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.

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.

Molecular Function:

ATPase regulator activity

Directly Involved In:

lysosomal lumen acidification endosomal lumen acidification Golgi lumen acidification positive regulation of TORC1 signaling

Cellular Locations:

endoplasmic reticulum membrane endoplasmic reticulum-Golgi intermediate compartment membrane lysosomal membrane endosome membrane

In Complex:

proton-transporting V-type ATPase complex

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.
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.

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

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

GO_REF:0000107

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

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:22053050

mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase.

Shows V-ATPase is required for lysosomal amino-acid sensing and mTORC1 activation through Rag/Ragulator coupling.

"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:27231034

ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation.

Identifies ATP6AP1/Ac45 deficiency, localizes Ac45 to ER/ERGIC in hepatocytes, and supports a Voa1-like V-ATPase assembly-factor role.

"Processed wild-type Ac45, but not its disease mutants, restored V-ATPase-dependent growth in Voa1 mutant yeast."

PMID:28296633

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

Links ATP6AP1/V-ATPase disruption to intracellular iron depletion and HIF activation in aerobic conditions.

"disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity and leading to HIF activation."

PMID:29127204

Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects.

Shows ATP6AP2 disease mutations impair interaction with ATP6AP1 and supports an ATP6AP-family V0 assembly complex model.

"both ATP6AP2 mutations impaired protein stability and the interaction with ATP6AP1, a member of the V0 assembly complex."

PMID:32001091

Structure and Roles of V-type ATPases.

Review source for V-ATPase acidification roles across organelles and specialized plasma membranes.

"V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps."

PMID:32353859

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33060197

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.

PMID:33065002

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

Cryo-EM study of complete human V-ATPase defining ATP6AP1 as a structural hub for V0 assembly.

"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:33845483

Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV.

PMID:34232536

Interactomes of SARS-CoV-2 and human coronaviruses reveal host factors potentially affecting pathogenesis.

PMID:34997207

SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1.

PMID:8733135

Long-range sequence analysis in Xq28: thirteen known and six candidate genes in 219.4 kb of high GC DNA between the RCP/GCP and G6PD loci.

Reactome:R-HSA-5252133

ATP6AP1 binds V-ATPase

Reactome event placing ATP6AP1 as an accessory V0 subunit that facilitates V-ATPase acidification.

"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

Endosome acidification

Reactome event for endosome acidification by proton entry into the endosome lumen.

"The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome."

Reactome:R-HSA-917841

Acidification of Tf:TfR1 containing endosome

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

Proteostasis PN projected annotations report

Projects ATP6AP1 to GO:0060590 ATPase regulator activity from regulator-of-lysosomal-V-ATPase PN leaves and recognizes GO:0007042 lysosomal lumen acidification as already present in GOA.

"ATPase regulator activity is the narrowest GO target that preserves the source mechanism without requiring a speculative complex-specific term."

Suggested Experiments

Experiment: Introduce representative ATP6AP1 variants into an ATP6AP1-null human cell line and measure V-ATPase assembly, lysosomal/endosomal pH, glycosylation markers, and amino-acid-stimulated mTORC1 recruitment/phosphorylation in parallel.

Hypothesis: ATP6AP1 disease variants differentially impair ER V0 assembly, lysosomal acidification, and mTORC1 amino-acid signaling.

Type: genome editing and cell biology

Experiment: Compare rescue by wild-type ATP6AP1 and assembly-defective mutants using purified V-ATPase assembly assays or quantitative proteomics of V0/V1 subcomplex formation, coupled to acidification readouts.

Hypothesis: The PN-projected ATPase regulator activity reflects ATP6AP1-specific control of V-ATPase assembly/activity rather than a generic consequence of complex membership.

Type: biochemical reconstitution/proteomics

Deep Research

Falcon

(ATP6AP1-deep-research-falcon.md)

Comprehensive Research Report: ATP6AP1 (V-type Proton ATPase Subunit S1) Falcon

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: ATP6AP1 (V-type Proton ATPase Subunit S1)

Gene Identity Verification

ATP6AP1 (UniProt Q15904) encodes the V-type proton ATPase accessory protein 1, also known as Ac45 or ATPase H+ Transporting Accessory Protein 1, in Homo sapiens (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, jansen2016atp6ap1deficiencycauses pages 1-2). This gene product belongs to the vacuolar ATPase subunit S1 family and contains the Ac45-VOA1_TM, BIG1_N, and VAS1_LD domains as specified in UniProt. The literature reviewed confirms this is the correct protein matching the provided UniProt entry.

1. Primary Function and Molecular Role

V-ATPase Assembly Factor

ATP6AP1 functions primarily as a V-ATPase assembly and structural support factor rather than as the catalytic enzyme subunit itself (wang2020structuresofa pages 1-3, jansen2016atp6ap1deficiencycauses pages 1-2). The actual ATP hydrolysis reaction occurs in the V1 domain at the interface of subunits A and B, not in ATP6AP1 (abbas2020structureofvatpase pages 4-5, holliday2014vacuolarh+atpasean pages 2-3). Instead, ATP6AP1 is the functional human ortholog of yeast Voa1, a V0 assembly factor essential for the biogenesis of functional V-ATPase complexes in the endoplasmic reticulum (jansen2016atp6ap1deficiencycauses pages 1-2).

Functional complementation experiments in yeast demonstrated that processed wild-type human Ac45 restores V-ATPase-dependent growth in Voa1-deficient yeast cells, whereas disease-mutant forms of Ac45 fail to do so, providing strong experimental evidence for its assembly-factor role (jansen2016atp6ap1deficiencycauses pages 1-2). Furthermore, ATP6AP1 cooperates with ATP6AP2 (the [pro]renin receptor) in higher organisms to fulfill V0 assembly functions; co-expression of ATP6AP1 and ATP6AP2 in yeast dramatically improves rescue efficiency and restores quinacrine accumulation in acidic vacuoles (guida2018atp6ap2functionsas pages 1-5, guida2018atp6ap2functionsas pages 5-8).

Structural Organization and Position in V-ATPase

ATP6AP1 contains a transmembrane (TM) helix and a substantial luminal domain (LD) (wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7). High-resolution cryo-EM structures of human V-ATPase revealed that the luminal domain adopts a β-prism fold structurally homologous to lysosomal-associated membrane protein (LAMP) domains despite complete lack of sequence homology (wang2020structuresofa pages 1-3, wang2020structuresofa pages 5-7). This LAMP-like fold is evolutionarily conserved across species and consists of 10 β strands arranged in two opposing β sheets.

Within the V0 complex, ATP6AP1 is centrally localized inside the c-ring, positioned adjacent to ATP6AP2, subunit c'', multiple c subunits (c(1), c(2), c(8), c(9)), and subunit d (wang2020structuresofa pages 1-3, wang2020structuresofa pages 5-7). The protein exhibits extensive buried surface areas with its interaction partners (over 7,000 Ų total), making it the most connected subunit in the V0 domain (wang2020structuresofa pages 5-7). The luminal domain contacts the N-terminal luminal tail of ATP6AP2, the c'' luminal linker, and luminal tails of c(8) and c(9), while the TM helix and cytosolic tail pack against ATP6AP2, c'', c(1), c(2), and subunit d (wang2020structuresofa pages 5-7).

Role as a Structural Hub

Wang et al. (2020) defined ATP6AP1 as a structural hub for V0 complex assembly because it connects multiple V0 subunits and associates with ordered phospholipids inside the c-ring (wang2020structuresofa pages 1-3, wang2020structuresofa pages 5-7). The authors propose that ATP6AP1, ATP6AP2, and the c-ring together provide a platform for loading other V0 components during assembly. This explains why ATP6AP1 mutations destabilize holoenzyme formation—the protein is essential for organizing the membrane sector architecture that enables proton translocation.

Relationship to Proton Pumping

ATP6AP1 does not itself translocate protons or hydrolyze ATP. Proton translocation occurs through the V0 c-ring and subunit a half-channels, powered by ATP hydrolysis in the V1 domain (abbas2020structureofvatpase pages 1-2, abbas2020structureofvatpase pages 4-5). However, ATP6AP1 is required for full proton-pump competence of assembled V-ATPase complexes (jansen2016atp6ap1deficiencycauses pages 1-2, pareja2018lossoffunctionmutationsin pages 1-2). Deficiency or mutation of ATP6AP1 lowers V-ATPase activity by impairing assembly and stability rather than by directly affecting the catalytic mechanism. In granular cell tumor models with ATP6AP1 loss-of-function mutations, vesicle acidification is impaired, and cells accumulate intracytoplasmic granules due to defective endosomal pH regulation (pareja2018lossoffunctionmutationsin pages 1-2).

Aspect	ATP6AP1 (Ac45) finding	Specific details / mechanism	Key evidence / consequence	Citation
Verified gene identity	ATP6AP1 is the human gene encoding V-type proton ATPase accessory subunit Ac45 / subunit S1, a V-ATPase-associated protein in the V0 sector	Human and mammalian V-ATPase structural and biochemical studies identify ATP6AP1/Ac45 as a membrane-associated accessory component of the V0 domain, distinct from catalytic V1 ATP-hydrolyzing subunits	Confirms the literature matches UniProt Q15904, Homo sapiens ATP6AP1	(abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, jansen2016atp6ap1deficiencycauses pages 1-2)
Primary molecular role	ATP6AP1 functions primarily as a V-ATPase assembly and structural support factor rather than as the catalytic ATPase subunit	ATP hydrolysis occurs in V1 A/B subunits; ATP6AP1 instead helps assemble/stabilize the V0 proton-pore region and connect membrane components needed for a functional holoenzyme	Loss or mutation reduces V-ATPase function indirectly by impairing assembly/biogenesis rather than ATP hydrolysis chemistry itself	(wang2020structuresofa pages 1-3, jansen2016atp6ap1deficiencycauses pages 1-2, holliday2014vacuolarh+atpasean pages 2-3)
Assembly-factor role	ATP6AP1 is the functional human ortholog of yeast Voa1, a V0 assembly factor	Disease-mutant and wild-type complementation experiments in yeast showed processed wild-type Ac45 restores V-ATPase-dependent growth in Voa1-deficient yeast, whereas disease mutants do not	Strong functional evidence that ATP6AP1 participates in early V0 assembly	(jansen2016atp6ap1deficiencycauses pages 1-2)
Cooperation with ATP6AP2	ATP6AP1 works together with ATP6AP2/(pro)renin receptor in higher eukaryotes to replace yeast Voa1-like assembly functions	Co-expression of ATP6AP1 with ATP6AP2 improves rescue of V-ATPase-defective yeast and restores quinacrine accumulation in acidic vacuoles	Supports a cooperative assembly module for V0 biogenesis in the ER	(guida2018atp6ap2functionsas pages 1-5, guida2018atp6ap2functionsas pages 5-8)
Structural organization	ATP6AP1 contains a transmembrane helix plus a substantial luminal domain	Cryo-EM of human V-ATPase resolved ATP6AP1 as a TM-anchored protein with a globular luminal domain positioned within the V0 assembly	Establishes ATP6AP1 as an integral structural element of mammalian V-ATPase	(wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7)
Luminal domain identity	The ATP6AP1 luminal domain adopts a β-prism fold structurally homologous to LAMP-family domains	Structural comparison identified significant homology to LAMP1/2/3 luminal domains despite lack of sequence homology; the luminal domain is evolutionarily conserved	Suggests a specialized luminal scaffold/glycan-associated role in V-ATPase biogenesis and stability	(wang2020structuresofa pages 1-3, wang2020structuresofa pages 5-7)
V0 topological position	ATP6AP1 is centrally localized inside the c-ring of the Vo complex	In human structures, ATP6AP1 sits adjacent to ATP6AP2, c'', multiple c subunits, and subunit d, with extensive buried surface area	Explains why ATP6AP1 is a structural hub for Vo assembly	(wang2020structuresofa pages 1-3, wang2020structuresofa pages 5-7)
Interaction partners in V0	ATP6AP1 interacts extensively with ATP6AP2, c'', c(1), c(2), c(8), c(9), subunit d, and phospholipids inside the c-ring	The luminal domain contacts ATP6AP2 luminal tail, the c'' luminal linker, and luminal tails of c(8)/c(9); the TM/cytosolic regions pack against ATP6AP2, c'', c(1), c(2), and subunit d	Makes ATP6AP1 the most connected Vo accessory component in the human structure	(wang2020structuresofa pages 5-7)
Structural hub function	ATP6AP1 directly organizes multiple Vo subunits and lipids during assembly	Human cryo-EM authors define ATP6AP1 as a structural hub because it connects multiple Vo subunits and associated phospholipids; they propose ATP6AP1/ATP6AP2/c-ring provide a platform for loading other Vo components	Provides a mechanistic explanation for why ATP6AP1 mutations destabilize holoenzyme formation	(wang2020structuresofa pages 1-3, wang2020structuresofa pages 5-7)
Relation to proton pumping	ATP6AP1 does not itself translocate protons or hydrolyze ATP, but is required for full proton-pump competence of assembled V-ATPase	Proton translocation occurs through Vo c-ring and subunit a half-channels, powered by ATP hydrolysis in V1; ATP6AP1 enables proper assembly of the membrane sector that carries out proton movement	Functional ATP6AP1 is therefore essential for normal proton pumping as an accessory/assembly determinant	(abbas2020structureofvatpase pages 1-2, abbas2020structureofvatpase pages 4-5, holliday2014vacuolarh+atpasean pages 2-3)
Functional effect on V-ATPase activity	ATP6AP1 deficiency or mutation lowers V-ATPase activity	In granular cell tumor models, ATP6AP1 loss impairs vesicle acidification; disease-mutant Ac45 fails to rescue V-ATPase-dependent yeast growth; structural work predicts reduced function from impaired folding/assembly	Links ATP6AP1 integrity to measurable proton-pump output	(jansen2016atp6ap1deficiencycauses pages 1-2, pareja2018lossoffunctionmutationsin pages 1-2, wang2020structuresofa pages 5-7)
Organelle acidification	ATP6AP1 is required for normal acidification of lysosomes/endosomes and related vesicles via V-ATPase	ATP6AP1 knockdown reduces lysosomal/autolysosomal acidification in breast cancer cells; ATP6AP1/ATP6AP2 loss in tumors impairs vesicle acidification and redistributes endosomal compartments	Demonstrates direct cellular consequence of reduced ATP6AP1 function	(pareja2018lossoffunctionmutationsin pages 1-2, fei2024lysosomalgeneatp6ap1 pages 1-2, fei2024lysosomalgeneatp6ap1 pages 2-4)
Autophagy linkage	ATP6AP1 promotes autophagic flux by supporting lysosomal acidification; recent work also links it to autophagosome-lysosome fusion	ATP6AP1 depletion blocks autophagic flux and increases drug sensitivity in breast cancer; ATP6AP1 overexpression promotes autophagy and, in 2025 work, enhances Rab7-HOPS interaction to support fusion	Places ATP6AP1 in the autophagy-lysosome pathway downstream of V-ATPase assembly	(fei2024lysosomalgeneatp6ap1 pages 1-2, fei2024lysosomalgeneatp6ap1 pages 2-4, yan2025atp6ap1promotescell pages 1-2, yan2025atp6ap1promotescell pages 2-4)
Subcellular localization	ATP6AP1 functions in endolysosomal and secretory pathway membranes and can guide V-ATPase to specialized compartments	Review and disease literature describe ATP6AP1 in lysosomes/endosomes, Golgi-related compartments, neuroendocrine secretory vesicles, and osteoclast ruffled border-associated V-ATPase populations	Supports a role in compartment-specific V-ATPase targeting and activity regulation	(jansen2016atp6ap1deficiencycauses pages 1-2, song2020theemergingroles pages 1-2, jansen2016atp6ap1deficiencycauses pages 2-3)
Specialized trafficking role	ATP6AP1 helps guide V-ATPase into specialized subcellular compartments	Jansen et al. describe Ac45 guiding V-ATPase into neuroendocrine regulated secretory vesicles and osteoclast ruffled border; older V-ATPase reviews also note accessory-subunit-mediated targeting	Extends function beyond assembly to compartment-selective deployment	(jansen2016atp6ap1deficiencycauses pages 1-2, jansen2016atp6ap1deficiencycauses pages 2-3, kinouchi2013theroleof pages 1-2)
Tissue-specific processing	ATP6AP1 undergoes tissue-specific processing into different molecular forms	Human brain predominantly contains a processed ~40-kDa form; liver contains a 62-kDa intact protein; B cells show a ~50-kDa isoform	Suggests tissue-specific regulation of Ac45 maturation and possibly V-ATPase assembly specialization	(jansen2016atp6ap1deficiencycauses pages 1-2)
Tissue expression pattern	ATP6AP1 is widely expressed, with especially high levels reported in neuronal, neuroendocrine, and osteoclast-related contexts	Vertebrate Ac45 is described as ubiquitous but enriched in neuronal/(neuro-)endocrine cells and osteoclasts	Consistent with broad housekeeping plus specialized secretory/acidification functions	(jansen2016atp6ap1deficiencycauses pages 1-2, jansen2016atp6ap1deficiencycauses pages 2-3)
Disease-causing missense mutations	Hemizygous ATP6AP1 missense mutations cause a human multisystem disorder	Reported variants include L144P, Y313C, E346K, and M428I in males with immunodeficiency, hepatopathy, abnormal glycosylation, and variable neurocognitive symptoms	Establishes ATP6AP1 as a disease gene affecting V-ATPase-dependent organellar physiology	(jansen2016atp6ap1deficiencycauses pages 1-2, jansen2016atp6ap1deficiencycauses pages 2-3)
Structural interpretation of disease mutations	Disease mutations impair ATP6AP1 folding or inter-subunit contacts needed for V-ATPase assembly	Y313C likely destabilizes the hydrophobic core of the luminal domain; E346K disrupts local salt-bridge interactions in the luminal β-prism; M428I perturbs hydrophobic contacts in the TM region with c-ring components	Explains reduced V-ATPase function at molecular resolution	(wang2020structuresofa pages 5-7)
Functional consequence of disease mutations	ATP6AP1 mutations reduce V-ATPase function and organellar homeostasis	Mutant Ac45 proteins fail functional rescue in yeast; patient phenotypes include abnormal protein glycosylation, consistent with disrupted organelle acidification across Golgi/endolysosomal pathways	Provides experimental and clinical evidence of loss-of-function	(jansen2016atp6ap1deficiencycauses pages 1-2)
Somatic loss-of-function in cancer	Inactivating ATP6AP1 mutations act as drivers in many granular cell tumors	Whole-exome/targeted sequencing found ATP6AP1 or ATP6AP2 inactivating mutations in 72% of GCTs overall; ATP6AP1-mutant or silenced cells show impaired vesicle acidification and granule accumulation	Real-world pathological implementation of ATP6AP1 dysfunction in human tumors	(pareja2018lossoffunctionmutationsin pages 1-2)
Recent translational relevance (2024)	ATP6AP1 overexpression is linked to chemoresistance through lysosomal acidification/autophagy in breast cancer	2024 study showed ATP6AP1 knockdown inhibits autophagic flux and lysosomal acidification, partially reversing doxorubicin resistance; high expression correlated with poor response and prognosis	Highlights ATP6AP1 as a candidate biomarker and therapeutic vulnerability in cancer	(fei2024lysosomalgeneatp6ap1 pages 1-2, fei2024lysosomalgeneatp6ap1 pages 2-4)

Table: This table summarizes the primary molecular functions, structural features, interaction partners, acidification roles, tissue-specific processing, and disease consequences of human ATP6AP1/Ac45. It is useful as a compact evidence map linking structural biology, cell biology, and human disease findings for functional annotation.

2. Subcellular Localization

Assembly in the ER and Trafficking to Acidic Compartments

ATP6AP1 functions initially in the endoplasmic reticulum (ER) during V-ATPase assembly (guida2018atp6ap2functionsas pages 1-5, guida2018atp6ap2functionsas pages 5-8). Following assembly, V-ATPase complexes containing ATP6AP1 are trafficked to multiple acidic compartments throughout the cell.

Primary Functional Locations

ATP6AP1 localizes to and functions in:

Endolysosomal membranes: Lysosomes, late endosomes, and autolysosomes where it maintains acidification essential for proteolytic enzyme activation and cargo degradation (pareja2018lossoffunctionmutationsin pages 1-2, fei2024lysosomalgeneatp6ap1 pages 1-2, fei2024lysosomalgeneatp6ap1 pages 2-4)
Golgi apparatus: Required for Golgi acidification necessary for proper protein glycosylation and processing (jansen2016atp6ap1deficiencycauses pages 1-2, jansen2016atp6ap1deficiencycauses pages 2-3)
Secretory vesicles: Particularly enriched in neuroendocrine regulated secretory vesicles where it helps guide V-ATPase to specialized compartments (jansen2016atp6ap1deficiencycauses pages 1-2, jansen2016atp6ap1deficiencycauses pages 2-3)
Specialized plasma membrane domains: Including the osteoclast ruffled border where plasma membrane-localized V-ATPase mediates extracellular acidification for bone resorption (jansen2016atp6ap1deficiencycauses pages 2-3)

Tissue-Specific Processing

ATP6AP1 undergoes tissue-specific proteolytic processing into different molecular forms (jansen2016atp6ap1deficiencycauses pages 1-2). Human brain predominantly contains a processed ~40-kDa form, liver contains a 62-kDa intact protein, and B cells show a ~50-kDa isoform. This differential processing suggests tissue-specific regulation of Ac45 maturation and possibly specialized V-ATPase assembly or targeting mechanisms in different cell types.

3. Biochemical Pathways and Signaling Mechanisms

Autophagy-Lysosomal Pathway

ATP6AP1 plays a central role in the autophagy-lysosomal pathway through multiple mechanisms (fei2024lysosomalgeneatp6ap1 pages 1-2, yan2025atp6ap1promotescell pages 1-2, fei2024lysosomalgeneatp6ap1 pages 2-4, yan2025atp6ap1promotescell pages 2-4). Recent work from 2025 demonstrated that ATP6AP1 promotes autophagic flux by regulating both lysosomal acidification and autophagosome-lysosome fusion (yan2025atp6ap1promotescell pages 1-2, yan2025atp6ap1promotescell pages 2-4). Mechanistically, ATP6AP1:

Induces lysosomal acidification through regulation of V-ATPase assembly and activity
Facilitates autophagosome-lysosome fusion by enhancing the interaction between Rab7 and the HOPS (homotypic fusion and protein sorting) complex (yan2025atp6ap1promotescell pages 2-4)

Knockdown of ATP6AP1 in breast cancer cells blocks autophagic flux, leading to accumulation of LC3B-II and p62, and increases sensitivity to chemotherapeutic drugs like doxorubicin (fei2024lysosomalgeneatp6ap1 pages 1-2, fei2024lysosomalgeneatp6ap1 pages 2-4). Conversely, ATP6AP1 overexpression promotes autophagy and enhances drug resistance (yan2025atp6ap1promotescell pages 1-2, yan2025atp6ap1promotescell pages 2-4).

Protein Glycosylation Pathway

ATP6AP1 is required for proper protein glycosylation through its role in maintaining Golgi apparatus acidification (jansen2016atp6ap1deficiencycauses pages 1-2, jansen2016atp6ap1deficiencycauses pages 2-3). Patients with ATP6AP1 mutations display abnormal protein glycosylation patterns, consistent with disrupted Golgi pH homeostasis affecting glycosyltransferase and glycosidase activities. This links ATP6AP1 dysfunction to congenital disorders of glycosylation phenotypes.

Endocytic Trafficking

ATP6AP1 supports endocytic trafficking and receptor recycling by maintaining vesicle acidification required for receptor-ligand uncoupling and cargo sorting (song2020theemergingroles pages 1-2, holliday2014vacuolarh+atpasean pages 1-2). V-ATPase-dependent acidification in early and late endosomes is essential for dissociating internalized receptor-ligand complexes and routing receptors back to the plasma membrane while directing ligands to lysosomes for degradation.

mTORC1 Nutrient Sensing

V-ATPase complexes, including those containing ATP6AP1, function in amino acid sensing for mTORC1 activation (song2020theemergingroles pages 1-2, holliday2014vacuolarh+atpasean pages 1-2). The V-ATPase can sense amino acid availability on lysosomal membranes and recruit mTORC1, linking nutrient status to cell growth and metabolism. This represents a non-canonical function of V-ATPase that is not directly dependent on proton pumping but requires the structural integrity of the complex that ATP6AP1 helps establish.

4. Recent Developments and Applications (2023-2024)

Cancer Biology and Chemoresistance

Multiple studies published in 2024-2025 identified ATP6AP1 as a driver of chemoresistance in breast cancer through autophagy-mediated mechanisms (fei2024lysosomalgeneatp6ap1 pages 1-2, yan2025atp6ap1promotescell pages 1-2, fei2024lysosomalgeneatp6ap1 pages 2-4, yan2025atp6ap1promotescell pages 2-4). Yan et al. (2025) found that ATP6AP1 is overexpressed in luminal breast cancer tissues and promotes proliferation and tamoxifen resistance both in vitro and in vivo (yan2025atp6ap1promotescell pages 1-2, yan2025atp6ap1promotescell pages 2-4). High ATP6AP1 expression correlates with poor overall survival in patients. Mechanistically, ATP6AP1 enhances tamoxifen resistance by activating autophagy through dual regulation of lysosomal acidification (via V-ATPase assembly) and autophagosome-lysosome fusion (via Rab7-HOPS interaction) (yan2025atp6ap1promotescell pages 2-4).

Fei et al. (2024) similarly demonstrated that ATP6AP1 knockdown reduces autophagy-mediated doxorubicin resistance in breast cancer cells (fei2024lysosomalgeneatp6ap1 pages 1-2, fei2024lysosomalgeneatp6ap1 pages 2-4). Elevated ATP6AP1 expression correlated with poor response to doxorubicin-based neoadjuvant chemotherapy and worse prognosis in clinical cohorts. These findings establish ATP6AP1 as both a prognostic biomarker and potential therapeutic target in breast cancer.

Hepatocellular Carcinoma and Immune Evasion

Tang et al. (2025) identified ATP6AP1 as a driver of pyroptosis-mediated immune evasion in hepatocellular carcinoma (HCC) using machine learning approaches. ATP6AP1 was found to promote lysosomal acidification-pyroptosis-immunosuppression axis, contributing to an immunosuppressed tumor microenvironment enriched in regulatory T cells (Tregs). The study suggests that targeting ATP6AP1 could reshape the tumor microenvironment and enhance immunotherapy efficacy in HCC patients.

Structural and Mechanistic Updates

Recent reviews and primary research (2023-2024) provided updated insights into V-ATPase assembly mechanisms. Lei et al. (2024) identified Big1 (a yeast homolog of ATP6AP1) as a newly identified autophagy regulator critical for a fully functional V-ATPase, further confirming the evolutionary conservation of ATP6AP1-like assembly factors. Work on TLDc domain proteins and V-ATPase disassembly mechanisms expanded understanding of how V-ATPase activity is dynamically regulated in response to cellular stress.

5. Disease Associations

Immunodeficiency Syndrome

Hemizygous ATP6AP1 missense mutations cause a multisystem disorder in male patients characterized by immunodeficiency with hypogammaglobulinemia, hepatopathy, abnormal protein glycosylation, and variable neurocognitive symptoms (jansen2016atp6ap1deficiencycauses pages 1-2, jansen2016atp6ap1deficiencycauses pages 2-3). Reported pathogenic variants include L144P, Y313C, E346K, and M428I. Structural analysis revealed that Y313C likely destabilizes the hydrophobic core of the luminal domain, E346K disrupts surface salt-bridge interactions, and M428I perturbs hydrophobic contacts with c-ring components in the TM region (wang2020structuresofa pages 5-7).

These mutations impair V-ATPase assembly and function, leading to:
- Recurrent bacterial infections due to impaired B-cell differentiation and immunoglobulin production
- Hepatopathy ranging from hypertransaminasemia to cirrhosis
- Abnormal protein glycosylation affecting multiple organ systems
- Neurocognitive impairment in some patients

Granular Cell Tumors

Somatic inactivating mutations in ATP6AP1 (or ATP6AP2) act as oncogenic drivers in 72% of granular cell tumors (GCTs) (pareja2018lossoffunctionmutationsin pages 1-2). These loss-of-function mutations (nonsense, frameshift, splice-site, or in-frame deletions) impair vesicle acidification, cause redistribution of endosomal compartments, and lead to accumulation of characteristic intracytoplasmic granules. Silencing ATP6AP1 or ATP6AP2 in vitro recapitulates GCT phenotypes and results in acquisition of oncogenic properties, providing a direct genetic link between endosomal pH regulation and tumorigenesis (pareja2018lossoffunctionmutationsin pages 1-2).

Summary

ATP6AP1 is an essential accessory protein of the V-ATPase complex that functions primarily as an assembly factor and structural hub within the V0 membrane domain. While it does not itself catalyze ATP hydrolysis or directly translocate protons, ATP6AP1 is indispensable for V-ATPase biogenesis, stability, and full proton-pumping activity. The protein contains a transmembrane helix and a LAMP-like luminal domain that coordinates multiple V0 subunits and lipids inside the c-ring.

ATP6AP1 localizes to endolysosomal membranes, Golgi apparatus, secretory vesicles, and specialized plasma membrane domains where it maintains organellar acidification essential for autophagy-lysosomal degradation, protein glycosylation, endocytic trafficking, and nutrient sensing. Recent work (2024-2025) has identified ATP6AP1 as a critical regulator of autophagy that promotes both lysosomal acidification and autophagosome-lysosome fusion through Rab7-HOPS interaction, establishing it as a therapeutic vulnerability in chemoresistant cancers.

Disease-causing mutations in ATP6AP1 result in immunodeficiency syndromes and contribute to tumor development through impaired organellar pH homeostasis. The convergence of structural biology, disease genetics, and translational cancer research positions ATP6AP1 as an important node in cellular pH regulation with significant implications for human health and disease.

References

(abbas2020structureofvatpase pages 1-2): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(wang2020structuresofa pages 1-3): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(jansen2016atp6ap1deficiencycauses pages 1-2): Eric J. R. Jansen, Sharita Timal, Margret Ryan, Angel Ashikov, Monique van Scherpenzeel, Laurie A. Graham, Hanna Mandel, Alexander Hoischen, Theodore C. Iancu, Kimiyo Raymond, Gerry Steenbergen, Christian Gilissen, Karin Huijben, Nick H. M. van Bakel, Yusuke Maeda, Richard J. Rodenburg, Maciej Adamowicz, Ellen Crushell, Hans Koenen, Darius Adams, Julia Vodopiutz, Susanne Greber-Platzer, Thomas Müller, Gregor Dueckers, Eva Morava, Jolanta Sykut-Cegielska, Gerard J. M. Martens, Ron A. Wevers, Tim Niehues, Martijn A. Huynen, Joris A. Veltman, Tom H. Stevens, and Dirk J. Lefeber. Atp6ap1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. Nature Communications, May 2016. URL: https://doi.org/10.1038/ncomms11600, doi:10.1038/ncomms11600. This article has 159 citations and is from a highest quality peer-reviewed journal.
(abbas2020structureofvatpase pages 4-5): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(holliday2014vacuolarh+atpasean pages 2-3): L. Shannon Holliday. Vacuolar h+-atpase: an essential multitasking enzyme in physiology and pathophysiology. New Journal of Science, 2014:1-21, Jan 2014. URL: https://doi.org/10.1155/2014/675430, doi:10.1155/2014/675430. This article has 59 citations.
(guida2018atp6ap2functionsas pages 1-5): Maria Clara Guida, Tobias Hermle, Laurie A. Graham, Virginie Hauser, Margret Ryan, Tom H. Stevens, and Matias Simons. Atp6ap2 functions as a v-atpase assembly factor in the endoplasmic reticulum. Sep 2018. URL: https://doi.org/10.1091/mbc.e18-04-0234, doi:10.1091/mbc.e18-04-0234. This article has 41 citations and is from a domain leading peer-reviewed journal.
(guida2018atp6ap2functionsas pages 5-8): Maria Clara Guida, Tobias Hermle, Laurie A. Graham, Virginie Hauser, Margret Ryan, Tom H. Stevens, and Matias Simons. Atp6ap2 functions as a v-atpase assembly factor in the endoplasmic reticulum. Sep 2018. URL: https://doi.org/10.1091/mbc.e18-04-0234, doi:10.1091/mbc.e18-04-0234. This article has 41 citations and is from a domain leading peer-reviewed journal.
(wang2020structuresofa pages 3-5): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(wang2020structuresofa pages 5-7): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(pareja2018lossoffunctionmutationsin pages 1-2): Fresia Pareja, Alissa H. Brandes, Thais Basili, Pier Selenica, Felipe C. Geyer, Dan Fan, Arnaud Da Cruz Paula, Rahul Kumar, David N. Brown, Rodrigo Gularte-Mérida, Barbara Alemar, Rui Bi, Raymond S. Lim, Ino de Bruijn, Sho Fujisawa, Rui Gardner, Elvin Feng, Anqi Li, Edaise M. da Silva, John R. Lozada, Pedro Blecua, Leona Cohen-Gould, Achim A. Jungbluth, Emad A. Rakha, Ian O. Ellis, Maria I. A. Edelweiss, Juan Palazzo, Larry Norton, Travis Hollmann, Marcia Edelweiss, Brian P. Rubin, Britta Weigelt, and Jorge S. Reis-Filho. Loss-of-function mutations in atp6ap1 and atp6ap2 in granular cell tumors. Nature Communications, Aug 2018. URL: https://doi.org/10.1038/s41467-018-05886-y, doi:10.1038/s41467-018-05886-y. This article has 154 citations and is from a highest quality peer-reviewed journal.
(fei2024lysosomalgeneatp6ap1 pages 1-2): Yin-Jiao Fei, Xueqin Yan, Mingxing Liang, Shu Zhou, Di Xu, Lei Li, Weilin Xu, Yuxin Song, Zhen Zhu, and Jian Zhang. Lysosomal gene atp6ap1 promotes doxorubicin resistance via up-regulating autophagic flux in breast cancer. Cancer Cell International, Dec 2024. URL: https://doi.org/10.1186/s12935-024-03579-9, doi:10.1186/s12935-024-03579-9. This article has 8 citations and is from a peer-reviewed journal.
(fei2024lysosomalgeneatp6ap1 pages 2-4): Yin-Jiao Fei, Xueqin Yan, Mingxing Liang, Shu Zhou, Di Xu, Lei Li, Weilin Xu, Yuxin Song, Zhen Zhu, and Jian Zhang. Lysosomal gene atp6ap1 promotes doxorubicin resistance via up-regulating autophagic flux in breast cancer. Cancer Cell International, Dec 2024. URL: https://doi.org/10.1186/s12935-024-03579-9, doi:10.1186/s12935-024-03579-9. This article has 8 citations and is from a peer-reviewed journal.
(yan2025atp6ap1promotescell pages 1-2): Zhengwei Yan, Aidi Huang, Dongwen Ma, Chenao Hong, Shengmiao Zhang, Luling He, Hai Rao, and Shiwen Luo. Atp6ap1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy. Cell Death & Disease, Mar 2025. URL: https://doi.org/10.1038/s41419-025-07534-y, doi:10.1038/s41419-025-07534-y. This article has 6 citations and is from a peer-reviewed journal.
(yan2025atp6ap1promotescell pages 2-4): Zhengwei Yan, Aidi Huang, Dongwen Ma, Chenao Hong, Shengmiao Zhang, Luling He, Hai Rao, and Shiwen Luo. Atp6ap1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy. Cell Death & Disease, Mar 2025. URL: https://doi.org/10.1038/s41419-025-07534-y, doi:10.1038/s41419-025-07534-y. This article has 6 citations and is from a peer-reviewed journal.
(song2020theemergingroles pages 1-2): Qiaoyun Song, Bo Meng, Haidong Xu, and Zixu Mao. The emerging roles of vacuolar-type atpase-dependent lysosomal acidification in neurodegenerative diseases. Translational Neurodegeneration, May 2020. URL: https://doi.org/10.1186/s40035-020-00196-0, doi:10.1186/s40035-020-00196-0. This article has 255 citations and is from a domain leading peer-reviewed journal.
(jansen2016atp6ap1deficiencycauses pages 2-3): Eric J. R. Jansen, Sharita Timal, Margret Ryan, Angel Ashikov, Monique van Scherpenzeel, Laurie A. Graham, Hanna Mandel, Alexander Hoischen, Theodore C. Iancu, Kimiyo Raymond, Gerry Steenbergen, Christian Gilissen, Karin Huijben, Nick H. M. van Bakel, Yusuke Maeda, Richard J. Rodenburg, Maciej Adamowicz, Ellen Crushell, Hans Koenen, Darius Adams, Julia Vodopiutz, Susanne Greber-Platzer, Thomas Müller, Gregor Dueckers, Eva Morava, Jolanta Sykut-Cegielska, Gerard J. M. Martens, Ron A. Wevers, Tim Niehues, Martijn A. Huynen, Joris A. Veltman, Tom H. Stevens, and Dirk J. Lefeber. Atp6ap1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. Nature Communications, May 2016. URL: https://doi.org/10.1038/ncomms11600, doi:10.1038/ncomms11600. This article has 159 citations and is from a highest quality peer-reviewed journal.
(kinouchi2013theroleof pages 1-2): Kenichiro Kinouchi, Atsuhiro Ichihara, Motoaki Sano, Ge-Hong Sun-Wada, Yoh Wada, Hiroki Ochi, Toru Fukuda, Kanako Bokuda, Hideaki Kurosawa, Naohiro Yoshida, Shu Takeda, Keiichi Fukuda, and Hiroshi Itoh. The role of individual domains and the significance of shedding of atp6ap2/(pro)renin receptor in vacuolar h+-atpase biogenesis. PLoS ONE, 8:e78603, Nov 2013. URL: https://doi.org/10.1371/journal.pone.0078603, doi:10.1371/journal.pone.0078603. This article has 53 citations and is from a peer-reviewed journal.
(holliday2014vacuolarh+atpasean pages 1-2): L. Shannon Holliday. Vacuolar h+-atpase: an essential multitasking enzyme in physiology and pathophysiology. New Journal of Science, 2014:1-21, Jan 2014. URL: https://doi.org/10.1155/2014/675430, doi:10.1155/2014/675430. This article has 59 citations.

📚 Additional Documentation

Notes

(ATP6AP1-notes.md)

ATP6AP1 notes

2026-06-03 Proteostasis PN review

Deep research status: Falcon deep research has now completed successfully (ATP6AP1-deep-research-falcon.md, 19 citations); see the synthesis section at the end of this file. The original PN-batch attempt timed out before the deep_research_unified tool bugs were fixed. This review uses that report together with the fetched UniProt and GOA records, cached publications, local Reactome entries, and the PN projection report.

Core function synthesis: ATP6AP1/Ac45 is best reviewed as an accessory/regulatory V0-sector subunit of the V-ATPase that supports complex assembly, targeting, stability, and activity rather than as a catalytic proton pump subunit. Human V-ATPase structure work defines ATP6AP1 as a V0 assembly hub PMID:33065002. The human deficiency study supports an Ac45/Voa1-like assembly-factor role and shows disease mutants fail to restore V-ATPase-dependent growth in yeast PMID:27231034.

Localization/function context: Ac45 localizes mainly to the ER and ERGIC in hepatocytes, not predominantly to the TGN or endosomal system in that experiment PMID:27231034. Mature V-ATPase activity is nevertheless central to endolysosomal and secretory-compartment acidification, and Reactome represents ATP6AP1 as an accessory V0 subunit facilitating acidification [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"].

PN projection decision: the PN projection reports GO:0007042 lysosomal lumen acidification as already present in GOA and projects ATP6AP1 to GO:0060590 ATPase regulator activity [file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv "ATPase regulator activity is the narrowest GO target that preserves the source mechanism without requiring a speculative complex-specific term."]. I accepted the lysosomal acidification projection as already supported and added GO:0060590 conservatively as a new reviewed MF term, using the same evidence to modify the broad GO:0140677 molecular function activator activity row.

Conservative exclusions: generic GO:0005515 protein binding rows were marked over-annotated because they do not describe the ATP6AP1 molecular function. Direct GO:0031267 small GTPase binding rows were removed because the key mTORC1 paper supports V-ATPase-dependent Rag nucleotide loading but did not detect direct Rag interactions with purified V-ATPase subunits PMID:22053050. HIF/iron and broad trafficking terms were kept as non-core secondary consequences where supported PMID:28296633.

Falcon deep research synthesis (2026-06-21)

The Falcon report (file:human/ATP6AP1/ATP6AP1-deep-research-falcon.md) is fully
consistent with the assembly-factor / structural-hub framing above and adds
structural and pathway detail. Citations use the report's DOIs except where a
PMID is already established in this file.

Structural confirmation of the V0 hub role (Wang et al. 2020, Mol Cell 80:501,
doi:10.1016/j.molcel.2020.09.029; the "structural hub" finding already cited here
as PMID:33065002). The cryo-EM structure shows ATP6AP1's luminal domain adopts a
β-prism fold homologous to LAMP-family domains (despite no sequence homology),
sits centrally inside the c-ring, and is the most connected V0 subunit
(>7,000 Å² buried surface), contacting ATP6AP2, c'', c(1/2/8/9) and subunit d.
This directly supports the assembly/stability MF over any catalytic role and
explains, at residue level, why disease mutations are loss-of-function: Y313C
destabilizes the luminal hydrophobic core, E346K disrupts a luminal salt bridge,
M428I perturbs TM contacts with the c-ring.

Cooperative V0 assembly with ATP6AP2 (Guida et al. 2018,
doi:10.1091/mbc.e18-04-0234). ATP6AP1 and ATP6AP2/(pro)renin receptor together
act as ER V0 assembly factors replacing the single yeast Voa1 function;
co-expression rescues V-ATPase-defective yeast and restores vacuolar quinacrine
accumulation. Relevant context for the neighboring ATP6AP2 review.

Autophagy linkage (non-core, recent/translational). Fei et al. 2024
(doi:10.1016/... breast-cancer lysosomal-gene study) and Yan et al. 2025 report
that ATP6AP1 supports autophagic flux via lysosomal acidification and, newly,
promotes autophagosome-lysosome fusion by enhancing Rab7-HOPS interaction;
overexpression drives chemoresistance. These are downstream/disease-context roles
and should remain non-core relative to the V0 assembly MF, but the Rab7-HOPS
fusion link is worth flagging as a candidate ALP-branch secondary function if it
is independently corroborated.

Other corroborated points (no change to calls): ER assembly then trafficking
to endolysosomes, Golgi (glycosylation), neuroendocrine secretory vesicles, and
osteoclast ruffled border; tissue-specific proteolytic processing (~40 kDa brain,
62 kDa liver, ~50 kDa B cells); V-ATPase-dependent (structural, not pump-direct)
role in mTORC1 amino-acid sensing. Net: no change to the core call (accessory V0
assembly/structural-hub subunit; GO:0060590 ATPase regulator activity + lysosomal
acidification), with strengthened structural justification.

Pn Notes

(ATP6AP1-pn-notes.md)

ATP6AP1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q15904
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1383)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6AP1/ATP6AP1-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6AP1/ATP6AP1-ai-review.html
Gene notes: present - genes/human/ATP6AP1/ATP6AP1-notes.md
GOA TSV: present - genes/human/ATP6AP1/ATP6AP1-goa.tsv
UniProt record: present - genes/human/ATP6AP1/ATP6AP1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6AP1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6AP1.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

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: ATP6AP1 encodes V-type proton ATPase subunit S1, also known as Ac45, a single-pass glycoprotein accessory subunit of the vacuolar H+-ATPase. It is synthesized in the secretory pathway, localizes prominently to the ER and ER-Golgi intermediate compartment in hepatocytes, and is incorporated into the V0 sector of mature V-ATPase complexes in endolysosomal and specialized secretory membranes. ATP6AP1 supports V-ATPase assembly, targeting, stability, and activity, thereby contributing to acidification of lysosomes, endosomes, Golgi/secretory compartments, and specialized plasma-membrane domains. Through the lysosomal V-ATPase-Ragulator machinery it contributes to amino-acid-dependent mTORC1 signaling, and disruption of V-ATPase function secondarily affects iron handling and HIF1alpha regulation. Pathogenic ATP6AP1 variants cause an X-linked disorder with immunodeficiency, hepatopathy, cognitive or neurologic features, and abnormal protein glycosylation, consistent with tissue-specific defects in V-ATPase assembly and organelle homeostasis.
Existing/core annotation action counts: ACCEPT: 26; KEEP_AS_NON_CORE: 13; MARK_AS_OVER_ANNOTATED: 11; MODIFY: 2; NEW: 1; REMOVE: 2

PN Consistency Summary

Consistency: Deep research/notes, review, and PN agree: ATP6AP1/Ac45 is an accessory V0 assembly-hub/regulatory subunit (PMID:33065002, PMID:27231034). Review adds GO:0060590 (action NEW, IC) and ACCEPTs GO:0007042 — exactly matching both PN projections. Verified: GO:0060590 absent from goa.tsv (genuinely new); GO:0007042 present (NAS, ComplexPortal) confirming "already_in_goa_exact". No contradictions.
PN story / NEW pressure: PN asserts a regulator MF not previously in GOA. Review correctly converts the legacy GO:0140677 (molecular function activator activity) → GO:0060590 and adds it as NEW core MF. GO:0060590 is a real term and the conservative right target (vs. uninformative protein binding, six of which are MARK_AS_OVER_ANNOTATED). ADD GO:0060590 — implemented.
Evidence alignment: PN cites one title (Translational Neurodegeneration V-ATPase/lysosomal acidification review); review's supporting PMIDs (33065002 structural, 27231034 disease/localization, 22053050 mTORC1) are stronger and fully cover the claims. Minor: PN's single secondary-review citation is thinner than the review's primary set, but no conflict.
Verdict: CONSISTENT — NEW GO:0060590 (verified real) appropriately added; PN leaf and acidification mappings align with review. No edits required.

Full Consistency Review

UniProt: Q15904 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
PN placement: two rows, both leaf "Regulator of the lysosomal v-ATPase proton pump": (1) ALP|Pre-initiation autophagy signaling|mTORC1 upstream|Nutrient sensing|... and (2) ALP|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|.... PN-node mapping: leaves = mapped, GO:0060590 ATPase regulator activity (new_to_goa); plus type-node GO:0007042 lysosomal lumen acidification (already_in_goa_exact).
Consistency: Deep research/notes, review, and PN agree: ATP6AP1/Ac45 is an accessory V0 assembly-hub/regulatory subunit (PMID:33065002, PMID:27231034). Review adds GO:0060590 (action NEW, IC) and ACCEPTs GO:0007042 — exactly matching both PN projections. Verified: GO:0060590 absent from goa.tsv (genuinely new); GO:0007042 present (NAS, ComplexPortal) confirming "already_in_goa_exact". No contradictions.
PN story / NEW pressure: PN asserts a regulator MF not previously in GOA. Review correctly converts the legacy GO:0140677 (molecular function activator activity) → GO:0060590 and adds it as NEW core MF. GO:0060590 is a real term and the conservative right target (vs. uninformative protein binding, six of which are MARK_AS_OVER_ANNOTATED). ADD GO:0060590 — implemented.
Mapping strategy: Gene meaningfully supports the leaf mapping (it is the archetypal "regulator of lysosomal V-ATPase"). Projected GO:0060590 is neither broader nor narrower than the review's chosen core MF — they coincide. GO:0007042 type-node projection matches existing GOA. Mapping is appropriate; no change.
Evidence alignment: PN cites one title (Translational Neurodegeneration V-ATPase/lysosomal acidification review); review's supporting PMIDs (33065002 structural, 27231034 disease/localization, 22053050 mTORC1) are stronger and fully cover the claims. Minor: PN's single secondary-review citation is thinner than the review's primary set, but no conflict.
Verdict: CONSISTENT — NEW GO:0060590 (verified real) appropriately added; PN leaf and acidification mappings align with review. No edits required.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ATP6AP1/ATP6AP1-ai-review.yaml
PN workbook rows: 2

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

UniProt: Q15904
In branches: ALP
Notes: Adapter protein for v-ATPase and its regulators
PN references (titles):
- 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|Regulator of the lysosomal v-ATPase proton pump
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0060590 ATPase regulator activity]
  rationale: This PN leaf contains ATP6AP-family regulators of the lysosomal V-ATPase. ATPase regulator activity is the safe shared molecular-function 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 | Regulator of the lysosomal v-ATPase proton pump

UniProt: Q15904
In branches: ALP
Notes: Adapter protein for v-ATPase and its regulators
PN references (titles):
- 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|Regulator of the lysosomal v-ATPase proton pump
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0060590 ATPase regulator activity]
  rationale: This PN subtype is a regulator of the lysosomal V-ATPase proton pump. ATPase regulator activity is the narrowest GO target that preserves the source mechanism without requiring a speculative complex-specific term.
- [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:0060590 ATPase regulator activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|Regulator of the lysosomal v-ATPase proton pump
GO:0007042 lysosomal lumen acidification | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
GO:0060590 ATPase regulator activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|Regulator of the lysosomal v-ATPase proton pump

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: Q15904
gene_symbol: ATP6AP1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ATP6AP1 encodes V-type proton ATPase subunit S1, also known as Ac45, a single-pass glycoprotein accessory
  subunit of the vacuolar H+-ATPase. It is synthesized in the secretory pathway, localizes prominently to the ER and
  ER-Golgi intermediate compartment in hepatocytes, and is incorporated into the V0 sector of mature V-ATPase complexes
  in endolysosomal and specialized secretory membranes. ATP6AP1 supports V-ATPase assembly, targeting, stability, and
  activity, thereby contributing to acidification of lysosomes, endosomes, Golgi/secretory compartments, and specialized
  plasma-membrane domains. Through the lysosomal V-ATPase-Ragulator machinery it contributes to amino-acid-dependent
  mTORC1 signaling, and disruption of V-ATPase function secondarily affects iron handling and HIF1alpha regulation.
  Pathogenic ATP6AP1 variants cause an X-linked disorder with immunodeficiency, hepatopathy, cognitive or neurologic
  features, and abnormal protein glycosylation, consistent with tissue-specific defects in V-ATPase assembly and
  organelle homeostasis.
existing_annotations:
- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Accept V-type ATPase complex membership. ATP6AP1/Ac45 is an accessory V0-associated subunit and structural
      hub of the mature human V-ATPase.
    action: ACCEPT
    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.
    additional_reference_ids:
    - PMID:33065002
    - PMID:27231034
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
    - reference_id: PMID:27231034
      supporting_text: Processed wild-type Ac45, but not its disease mutants, restored V-ATPase-dependent growth in Voa1
        mutant yeast.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Accept ER membrane localization. Human hepatocyte immunostaining places Ac45 mainly in the ER and ERGIC.
    action: ACCEPT
    reason: This UniProt-location-derived annotation is supported by direct immunostaining in human hepatocytes and by
      the Voa1 assembly-factor model in the ER.
    additional_reference_ids:
    - PMID:27231034
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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
- term:
    id: GO:0012505
    label: endomembrane system
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:27231034
    - PMID:33065002
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:0030659
    label: cytoplasmic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:27231034
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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.
- term:
    id: GO:0030665
    label: clathrin-coated vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Clathrin-coated vesicle membrane localization is retained as a non-core location inferred from UniProt
      subcellular mapping and vesicle-trafficking context.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:27231034
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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.
- term:
    id: GO:0030672
    label: synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Synaptic vesicle membrane localization is plausible by similarity and neuroendocrine vesicle biology, but
      should be non-core for the human gene review.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:27231034
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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.
- term:
    id: GO:0033116
    label: endoplasmic reticulum-Golgi intermediate compartment membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Accept ERGIC membrane localization. Human hepatocyte immunostaining directly localized Ac45 to ER and
      ERGIC.
    action: ACCEPT
    reason: This is a directly supported early-secretory-pathway location and fits the V0 assembly-factor role of
      ATP6AP1/Ac45.
    additional_reference_ids:
    - PMID:27231034
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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
- term:
    id: GO:0098588
    label: bounding membrane of organelle
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Bounding membrane of organelle is technically consistent with ATP6AP1 membrane localization but is too
      broad to add biological value.
    action: MARK_AS_OVER_ANNOTATED
    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.
    additional_reference_ids:
    - PMID:27231034
    - PMID:33065002
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32353859
  qualifier: enables
  review:
    summary: The reported physical interaction is retained only as interaction context; generic protein binding is not
      an informative ATP6AP1 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: The reported physical interaction is retained only as interaction context; generic protein binding is not
      an informative ATP6AP1 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome maps are valuable resources to elucidate protein function and disease mechanisms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33060197
  qualifier: enables
  review:
    summary: The reported physical interaction is retained only as interaction context; generic protein binding is not
      an informative ATP6AP1 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33845483
  qualifier: enables
  review:
    summary: The reported physical interaction is retained only as interaction context; generic protein binding is not
      an informative ATP6AP1 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34232536
  qualifier: enables
  review:
    summary: The reported physical interaction is retained only as interaction context; generic protein binding is not
      an informative ATP6AP1 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34997207
  qualifier: enables
  review:
    summary: The reported physical interaction is retained only as interaction context; generic protein binding is not
      an informative ATP6AP1 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Accept endosome membrane activity context for ATP6AP1-containing V-ATPase.
    action: ACCEPT
    reason: Endosomal V-ATPase activity acidifies endosomal lumen and supports membrane trafficking; ATP6AP1 is a V0
      accessory subunit of the same complex.
    additional_reference_ids:
    - Reactome:R-HSA-74723
    - PMID:33065002
    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:33065002
      supporting_text: 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
- term:
    id: GO:0031267
    label: small GTPase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    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.
    action: REMOVE
    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.
    additional_reference_ids:
    - PMID:22053050
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: Ragulator provides a physical and functional link between the v-ATPase and the Rag GTPases.
    - reference_id: PMID:22053050
      supporting_text: No direct interactions were detected between the Rag GTPases and purified v-ATPase subunits
- term:
    id: GO:0036035
    label: osteoclast development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Keep osteoclast development as a non-core, orthology-derived tissue context.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:27231034
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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.
- term:
    id: GO:0046611
    label: lysosomal proton-transporting V-type ATPase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: Accept lysosomal V-type ATPase complex membership.
    action: ACCEPT
    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.
    additional_reference_ids:
    - PMID:33065002
    - Reactome:R-HSA-5252133
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
    - reference_id: Reactome:R-HSA-5252133
      supporting_text: V-type proton ATPase subunit S1 (ATP6AP1) is thought to function as an accessory subunit of the
        V0 subcomplex of V-ATPase, facilitating acidification
- term:
    id: GO:0097401
    label: synaptic vesicle lumen acidification
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Keep synaptic vesicle lumen acidification as a non-core, tissue-specific V-ATPase context.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:27231034
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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.
- term:
    id: GO:0099638
    label: endosome to plasma membrane protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Keep endosome-to-plasma-membrane protein transport as a non-core trafficking consequence of
      ATP6AP1/V-ATPase function.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:27231034
    - PMID:33065002
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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.
    - reference_id: PMID:33065002
      supporting_text: 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
- term:
    id: GO:0140677
    label: molecular function activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0060590
      label: ATPase regulator activity
    additional_reference_ids:
    - PMID:27231034
    - PMID:33065002
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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.
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:1904263
    label: positive regulation of TORC1 signaling
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Accept positive regulation of TORC1 signaling as an ATP6AP1/V-ATPase nutrient-sensing process.
    action: ACCEPT
    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.
    additional_reference_ids:
    - PMID:22053050
    - PMID:33065002
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and
        the nucleotide loading of the Rag GTPases.
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: is_active_in
  review:
    summary: Accept lysosomal membrane active-in annotation for the ATP6AP1-containing V-ATPase in mTORC1 amino-acid
      sensing.
    action: ACCEPT
    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.
    additional_reference_ids:
    - PMID:22053050
    - PMID:33065002
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and
        the nucleotide loading of the Rag GTPases.
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:0046611
    label: lysosomal proton-transporting V-type ATPase complex
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: part_of
  review:
    summary: Accept lysosomal V-type ATPase complex membership.
    action: ACCEPT
    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.
    additional_reference_ids:
    - PMID:22053050
    - PMID:33065002
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and
        the nucleotide loading of the Rag GTPases.
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:0071230
    label: cellular response to amino acid stimulus
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: involved_in
  review:
    summary: Accept cellular response to amino-acid stimulus through lysosomal V-ATPase/mTORC1 signaling.
    action: ACCEPT
    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.
    additional_reference_ids:
    - PMID:22053050
    - PMID:33065002
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and
        the nucleotide loading of the Rag GTPases.
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:0160124
    label: guanyl nucleotide exchange factor activator activity
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: contributes_to
  review:
    summary: Accept contributes_to guanyl nucleotide exchange factor activator activity for the V-ATPase/Ragulator
      system.
    action: ACCEPT
    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.'
    additional_reference_ids:
    - PMID:22053050
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and
        the nucleotide loading of the Rag GTPases.
    - reference_id: PMID:22053050
      supporting_text: Ragulator provides a physical and functional link between the v-ATPase and the Rag GTPases.
- term:
    id: GO:1904263
    label: positive regulation of TORC1 signaling
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Accept orthology-supported positive regulation of TORC1 signaling.
    action: ACCEPT
    reason: This ISS annotation matches direct human V-ATPase evidence from the amino-acid sensing pathway and is
      consistent with ATP6AP1 complex membership.
    additional_reference_ids:
    - PMID:22053050
    - PMID:33065002
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and
        the nucleotide loading of the Rag GTPases.
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:1904263
    label: positive regulation of TORC1 signaling
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: involved_in
  review:
    summary: Accept direct evidence for positive regulation of TORC1 signaling by the ATP6AP1-containing V-ATPase
      system.
    action: ACCEPT
    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.
    additional_reference_ids:
    - PMID:22053050
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and
        the nucleotide loading of the Rag GTPases.
    - reference_id: PMID:22053050
      supporting_text: Ragulator provides a physical and functional link between the v-ATPase and the Rag GTPases.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: Golgi membrane localization is plausible for V-ATPase biology, but this protein-specific location is less
      directly supported than the Golgi acidification process.
    action: MARK_AS_OVER_ANNOTATED
    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.
    additional_reference_ids:
    - PMID:27231034
    - PMID:32001091
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton
        pumps.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: Accept lysosomal membrane localization for ATP6AP1-containing V-ATPase.
    action: ACCEPT
    reason: V-ATPases are central endolysosomal proton pumps, and ATP6AP1 is a structural V0-associated hub in human
      V-ATPase.
    additional_reference_ids:
    - PMID:32001091
    - PMID:33065002
    supported_by:
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton
        pumps.
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: Keep plasma membrane localization as a non-core specialized V-ATPase context.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:27231034
    - PMID:33065002
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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.
    - reference_id: PMID:33065002
      supporting_text: 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
- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Accept vacuolar acidification as the broad V-ATPase acidification process.
    action: ACCEPT
    reason: ATP6AP1 is an accessory V-ATPase subunit. V-ATPases are ATP-driven proton pumps that acidify intracellular
      vesicles and organelles.
    additional_reference_ids:
    - PMID:32001091
    - PMID:33065002
    supported_by:
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton
        pumps.
    - reference_id: PMID:33065002
      supporting_text: 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.
- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Accept lysosomal lumen acidification. This is the existing GOA term that the PN projection already
      recognizes as an exact match.
    action: ACCEPT
    reason: V-ATPase establishes lysosomal pH homeostasis, and ATP6AP1 is part of the human V-ATPase assembly/function
      machinery.
    additional_reference_ids:
    - PMID:33065002
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: 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
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: Accept lysosomal lumen acidification based on structural evidence for ATP6AP1 in human V-ATPase.
    action: ACCEPT
    reason: The structural study defines ATP6AP1 as a Vo assembly hub in an ATP-driven proton pump that maintains
      lysosomal and endosomal pH.
    additional_reference_ids:
    - PMID:33065002
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: 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.
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: Accept endosome membrane localization for ATP6AP1-containing V-ATPase.
    action: ACCEPT
    reason: Endosomal pH homeostasis is a core V-ATPase function, and Reactome also places ATP6AP1-associated V-ATPase
      in endosome acidification events.
    additional_reference_ids:
    - PMID:33065002
    - Reactome:R-HSA-74723
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: 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
    - 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.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:33065002
  qualifier: located_in
  review:
    summary: Membrane is true for ATP6AP1 but too broad to be useful.
    action: MARK_AS_OVER_ANNOTATED
    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.
    additional_reference_ids:
    - PMID:33065002
    - PMID:27231034
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
    - reference_id: PMID:27231034
      supporting_text: 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
- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: part_of
  review:
    summary: Accept V-type ATPase complex membership from human structural data.
    action: ACCEPT
    reason: Cryo-EM and mass-spectrometry-supported modeling place ATP6AP1 within the complete human V-ATPase as a
      structural hub for Vo assembly.
    additional_reference_ids:
    - PMID:33065002
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:0048388
    label: endosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Accept endosomal lumen acidification.
    action: ACCEPT
    reason: Endosomal acidification is a core V-ATPase process and Reactome describes proton entry into the endosome
      lumen.
    additional_reference_ids:
    - PMID:33065002
    - Reactome:R-HSA-74723
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: 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
    - 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.
- term:
    id: GO:0051452
    label: intracellular pH reduction
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Intracellular pH reduction is a true but broad consequence of V-ATPase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: More specific organelle-acidification annotations already capture ATP6AP1/V-ATPase biology. The generic
      intracellular pH term is less useful for PN propagation.
    additional_reference_ids:
    - PMID:33065002
    - PMID:32001091
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: 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.
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton
        pumps.
- term:
    id: GO:0061795
    label: Golgi lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Accept Golgi lumen acidification as a V-ATPase-dependent process with disease relevance to ATP6AP1
      glycosylation defects.
    action: ACCEPT
    reason: ATP6AP1 deficiency causes abnormal protein glycosylation, consistent with defective organelle/Golgi
      homeostasis; V-ATPase acidifies the Golgi apparatus.
    additional_reference_ids:
    - PMID:27231034
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: Accept proton transmembrane transport as the process mediated by the ATP6AP1-containing V-ATPase complex.
    action: ACCEPT
    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.
    additional_reference_ids:
    - PMID:33065002
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: 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.
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:27231034
  qualifier: located_in
  review:
    summary: Accept experimentally supported ER membrane localization.
    action: ACCEPT
    reason: Human hepatocyte immunostaining directly localizes Ac45 mainly to ER and ERGIC, consistent with its V0
      assembly-factor role.
    additional_reference_ids:
    - PMID:27231034
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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
- term:
    id: GO:0033116
    label: endoplasmic reticulum-Golgi intermediate compartment membrane
  evidence_type: EXP
  original_reference_id: PMID:27231034
  qualifier: located_in
  review:
    summary: Accept experimentally supported ERGIC membrane localization.
    action: ACCEPT
    reason: Human hepatocyte immunostaining directly localizes Ac45 to ER and ERGIC and not to TGN or endosomal system
      markers in that assay.
    additional_reference_ids:
    - PMID:27231034
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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
- term:
    id: GO:0036035
    label: osteoclast development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Keep osteoclast development as a non-core orthology-derived context.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:27231034
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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.
- term:
    id: GO:0099638
    label: endosome to plasma membrane protein transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Keep endosome-to-plasma-membrane protein transport as a non-core trafficking context.
    action: KEEP_AS_NON_CORE
    reason: ATP6AP1/V-ATPase biology includes membrane trafficking and endolysosomal acidification, but this process is
      secondary to the core complex/regulatory functions.
    additional_reference_ids:
    - PMID:27231034
    - PMID:33065002
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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.
    - reference_id: PMID:33065002
      supporting_text: 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
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29127204
  qualifier: enables
  review:
    summary: ATP6AP1-ATP6AP2 physical interaction is biologically relevant to V0 assembly, but protein binding is not an
      informative GO molecular function.
    action: MARK_AS_OVER_ANNOTATED
    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.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - reference_id: PMID:29127204
      supporting_text: Finally, both ATP6AP2 mutations impaired protein stability and the interaction with ATP6AP1, a
        member of the V0 assembly complex.
- term:
    id: GO:0006879
    label: intracellular iron ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:28296633
  qualifier: involved_in
  review:
    summary: Keep intracellular iron ion homeostasis as a supported non-core consequence of V-ATPase disruption.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:28296633
    supported_by:
    - reference_id: PMID:28296633
      supporting_text: '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'
    - reference_id: PMID:28296633
      supporting_text: disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity
        and leading to HIF activation.
- term:
    id: GO:0036295
    label: cellular response to increased oxygen levels
  evidence_type: IMP
  original_reference_id: PMID:28296633
  qualifier: involved_in
  review:
    summary: Keep cellular response to increased oxygen levels as a non-core downstream HIF/iron consequence.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:28296633
    supported_by:
    - reference_id: PMID:28296633
      supporting_text: disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity
        and leading to HIF activation.
- term:
    id: GO:0031267
    label: small GTPase binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    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.'
    action: REMOVE
    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.
    additional_reference_ids:
    - PMID:22053050
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and
        the nucleotide loading of the Rag GTPases.
    - reference_id: PMID:22053050
      supporting_text: No direct interactions were detected between the Rag GTPases and purified v-ATPase subunits
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252133
  qualifier: located_in
  review:
    summary: Accept endosome membrane context for the Reactome ATP6AP1-binds-V-ATPase event.
    action: ACCEPT
    reason: Reactome places ATP6AP1 as an accessory V0 subunit facilitating V-ATPase acidification; endosomal V-ATPase
      acidification is also directly described in Reactome events.
    additional_reference_ids:
    - Reactome:R-HSA-5252133
    - Reactome:R-HSA-74723
    supported_by:
    - reference_id: Reactome:R-HSA-5252133
      supporting_text: V-type proton ATPase subunit S1 (ATP6AP1) is thought to function as an accessory subunit of the
        V0 subcomplex of V-ATPase, facilitating acidification
    - 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.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74723
  qualifier: located_in
  review:
    summary: Accept endosome membrane for the Reactome endosome acidification event.
    action: ACCEPT
    reason: Reactome describes proton entry into the endosome lumen by the proton pump; ATP6AP1 is curated in the
      associated V-ATPase event.
    additional_reference_ids:
    - Reactome:R-HSA-74723
    - Reactome:R-HSA-5252133
    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: Reactome:R-HSA-5252133
      supporting_text: V-type proton ATPase subunit S1 (ATP6AP1) is thought to function as an accessory subunit of the
        V0 subcomplex of V-ATPase, facilitating acidification
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917841
  qualifier: located_in
  review:
    summary: Accept endosome membrane for transferrin-receptor endosome acidification context.
    action: ACCEPT
    reason: Reactome describes V-ATPase-driven proton movement in the endocytic compartment; ATP6AP1 complex membership
      supports its placement in this context.
    additional_reference_ids:
    - Reactome:R-HSA-917841
    - Reactome:R-HSA-74723
    - PMID:33065002
    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:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: Keep extracellular exosome as a non-core high-throughput localization.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - PMID:19056867
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: 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.
- term:
    id: GO:0016469
    label: proton-transporting two-sector ATPase complex
  evidence_type: TAS
  original_reference_id: PMID:8733135
  qualifier: part_of
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0033176
      label: proton-transporting V-type ATPase complex
    - id: GO:0046611
      label: lysosomal proton-transporting V-type ATPase complex
    additional_reference_ids:
    - PMID:33065002
    - PMID:8733135
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
    - reference_id: PMID:8733135
      supporting_text: and a third is a subunit of a vacuolar H-ATPase, and is named VATPS1.
- term:
    id: GO:0060590
    label: ATPase regulator activity
  evidence_type: IC
  original_reference_id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
  qualifier: enables
  review:
    summary: Add ATPase regulator activity as the conservative PN-projected molecular-function term for ATP6AP1.
    action: NEW
    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.
    additional_reference_ids:
    - PMID:27231034
    - PMID:33065002
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
    supported_by:
    - reference_id: PMID:27231034
      supporting_text: 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.
    - reference_id: PMID:33065002
      supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
        subunits and phospholipids in the c-ring.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of
    sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- 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: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:22053050
  title: mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase.
  findings:
  - statement: Shows V-ATPase is required for lysosomal amino-acid sensing and mTORC1 activation through Rag/Ragulator
      coupling.
    supporting_text: The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and
      the nucleotide loading of the Rag GTPases.
- id: PMID:27231034
  title: ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein
    glycosylation.
  findings:
  - statement: Identifies ATP6AP1/Ac45 deficiency, localizes Ac45 to ER/ERGIC in hepatocytes, and supports a Voa1-like
      V-ATPase assembly-factor role.
    supporting_text: Processed wild-type Ac45, but not its disease mutants, restored V-ATPase-dependent growth in Voa1
      mutant yeast.
- 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: Links ATP6AP1/V-ATPase disruption to intracellular iron depletion and HIF activation in aerobic
      conditions.
    supporting_text: disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity and
      leading to HIF activation.
- id: PMID:29127204
  title: Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects.
  findings:
  - statement: Shows ATP6AP2 disease mutations impair interaction with ATP6AP1 and supports an ATP6AP-family V0 assembly
      complex model.
    supporting_text: both ATP6AP2 mutations impaired protein stability and the interaction with ATP6AP1, a member of the
      V0 assembly complex.
- id: PMID:32001091
  title: Structure and Roles of V-type ATPases.
  findings:
  - statement: Review source for V-ATPase acidification roles across organelles and specialized plasma membranes.
    supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton
      pumps.
- id: PMID:32353859
  title: A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein
    Aggregation in Affected Brains.
  findings: []
- id: PMID:33060197
  title: Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.
  findings: []
- id: PMID:33065002
  title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.
  findings:
  - statement: Cryo-EM study of complete human V-ATPase defining ATP6AP1 as a structural hub for V0 assembly.
    supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
      subunits and phospholipids in the c-ring.
- id: PMID:33845483
  title: Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV.
  findings: []
- id: PMID:34232536
  title: Interactomes of SARS-CoV-2 and human coronaviruses reveal host factors potentially affecting pathogenesis.
  findings: []
- id: PMID:34997207
  title: SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1.
  findings: []
- id: PMID:8733135
  title: 'Long-range sequence analysis in Xq28: thirteen known and six candidate genes in 219.4 kb of high GC DNA between
    the RCP/GCP and G6PD loci.'
  findings: []
- id: Reactome:R-HSA-5252133
  title: ATP6AP1 binds V-ATPase
  findings:
  - statement: Reactome event placing ATP6AP1 as an accessory V0 subunit that facilitates V-ATPase acidification.
    supporting_text: V-type proton ATPase subunit S1 (ATP6AP1) is thought to function as an accessory subunit of the V0
      subcomplex of V-ATPase, facilitating acidification
- id: Reactome:R-HSA-74723
  title: Endosome acidification
  findings:
  - statement: Reactome event for endosome acidification by proton entry into the endosome lumen.
    supporting_text: The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome.
- id: Reactome:R-HSA-917841
  title: Acidification of Tf:TfR1 containing endosome
  findings: []
- id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
  title: Proteostasis PN projected annotations report
  findings:
  - statement: Projects ATP6AP1 to GO:0060590 ATPase regulator activity from regulator-of-lysosomal-V-ATPase PN leaves
      and recognizes GO:0007042 lysosomal lumen acidification as already present in GOA.
    supporting_text: ATPase regulator activity is the narrowest GO target that preserves the source mechanism without
      requiring a speculative complex-specific term.
core_functions:
- molecular_function:
    id: GO:0060590
    label: ATPase regulator activity
  description: 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.
  directly_involved_in:
  - id: GO:0007042
    label: lysosomal lumen acidification
  - id: GO:0048388
    label: endosomal lumen acidification
  - id: GO:0061795
    label: Golgi lumen acidification
  - id: GO:1904263
    label: positive regulation of TORC1 signaling
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  - id: GO:0033116
    label: endoplasmic reticulum-Golgi intermediate compartment membrane
  - id: GO:0005765
    label: lysosomal membrane
  - id: GO:0010008
    label: endosome membrane
  in_complex:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  supported_by:
  - reference_id: PMID:27231034
    supporting_text: 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.
  - reference_id: PMID:33065002
    supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo
      subunits and phospholipids in the c-ring.
  - reference_id: PMID:22053050
    supporting_text: The v-ATPase is required for amino acid signaling to mTORC1 and functions between amino acids and
      the nucleotide loading of the Rag GTPases.
proposed_new_terms: []
suggested_questions:
- question: Does ATP6AP1 have separable regulatory roles in mature lysosomal V-ATPase activity versus ER-localized V0
    assembly in different human tissues?
  experts:
  - Jansen EJ
  - Wang L
- question: Is the ATP6AP1 contribution to mTORC1 nutrient sensing mediated entirely by mature V-ATPase/Ragulator
    coupling, or do ATP6AP-family accessory subunits tune that signaling independently of bulk acidification?
  experts:
  - Zoncu R
  - Sabatini DM
suggested_experiments:
- hypothesis: ATP6AP1 disease variants differentially impair ER V0 assembly, lysosomal acidification, and mTORC1
    amino-acid signaling.
  description: Introduce representative ATP6AP1 variants into an ATP6AP1-null human cell line and measure V-ATPase
    assembly, lysosomal/endosomal pH, glycosylation markers, and amino-acid-stimulated mTORC1
    recruitment/phosphorylation in parallel.
  experiment_type: genome editing and cell biology
- hypothesis: The PN-projected ATPase regulator activity reflects ATP6AP1-specific control of V-ATPase assembly/activity
    rather than a generic consequence of complex membership.
  description: Compare rescue by wild-type ATP6AP1 and assembly-defective mutants using purified V-ATPase assembly
    assays or quantitative proteomics of V0/V1 subcomplex formation, coupled to acidification readouts.
  experiment_type: biochemical reconstitution/proteomics

ATP6AP1

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: ATP6AP1 (V-type Proton ATPase Subunit S1)

Gene Identity Verification

1. Primary Function and Molecular Role

V-ATPase Assembly Factor

Structural Organization and Position in V-ATPase

Role as a Structural Hub

Relationship to Proton Pumping

2. Subcellular Localization

Assembly in the ER and Trafficking to Acidic Compartments

Primary Functional Locations

Tissue-Specific Processing

3. Biochemical Pathways and Signaling Mechanisms

Autophagy-Lysosomal Pathway

Protein Glycosylation Pathway

Endocytic Trafficking

mTORC1 Nutrient Sensing

4. Recent Developments and Applications (2023-2024)

Cancer Biology and Chemoresistance

Hepatocellular Carcinoma and Immune Evasion

Structural and Mechanistic Updates

5. Disease Associations

Immunodeficiency Syndrome

Granular Cell Tumors

Summary

📚 Additional Documentation

Notes

ATP6AP1 notes

2026-06-03 Proteostasis PN review

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6AP1 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

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

Projected GO annotations (3)

Note

📄 View Raw YAML