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. 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. 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. 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	MARK AS OVER ANNOTATED	Summary: Bounding membrane of organelle is technically consistent with ATP6AP1 membrane localization but is too broad to add biological value. Reason: The annotation is not false, but it is much less informative than the specific ER, ERGIC, endosome, lysosome, and V-ATPase complex annotations already present. 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...	MARK AS OVER ANNOTATED	Summary: The reported physical interaction is retained only as interaction context; generic protein binding is not an informative ATP6AP1 molecular function. Reason: ATP6AP1 has meaningful V-ATPase accessory/regulatory roles. A bare protein-binding annotation from a high-throughput interaction or viral-host interactome does not describe the gene product function and should not drive PN curation.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: The reported physical interaction is retained only as interaction context; generic protein binding is not an informative ATP6AP1 molecular function. Reason: ATP6AP1 has meaningful V-ATPase accessory/regulatory roles. A bare protein-binding annotation from a high-throughput interaction or viral-host interactome does not describe the gene product function and should not drive PN curation. Supporting Evidence: PMID:32814053 Interactome maps are valuable resources to elucidate protein function and disease mechanisms.
GO:0005515 protein binding	IPI PMID:33060197 Comparative host-coronavirus protein interaction networks re...	MARK AS OVER ANNOTATED	Summary: The reported physical interaction is retained only as interaction context; generic protein binding is not an informative ATP6AP1 molecular function. Reason: ATP6AP1 has meaningful V-ATPase accessory/regulatory roles. A bare protein-binding annotation from a high-throughput interaction or viral-host interactome does not describe the gene product function and should not drive PN curation.
GO:0005515 protein binding	IPI PMID:33845483 Multilevel proteomics reveals host perturbations by SARS-CoV...	MARK AS OVER ANNOTATED	Summary: The reported physical interaction is retained only as interaction context; generic protein binding is not an informative ATP6AP1 molecular function. Reason: ATP6AP1 has meaningful V-ATPase accessory/regulatory roles. A bare protein-binding annotation from a high-throughput interaction or viral-host interactome does not describe the gene product function and should not drive PN curation.
GO:0005515 protein binding	IPI PMID:34232536 Interactomes of SARS-CoV-2 and human coronaviruses reveal ho...	MARK AS OVER ANNOTATED	Summary: The reported physical interaction is retained only as interaction context; generic protein binding is not an informative ATP6AP1 molecular function. Reason: ATP6AP1 has meaningful V-ATPase accessory/regulatory roles. A bare protein-binding annotation from a high-throughput interaction or viral-host interactome does not describe the gene product function and should not drive PN curation.
GO:0005515 protein binding	IPI PMID:34997207 SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent...	MARK AS OVER ANNOTATED	Summary: The reported physical interaction is retained only as interaction context; generic protein binding is not an informative ATP6AP1 molecular function. Reason: ATP6AP1 has meaningful V-ATPase accessory/regulatory roles. A bare protein-binding annotation from a high-throughput interaction or viral-host interactome does not describe the gene product function and should not drive PN curation.
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	REMOVE	Summary: Remove direct small GTPase binding. The best mTORC1 evidence places V-ATPase upstream of Rag nucleotide loading through Ragulator, not as a direct Rag-binding protein. Reason: The cited pathway supports V-ATPase-Ragulator functional coupling, but the paper explicitly reports no direct interaction between purified V-ATPase subunits and Rag GTPases. For ATP6AP1, ATPase regulator activity is the safer molecular-function assertion. Supporting Evidence: PMID:22053050 Ragulator provides a physical and functional link between the v-ATPase and the Rag GTPases. PMID:22053050 No direct interactions were detected between the Rag GTPases and purified v-ATPase subunits
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: Ac45 has reported osteoclast/ruffled-border targeting context, but ATP6AP1 deficiency in humans is dominated by immunodeficiency, hepatopathy, cognitive features, and glycosylation defects rather than a primary osteoclast-development phenotype. 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 PN-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. 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: The annotation is consistent with membrane trafficking and V-ATPase acidification biology, but it is less direct than ATP6AP1 complex membership, ATPase regulation, and organelle acidification. 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	MODIFY	Summary: The broad activator term captures the correct idea that ATP6AP1 regulates V-ATPase function, but it should be replaced by the PN-projected and more specific ATPase regulator activity term. Reason: ATP6AP1 is an accessory subunit that guides/regulates V-ATPase activity and serves as a structural hub for Vo assembly. GO:0060590 is the conservative specific MF target for this role. Proposed replacements: ATPase regulator activity 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 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	IEA GO_REF:0000107	ACCEPT	Summary: Accept positive regulation of TORC1 signaling as an ATP6AP1/V-ATPase nutrient-sensing process. 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. 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 active-in annotation for the ATP6AP1-containing V-ATPase in mTORC1 amino-acid sensing. 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. 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...	ACCEPT	Summary: Accept cellular response to amino-acid stimulus through lysosomal V-ATPase/mTORC1 signaling. 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. 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...	ACCEPT	Summary: Accept contributes_to guanyl nucleotide exchange factor activator activity for the V-ATPase/Ragulator system. Reason: The qualifier is important: ATP6AP1 does not independently enable a Rag GTPase GEF activator activity, but V-ATPase is positioned upstream of Rag nucleotide loading through Ragulator. 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	ACCEPT	Summary: Accept orthology-supported positive regulation of TORC1 signaling. Reason: This ISS annotation matches direct human V-ATPase evidence from the amino-acid sensing pathway and is consistent with ATP6AP1 complex membership. 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...	ACCEPT	Summary: Accept direct evidence for positive regulation of TORC1 signaling by the ATP6AP1-containing V-ATPase system. Reason: V-ATPase is required for amino-acid signaling to mTORC1 and acts upstream of Rag GTPase nucleotide loading; this is a PN-relevant signaling role but should not be confused with a chaperone/protein-folding 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: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.	MARK AS OVER ANNOTATED	Summary: Golgi membrane localization is plausible for V-ATPase biology, but this protein-specific location is less directly supported than the Golgi acidification process. Reason: The Golgi lumen acidification process annotation is retained because it reflects V-ATPase complex activity with ATP6AP1 disease relevance through glycosylation defects. This cellular-component annotation is protein-specific; direct human Ac45 staining found ER/ERGIC localization and not TGN, so Golgi membrane should not be treated as a core ATP6AP1 location. 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 for PN curation. 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: Accept lysosomal lumen acidification. This is the existing GOA term that the PN projection already recognizes as an exact match. Reason: V-ATPase establishes lysosomal pH homeostasis, and ATP6AP1 is part of the human V-ATPase assembly/function machinery. 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...	MARK AS OVER ANNOTATED	Summary: Membrane is true for ATP6AP1 but too broad to be useful. Reason: ATP6AP1 is a single-pass membrane protein and V0 accessory hub, but specific membrane compartments and V-ATPase complex membership are much more informative than the generic membrane term. 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.	MARK AS OVER ANNOTATED	Summary: Intracellular pH reduction is a true but broad consequence of V-ATPase activity. Reason: More specific organelle-acidification annotations already capture ATP6AP1/V-ATPase biology. The generic intracellular pH term is less useful for PN propagation. 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.	ACCEPT	Summary: Accept Golgi lumen acidification as a V-ATPase-dependent process with disease relevance to ATP6AP1 glycosylation defects. Reason: ATP6AP1 deficiency causes abnormal protein glycosylation, consistent with defective organelle/Golgi homeostasis; V-ATPase acidifies the Golgi apparatus. Supporting Evidence: PMID:27231034 The vacuolar H+-ATPase (V-ATPase) is a ubiquitously expressed protein complex, required for luminal acidification of secretory vesicles to acidify the extracellular milieu, compartments of the endocytic pathway including lysosomes, and of the Golgi apparatus
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: Ac45 has osteoclast ruffled-border targeting context, but this is tissue-specific and not the core human ATP6AP1 function captured by the PN review. 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: ATP6AP1/V-ATPase biology includes membrane trafficking and endolysosomal acidification, but this process is secondary to the core complex/regulatory functions. 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...	MARK AS OVER ANNOTATED	Summary: ATP6AP1-ATP6AP2 physical interaction is biologically relevant to V0 assembly, but protein binding is not an informative GO molecular function. Reason: The interaction supports the V-ATPase accessory/assembly model and the PN ATPase-regulator candidate, but the generic protein-binding term should not be treated as a core function. Supporting Evidence: PMID:29127204 Finally, both ATP6AP2 mutations impaired protein stability and the interaction with ATP6AP1, a member of the V0 assembly complex.
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	REMOVE	Summary: Remove direct small GTPase binding for the same reason as the IEA duplicate: V-ATPase functionally couples to Rag GTPases through Ragulator rather than direct Rag binding by ATP6AP1. Reason: The mTORC1 literature supports V-ATPase-dependent Rag nucleotide loading but explicitly reports no direct interaction between purified V-ATPase subunits and Rag GTPases. 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 No direct interactions were detected between the Rag GTPases and purified v-ATPase subunits
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...	KEEP AS NON CORE	Summary: Keep extracellular exosome as a non-core high-throughput localization. Reason: This HDA urinary-exosome annotation may reflect membrane protein detection in extracellular vesicles, but it is not central to ATP6AP1's V-ATPase accessory role. Supporting Evidence: PMID:19056867 Normal human urine contains large numbers of exosomes, which are 40- to 100-nm vesicles that originate as the internal vesicles in multivesicular bodies from every renal epithelial cell type facing the urinary space.
GO:0016469 proton-transporting two-sector ATPase complex	TAS PMID:8733135 Long-range sequence analysis in Xq28: thirteen known and six...	MODIFY	Summary: The two-sector ATPase complex term is directionally correct but too broad; ATP6AP1 should be captured as part of the proton-transporting V-type ATPase complex. Reason: ATP6AP1 is a V-ATPase S1/Ac45 accessory subunit, not a generic F/A/V two-sector ATPase component. Existing V-type complex terms are the better replacements. Proposed replacements: proton-transporting V-type ATPase complex lysosomal 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.
GO:0060590 ATPase regulator activity	IC file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv	NEW	Summary: Add ATPase regulator activity as the conservative PN-projected molecular-function term for ATP6AP1. Reason: The PN projection identifies ATP6AP1 under regulator of the lysosomal V-ATPase proton pump. This is supported by direct literature showing Ac45 guides/regulates V-ATPase targeting/activity and structural evidence defining ATP6AP1 as a Vo assembly hub. This term is preferable to generic molecular function activator activity or protein binding. 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 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring.

Gene Description

Existing Annotations Review

Core Functions

ATP6AP1/Ac45 is an accessory/regulatory subunit of the V-ATPase V0 sector. It promotes V-ATPase assembly, targeting, stability, and activity rather than catalyzing proton transport itself. This captures the PN-projected regulator-of-lysosomal-V-ATPase role conservatively.

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