosome membrane localization for ATP6AP1-containing V-ATPase. Reason: Endosomal pH homeostasis is a core V-ATPase function, and Reactome also places ATP6AP1-associated V-ATPase in endosome acidification events. Supporting Evidence: PMID:33065002 Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome.
GO:0016020 membrane	IDA PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	KEEP AS NON CORE	Summary: The broad membrane localization is correct and retained as non-core. Reason: The human protein has a membrane-spanning region and is structurally incorporated into the membrane V0 sector. More specific locations are more informative for synthesis, but breadth alone does not make this membrane assertion biologically over-annotated. Retain the original evidence and qualifier. Supporting Evidence: PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring. PMID:27231034 The subcellular localization of Ac45 in hepatocytes was studied by immunostaining of IHH cells. Ac45 was found to be mainly localized to the ER, and ER-to-Golgi Intermediate Compartment (ERGIC), but not to the trans-Golgi network (TGN) or components of the endosomal system
GO:0033176 proton-transporting V-type ATPase complex	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: Accept V-type ATPase complex membership from human structural data. Reason: Cryo-EM and mass-spectrometry-supported modeling place ATP6AP1 within the complete human V-ATPase as a structural hub for Vo assembly. Supporting Evidence: PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:0048388 endosomal lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: Accept endosomal lumen acidification. Reason: Endosomal acidification is a core V-ATPase process and Reactome describes proton entry into the endosome lumen. Supporting Evidence: PMID:33065002 Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome.
GO:0051452 intracellular pH reduction	NAS PMID:32001091 Structure and Roles of V-type ATPases.	KEEP AS NON CORE	Summary: The broad intracellular acidification process is retained as non-core. Reason: ATP6AP1 is a functional accessory component of the acidifying V-ATPase. More specific organellar acidification records provide the useful biological detail; a true broader process is not over-annotated merely because it is less informative. The cited review is cached as abstract-only, so no source-specific full-text assay reading is claimed. Supporting Evidence: PMID:33065002 Vesicular- or vacuolar-type adenosine triphosphatases (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. PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps.
GO:0061795 Golgi lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	UNDECIDED	Summary: ATP6AP1-specific Golgi lumen acidification support requires clarification. Reason: The cited review is abstract-only and its ATP6AP1-specific Golgi argument has not been inspected. Human glycosylation defects and the general ability of V-ATPase to acidify Golgi compartments are consistent with the annotation but do not by themselves establish the particular compartmental effect of ATP6AP1. Preserve this plausible NAS assertion pending source-specific evidence; ER/ERGIC localization in IHH cells is not a contradiction.
GO:1902600 proton transmembrane transport	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: Accept proton transmembrane transport as the process mediated by the ATP6AP1-containing V-ATPase complex. Reason: ATP6AP1 is not the catalytic proton-translocation subunit by itself, but as a V0 accessory/assembly hub it is appropriately involved in the V-ATPase proton-transport process. Supporting Evidence: PMID:33065002 Vesicular- or vacuolar-type adenosine triphosphatases (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. PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:27231034 ATP6AP1 deficiency causes an immunodeficiency with hepatopat...	ACCEPT	Summary: Accept experimentally supported ER membrane localization. Reason: Human hepatocyte immunostaining directly localizes Ac45 mainly to ER and ERGIC, consistent with its V0 assembly-factor role. Supporting Evidence: PMID:27231034 The subcellular localization of Ac45 in hepatocytes was studied by immunostaining of IHH cells. Ac45 was found to be mainly localized to the ER, and ER-to-Golgi Intermediate Compartment (ERGIC), but not to the trans-Golgi network (TGN) or components of the endosomal system
GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane	EXP PMID:27231034 ATP6AP1 deficiency causes an immunodeficiency with hepatopat...	ACCEPT	Summary: Accept experimentally supported ERGIC membrane localization. Reason: Human hepatocyte immunostaining directly localizes Ac45 to ER and ERGIC and not to TGN or endosomal system markers in that assay. Supporting Evidence: PMID:27231034 The subcellular localization of Ac45 in hepatocytes was studied by immunostaining of IHH cells. Ac45 was found to be mainly localized to the ER, and ER-to-Golgi Intermediate Compartment (ERGIC), but not to the trans-Golgi network (TGN) or components of the endosomal system
GO:0036035 osteoclast development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Keep osteoclast development as a non-core orthology-derived context. Reason: PMID:22467241 experimentally links mouse Ac45 depletion to impaired osteoclast differentiation, lysosomal delivery to the ruffled border and cathepsin-K exocytosis. Retain the existing orthology-supported process as specialized, non-core biology; do not describe the mouse perturbation as a human direct assay or treat absence of a prominent human bone phenotype as contrary evidence. Supporting Evidence: PMID:27231034 This accessory subunit of the proton pump guides the V-ATPase into specialized subcellular compartments such as neuroendocrine regulated secretory vesicles1415 or the ruffled border of the osteoclast101617 thereby regulating its activity.
GO:0099638 endosome to plasma membrane protein transport	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Keep endosome-to-plasma-membrane protein transport as a non-core trafficking context. Reason: PMID:22467241 experimentally links mouse Ac45 depletion to impaired osteoclast differentiation, lysosomal delivery to the ruffled border and cathepsin-K exocytosis. Retain the existing orthology-supported process as specialized, non-core biology; do not describe the mouse perturbation as a human direct assay or treat absence of a prominent human bone phenotype as contrary evidence. Supporting Evidence: PMID:27231034 This accessory subunit of the proton pump guides the V-ATPase into specialized subcellular compartments such as neuroendocrine regulated secretory vesicles1415 or the ruffled border of the osteoclast101617 thereby regulating its activity. PMID:33065002 Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation
GO:0005515 protein binding	IPI PMID:29127204 Mutations in the X-linked ATP6AP2 cause a glycosylation diso...	KEEP AS NON CORE	Summary: The ATP6AP1–ATP6AP2 association is experimentally supported and retained as non-core binding context. Reason: PMID:29127204 Results/Fig. 8 report AP-MS, tagged-protein co-IP and endogenous ATP6AP2/ATP6AP1 co-IP in human HEK293T cells. Initial Y2H used a mouse library, while one-by-one mapping used human ATP6AP1 residues 30–254 and human ATP6AP2 luminal constructs. Preserve these species and fragment distinctions; the generic binding term is valid but not the synthesized core activity. Supporting Evidence: PMID:29127204 For the top candidates ATP6AP1 and VMA21, the interaction was confirmed by coimmunoprecipitation (coIP) of overexpressed tagged proteins in HEK293T cells (Fig. 8 b), and for ATP6AP1 also by endogenous coIP (Fig. 8 c).
GO:0006879 intracellular iron ion homeostasis	IMP PMID:28296633 The vacuolar-ATPase complex and assembly factors, TMEM199 an...	KEEP AS NON CORE	Summary: Keep intracellular iron ion homeostasis as a supported non-core consequence of V-ATPase disruption. Reason: The screen included ATP6AP1 among V-ATPase genes whose disruption stabilizes HIF1alpha by lowering intracellular iron, but this is downstream of V-ATPase acidification rather than ATP6AP1's core molecular role. Supporting Evidence: PMID:28296633 the top ranked biological process was transferrin transport and V-ATPase function (Figure 1B), principally relating to mutagenesis of genes encoding five V-ATPase subunits: ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1 PMID:28296633 disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity and leading to HIF activation.
GO:0036295 cellular response to increased oxygen levels	IMP PMID:28296633 The vacuolar-ATPase complex and assembly factors, TMEM199 an...	KEEP AS NON CORE	Summary: Keep cellular response to increased oxygen levels as a non-core downstream HIF/iron consequence. Reason: V-ATPase disruption in aerobic conditions impairs HIF1alpha prolyl hydroxylation through iron depletion. This supports the annotation but makes it secondary to the endolysosomal V-ATPase role. Supporting Evidence: PMID:28296633 disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity and leading to HIF activation.
GO:0031267 small GTPase binding	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Retain orthology-supported small GTPase binding in a specialized trafficking context. Reason: The actual GOA donor is mouse Ac45 UniProtKB:Q9R1Q9 (the IEA also names ENSMUSP00000019231). PMID:22467241 uses mouse Ac45 NM_018794 and primary mouse bone-marrow osteoclasts; Fig. 6 reports Ac45/Rab7 colocalization and co-IP with wild-type and Q67L Rab7, with Rac1 as a negative comparison. These assays support association, not a purified binary-binding mechanism. This supports the existing human orthology transfer without relabeling it human IDA. The negative Rag-subunit assay in PMID:22053050 does not refute Rab7 binding. Supporting Evidence: PMID:22467241 We found that Ac45 colocalized with Rab7 in resorbing osteoclasts cultured on bone slices (Fig. 6A).
GO:0010008 endosome membrane	TAS Reactome:R-HSA-5252133	ACCEPT	Summary: Accept endosome membrane context for the Reactome ATP6AP1-binds-V-ATPase event. Reason: Reactome places ATP6AP1 as an accessory V0 subunit facilitating V-ATPase acidification; endosomal V-ATPase acidification is also directly described in Reactome events. Supporting Evidence: Reactome:R-HSA-5252133 V-type proton ATPase subunit S1 (ATP6AP1) is thought to function as an accessory subunit of the V0 subcomplex of V-ATPase, facilitating acidification Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome.
GO:0010008 endosome membrane	TAS Reactome:R-HSA-74723	ACCEPT	Summary: Accept endosome membrane for the Reactome endosome acidification event. Reason: Reactome describes proton entry into the endosome lumen by the proton pump; ATP6AP1 is curated in the associated V-ATPase event. 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. Reactome:R-HSA-5252133 V-type proton ATPase subunit S1 (ATP6AP1) is thought to function as an accessory subunit of the V0 subcomplex of V-ATPase, facilitating acidification
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917841	ACCEPT	Summary: Accept endosome membrane for transferrin-receptor endosome acidification context. Reason: Reactome describes V-ATPase-driven proton movement in the endocytic compartment; ATP6AP1 complex membership supports its placement in this context. 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:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	Summary: Detected in an extracellular-vesicle proteome, but the detection does not establish that this protein is an EV constituent. Reason: UniProt places ATP6AP1 in ER and ER-Golgi intermediate compartment membranes. Mainly resident in an intracellular compartment that MISEV2018 (PMID:30637094) lists as not enriched in small EVs of plasma-membrane/endosomal origin (category 4), and its own review keeps no experimental cell-surface or plasma-membrane pool; an exosome annotation from a bulk EV proteome is not supported. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: UNDECIDED.)
GO:0016469 proton-transporting two-sector ATPase complex	TAS PMID:8733135 Long-range sequence analysis in Xq28: thirteen known and six...	MODIFY	Summary: Refine the broad complex term to the proton-transporting V-type ATPase complex. Reason: Human structural evidence identifies ATP6AP1 in the V-type complex. Choose GO:0033176 once rather than simultaneously proposing its lysosomal subclass. The original sequence-reference assertion and the existing independently annotated lysosomal complex rows remain unchanged. Proposed replacements: proton-transporting V-type ATPase complex Supporting Evidence: PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring. PMID:8733135 and a third is a subunit of a vacuolar H-ATPase, and is named VATPS1.

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