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