id: O75787
gene_symbol: ATP6AP2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ATP6AP2 encodes a single-pass membrane accessory protein of the vacuolar H+-ATPase system,
  also known as the renin/prorenin receptor. The protein localizes to endoplasmic reticulum, endosomal,
  lysosomal, Golgi, and plasma-membrane contexts, where it is cleaved into N- and C-terminal fragments.
  Its best-supported cell-biological role is to support V-ATPase assembly and endolysosomal acidification,
  which are required for lysosomal protein degradation, autophagy, glycosylation homeostasis, and neuronal
  viability. ATP6AP2 also has context-dependent receptor and adaptor roles in renin/prorenin signaling
  and Wnt/V-ATPase signaling.
alternative_products:
- name: '1'
  id: O75787-1
- name: '2'
  id: O75787-2
  sequence_note: VSP_056910
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- 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: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:29127204
  title: Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects.
  findings:
  - statement: ATP6AP2 is an accessory V-ATPase subunit needed for V-ATPase assembly, organelle acidification,
      glycosylation, and autophagic degradation.
    supporting_text: Our results suggest that ATP6AP2 has a crucial role in V-ATPase assembly, both in
      invertebrates and vertebrates.
    reference_section_type: ABSTRACT
  - statement: ATP6AP2 interacts with V0 assembly factors including ATP6AP1 and VMA21.
    supporting_text: Together, these results suggest that ATP6AP2 forms a complex with other V-ATPase
      assembly factors
    reference_section_type: RESULTS
  - statement: ATP6AP2 loss-of-function reduces lysosomal acidity and impairs autophagic degradation.
    supporting_text: ATP6AP2L98S mutant clones showed a reduction in Lysotracker-positive organelles compared
      with the WT surrounding tissue, indicating reduced acidity
    reference_section_type: RESULTS
- id: PMID:30985297
  title: ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration.
  findings:
  - statement: ATP6AP2 deficiency impairs lysosomal acidification, protein degradation, and V-ATPase membrane
      assembly in neuronal disease models.
    supporting_text: severe deficiency in lysosomal acidification and protein degradation leading to neuronal
      cell death
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: The authors conclude ATP6AP2 mediates V-ATPase-dependent signaling and protein degradation
      in the developing CNS.
    supporting_text: ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation
      in the developing human central nervous system.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
- id: PMID:32276428
  title: Interaction between PHB2 and Enterovirus A71 VP1 Induces Autophagy and Affects EV-A71 Infection.
  findings:
  - statement: ATP6AP2 knockdown increases lysosomal pH and inhibits autolysosomal degradation in a viral
      autophagy model.
    supporting_text: To evaluate the effect of ATP6AP2 knockdown on lysosomal pH, we employed an acidophilic
      fluorescent probe to measure the lysosomal pH, which increased significantly
    reference_section_type: RESULTS
  - statement: The paper explicitly treats ATP6AP2 as an auxiliary V-ATPase component coordinating correct
      assembly.
    supporting_text: ATP6AP2 is an important auxiliary component of the V-ATPase complex and coordinates
      correct V-ATPase assembly
    reference_section_type: RESULTS
- id: PMID:33065002
  title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.
  findings:
  - statement: Human V-ATPases are ATP-driven proton pumps responsible for organelle and vesicle acidification.
    supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP
      hydrolysis and a membrane-embedded Vo complex for proton transfer.
    reference_section_type: ABSTRACT
- id: PMID:20093472
  title: Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling.
  findings:
  - statement: PRR/ATP6AP2 acts as an adaptor between Wnt receptors and the V-ATPase complex.
    supporting_text: PRR functions in a renin-independent manner as an adaptor between Wnt receptors and
      the vacuolar H+-adenosine triphosphatase (V-ATPase) complex.
    reference_section_type: ABSTRACT
  - statement: The Wnt developmental phenotypes are supported but secondary to the V-ATPase-linked receptor/adaptor
      role.
    supporting_text: PRR and V-ATPase were required to mediate Wnt signaling during antero-posterior patterning
      of Xenopus early central nervous system
    reference_section_type: ABSTRACT
- id: PMID:30374053
  title: "TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/\u03B2-catenin\
    \ signalling."
  findings:
  - statement: TMEM9/V-ATPase assembly and vesicular acidification provide additional support for the
      Wnt-acidification connection.
    supporting_text: TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), a vacuolar
      proton pump, resulting in enhanced vesicular acidification and trafficking.
    reference_section_type: ABSTRACT
- id: PMID:12045255
  title: Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses
    to renin.
  findings:
  - statement: ATP6AP2 is a renin/prorenin receptor that binds renin/prorenin, increases angiotensinogen
      conversion, and activates ERK1/2.
    supporting_text: Transfected cells stably expressing the receptor showed renin- and prorenin-specific
      binding.
    reference_section_type: ABSTRACT
- id: PMID:15746149
  title: A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy
    points to a novel role of the renin receptor.
  findings:
  - statement: A splice-affecting ATP6AP2 variant supports a role in brain development while preserving
      renin binding/catalytic enhancement.
    supporting_text: indicate a novel specific role for the renin receptor in cognitive functions and
      brain development.
    reference_section_type: ABSTRACT
- id: PMID:16374430
  title: Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated,
    angiotensin II-independent mechanisms.
  findings:
  - statement: Renin-induced TGF-beta1 production is receptor-mediated and angiotensin-II-independent
      in mesangial cells.
    supporting_text: renin upregulates MC TGF-beta1 through a receptor-mediated mechanism
    reference_section_type: ABSTRACT
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings:
  - statement: High-throughput source supporting a peripheral localization or interaction annotation.
    supporting_text: Normal human urine contains large numbers of exosomes, which are 40- to 100-nm vesicles
    reference_section_type: ABSTRACT
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification
    technology (MudPIT).
  findings:
  - statement: High-throughput source supporting a peripheral localization or interaction annotation.
    supporting_text: Using MudPIT (multidimensional protein identification technology) mass spectrometry,
      we catalogued 491 proteins in the exosome fraction of human parotid saliva.
    reference_section_type: ABSTRACT
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
  findings:
  - statement: High-throughput source supporting a peripheral localization or interaction annotation.
    supporting_text: In pooled EPS-urine exosome samples, ~900 proteins were detected.
    reference_section_type: ABSTRACT
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: High-throughput source supporting a peripheral localization or interaction annotation.
    supporting_text: Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'.
    reference_section_type: ABSTRACT
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings:
  - statement: High-throughput source supporting a peripheral localization or interaction annotation.
    supporting_text: Here we construct a global map of human subcellular architecture through joint measurement
      of biophysical interactions and immunofluorescence images for over 5,100 proteins
    reference_section_type: ABSTRACT
- id: PMID:32001091
  title: Structure and Roles of V-type ATPases.
  findings: []
- id: Reactome:R-HSA-2022403
  title: Renin:Prorenin Receptor hydrolyzes Angiotensinogen to AGT(25-34) (Angiotensin-(1-10))
  findings: []
- id: Reactome:R-HSA-2065357
  title: Prorenin:Prorenin Receptor hydrolyzes Angiotensinogen to AGT(25-35) (Angiotensin-(1-10))
  findings: []
- id: Reactome:R-HSA-6798747
  title: Exocytosis of tertiary granule membrane proteins
  findings: []
- id: Reactome:R-HSA-6800426
  title: Exocytosis of ficolin-rich granule membrane proteins
  findings: []
- id: file:human/ATP6AP2/ATP6AP2-uniprot.txt
  title: UniProt record for human ATP6AP2
  findings:
  - statement: UniProt summarizes ATP6AP2 as a multifunctional renin/prorenin receptor and V-ATPase accessory
      protein involved in endolysosomal acidification.
    supporting_text: Multifunctional protein which functions as a renin, prorenin cellular receptor and
      is involved in the assembly of the lysosomal proton-transporting V-type ATPase (V-ATPase) and the
      acidification of the endo-lysosomal system
  - statement: UniProt records ATP6AP2 as an accessory component of the multisubunit V-ATPase pump.
    supporting_text: Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase protein
      pump
- id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
  title: Proteostasis Network projected annotations for ATP6AP2
  findings:
  - statement: The PN projection maps ATP6AP2 to lysosomal acidification and ATPase regulator activity
      from the lysosomal V-ATPase regulator leaves.
    supporting_text: "ATP6AP2\t\tAutophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal\
      \ environment|Lysosomal acidification|Regulator of the lysosomal v-ATPase proton pump"
existing_annotations:
- term:
    id: GO:0009897
    label: external side of plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: The cell-surface/external-side annotation is supported by renin/prorenin receptor studies
      and is biologically distinct from ATP6AP2's endolysosomal V-ATPase role.
    action: KEEP_AS_NON_CORE
    reason: ATP6AP2 can be detected at the cell surface/external face in receptor assays, but most mechanistic
      PN-relevant evidence concerns its endomembrane V-ATPase accessory function.
    additional_reference_ids:
    - PMID:12045255
    - PMID:15746149
    supported_by:
    - &id013
      reference_id: PMID:12045255
      supporting_text: localized in the mesangium of glomeruli and in the subendothelium of coronary and
        kidney artery
    - &id003
      reference_id: PMID:12045255
      supporting_text: Transfected cells stably expressing the receptor showed renin- and prorenin-specific
        binding.
- term:
    id: GO:0030177
    label: positive regulation of Wnt signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Wnt signaling regulation is experimentally supported through a V-ATPase-dependent receptor/adaptor
      role, but it is context-specific and downstream of the core acidification machinery.
    action: KEEP_AS_NON_CORE
    reason: The IBA term is biologically plausible, but for PN review it should not be treated as the
      core proteostasis function.
    additional_reference_ids:
    - PMID:20093472
    - PMID:30374053
    supported_by:
    - &id009
      reference_id: PMID:20093472
      supporting_text: PRR functions in a renin-independent manner as an adaptor between Wnt receptors
        and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex.
    - &id010
      reference_id: PMID:20093472
      supporting_text: PRR and V-ATPase were required to mediate Wnt signaling during antero-posterior
        patterning of Xenopus early central nervous system
- term:
    id: GO:0000421
    label: autophagosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Autophagosome-membrane localization is plausible by UniProt similarity and consistent with
      autophagy phenotypes, but direct human localization evidence is limited.
    action: KEEP_AS_NON_CORE
    reason: Keep as a non-core location because ATP6AP2 loss perturbs autophagic degradation primarily
      through V-ATPase assembly and acidification rather than as a canonical autophagosome machinery component.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - &id001
      reference_id: file:human/ATP6AP2/ATP6AP2-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
    - reference_id: PMID:29127204
      supporting_text: Consistent with decreased autophagic degradation, Ref(2)p was increased in ATP6AP2L98S
        clones
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Generic cytoplasm is too broad for a single-pass endomembrane protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATP6AP2 has a cytosolic tail, but the reviewed literature and UniProt record support ER, lysosomal,
      endosomal, Golgi/plasma-membrane, and V-ATPase-complex contexts rather than a general cytoplasm
      annotation.
    supported_by:
    - *id001
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Lysosomal membrane localization is consistent with the UniProt record, V-ATPase accessory
      role, and lysosomal acidification phenotypes.
    action: ACCEPT
    reason: This location is central to ATP6AP2 function in the endolysosomal V-ATPase system.
    additional_reference_ids:
    - PMID:29127204
    - PMID:32276428
    supported_by:
    - *id001
    - &id012
      reference_id: PMID:32276428
      supporting_text: ATP6AP2 is an important auxiliary component of the V-ATPase complex and coordinates
        correct V-ATPase assembly
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ER membrane localization is supported by ATP6AP2 ER-retrieval/assembly-factor biology.
    action: ACCEPT
    reason: The V0 sector assembly model places ATP6AP2 among ER-associated V-ATPase assembly factors,
      and ER retrieval is required for autophagy-related function.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id001
    - &id020
      reference_id: PMID:29127204
      supporting_text: Our results suggest that ATP6AP2 has a crucial role in V-ATPase assembly, both
        in invertebrates and vertebrates.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Endosome membrane localization is consistent with the endolysosomal V-ATPase role and orthology-supported
      UniProt localization.
    action: ACCEPT
    reason: Endosomal membrane localization is appropriate for a V-ATPase accessory protein that supports
      endosomal and lysosomal acidification.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id001
    - &id011
      reference_id: PMID:29127204
      supporting_text: The multi-subunit vacuolar-type H+-ATPase (V-ATPase) acidifies intracellular organelles,
        thereby controlling several events in the secretory and endocytic pathway, such as proteolytic
        processing, protein degradation, autophagy, and glycosylation.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Generic membrane is true but under-informative for ATP6AP2.
    action: MODIFY
    reason: Replace broad membrane with the specific endomembrane/V-ATPase contexts supported by the UniProt
      record and literature.
    proposed_replacement_terms:
    - &id004
      id: GO:0005765
      label: lysosomal membrane
    - &id005
      id: GO:0010008
      label: endosome membrane
    - &id006
      id: GO:0005789
      label: endoplasmic reticulum membrane
    - &id007
      id: GO:0016471
      label: vacuolar proton-transporting V-type ATPase complex
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id001
    - &id008
      reference_id: PMID:29127204
      supporting_text: In addition, there are two accessory subunits named ATP6AP1 and ATP6AP2.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Axonal localization is similarity-based and relevant to neuronal contexts, but it is not
      the core ATP6AP2 function.
    action: KEEP_AS_NON_CORE
    reason: Human disease and mouse data support neuronal dependence on ATP6AP2, yet the primary mechanism
      remains V-ATPase assembly and lysosomal protein degradation.
    additional_reference_ids:
    - PMID:30985297
    supported_by:
    - &id002
      reference_id: PMID:30985297
      supporting_text: ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation
        in the developing human central nervous system.
- 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 plausible for an endomembrane V-ATPase accessory
      protein, but it is similarity-based and not central to the PN call.
    action: KEEP_AS_NON_CORE
    reason: Keep as a peripheral localization rather than a core functional assertion.
    supported_by:
    - *id001
- 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 similarity-based and relevant to neuronal phenotypes,
      but it is not the central curated function.
    action: KEEP_AS_NON_CORE
    reason: The CNS evidence supports V-ATPase-dependent protein degradation and signaling rather than
      a specific primary synaptic-vesicle role for human ATP6AP2.
    additional_reference_ids:
    - PMID:30985297
    supported_by:
    - *id002
- term:
    id: GO:0032591
    label: dendritic spine membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Dendritic spine membrane localization is similarity-based and consistent with neuronal disease
      context but non-core.
    action: KEEP_AS_NON_CORE
    reason: This should not drive PN proteostasis propagation beyond the stronger endolysosomal V-ATPase
      evidence.
    additional_reference_ids:
    - PMID:30985297
    supported_by:
    - *id002
- term:
    id: GO:0038023
    label: signaling receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Generic signaling receptor activity is supported by renin/prorenin receptor studies but is
      biologically distinct from ATP6AP2's endolysosomal V-ATPase role.
    action: KEEP_AS_NON_CORE
    reason: Keep as a real but non-core receptor/signaling activity; the stronger PN-relevant molecular
      function is ATPase regulator/accessory activity.
    additional_reference_ids:
    - PMID:12045255
    - PMID:15746149
    supported_by:
    - *id003
    - &id027
      reference_id: PMID:12045255
      supporting_text: activation of MAP kinases ERK1 and ERK2
- 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 too broad for ATP6AP2.
    action: MODIFY
    reason: Specific ER, lysosomal, endosomal, and V-ATPase-complex annotations are more informative and
      already supported.
    proposed_replacement_terms:
    - *id004
    - *id005
    - *id006
    - *id007
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id001
    - *id008
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: The binary interactome protein-binding annotation is not informative for ATP6AP2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interaction data should not be propagated as generic protein binding when
      mechanistic V-ATPase assembly/regulation evidence is available.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: The 2025 multimodal-map interaction annotation is broad and does not define ATP6AP2 molecular
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Avoid retaining generic protein binding as a functional endpoint; curated ATP6AP2 roles are
      V-ATPase accessory/regulator activity and receptor/adaptor signaling.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Here we construct a global map of human subcellular architecture through joint
        measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins
- term:
    id: GO:0021626
    label: central nervous system maturation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: CNS maturation is supported by human and mouse ATP6AP2 deficiency studies but is downstream
      of the V-ATPase/protein-degradation defect.
    action: KEEP_AS_NON_CORE
    reason: Keep as a disease/developmental outcome rather than a core molecular function.
    additional_reference_ids:
    - PMID:30985297
    supported_by:
    - &id014
      reference_id: PMID:30985297
      supporting_text: severe deficiency in lysosomal acidification and protein degradation leading to
        neuronal cell death
    - *id002
- term:
    id: GO:0030177
    label: positive regulation of Wnt signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Positive regulation of Wnt signaling is supported but context-dependent and secondary to
      ATP6AP2's endolysosomal V-ATPase role.
    action: KEEP_AS_NON_CORE
    reason: ATP6AP2 acts as a Wnt receptor-complex adaptor linked to V-ATPase-mediated acidification;
      this is a secondary signaling output.
    additional_reference_ids:
    - PMID:20093472
    - PMID:30374053
    supported_by:
    - *id009
    - *id010
- term:
    id: GO:0097401
    label: synaptic vesicle lumen acidification
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Synaptic vesicle lumen acidification is similarity-based and plausible in neuronal contexts,
      but human ATP6AP2 evidence supports broader V-ATPase-dependent endolysosomal acidification.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core; do not use it as the primary PN projection.
    additional_reference_ids:
    - PMID:30985297
    supported_by:
    - *id002
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: EXP
  original_reference_id: PMID:29127204
  qualifier: located_in
  review:
    summary: Experimental evidence supports lysosomal membrane localization.
    action: ACCEPT
    reason: ATP6AP2 is a single-pass membrane protein acting with the V-ATPase in endolysosomal compartments.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id001
    - *id008
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Endosome membrane localization by similarity is consistent with ATP6AP2 endolysosomal V-ATPase
      function.
    action: ACCEPT
    reason: The term fits the endosomal acidification role supported by V-ATPase biology.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id001
    - *id011
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: Golgi membrane localization is biologically plausible because ATP6AP2 is cleaved in the Golgi
      and V-ATPase activity supports secretory-pathway pH, but direct ATP6AP2 Golgi evidence is less central
      than ER/lysosome/endosome.
    action: KEEP_AS_NON_CORE
    reason: Keep as a non-core location.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id011
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: Lysosomal membrane is a supported core location for ATP6AP2.
    action: ACCEPT
    reason: This localization matches the lysosomal V-ATPase acidification and PN lysosomal-acidification
      projection.
    additional_reference_ids:
    - PMID:29127204
    - PMID:32276428
    supported_by:
    - *id001
    - *id012
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: Plasma membrane localization is supported by receptor biology and is distinct from ATP6AP2's
      endolysosomal V-ATPase localization.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the cell-surface renin/prorenin role is separate from the endolysosomal
      V-ATPase role.
    additional_reference_ids:
    - PMID:12045255
    supported_by:
    - *id003
    - *id013
- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Vacuolar acidification is directionally correct but broad.
    action: MODIFY
    reason: For ATP6AP2, the best supported acidification outputs are lysosomal, endosomal, and Golgi
      lumen acidification through V-ATPase assembly/regulation.
    proposed_replacement_terms:
    - &id017
      id: GO:0007042
      label: lysosomal lumen acidification
    - &id018
      id: GO:0048388
      label: endosomal lumen acidification
    - &id019
      id: GO:0061795
      label: Golgi lumen acidification
    additional_reference_ids:
    - PMID:29127204
    - PMID:32276428
    supported_by:
    - *id011
    - &id015
      reference_id: PMID:32276428
      supporting_text: To evaluate the effect of ATP6AP2 knockdown on lysosomal pH, we employed an acidophilic
        fluorescent probe to measure the lysosomal pH, which increased significantly
- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Lysosomal lumen acidification is a core supported ATP6AP2 process.
    action: ACCEPT
    reason: ATP6AP2 loss impairs lysosomal acidification and autophagic/protein degradation, matching
      the PN lysosomal-acidification projection.
    additional_reference_ids:
    - PMID:29127204
    - PMID:30985297
    - PMID:32276428
    supported_by:
    - reference_id: PMID:29127204
      supporting_text: ATP6AP2L98S mutant clones showed a reduction in Lysotracker-positive organelles
        compared with the WT surrounding tissue, indicating reduced acidity
    - *id014
    - *id015
- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: Lysosomal lumen acidification is supported as the functional output of the V-ATPase complex
      that includes ATP6AP2.
    action: ACCEPT
    reason: The ComplexPortal structural annotation is consistent with ATP6AP2 V-ATPase complex membership
      and the direct loss-of-function acidification evidence.
    additional_reference_ids:
    - PMID:29127204
    - PMID:32276428
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: acidification of intracellular vesicles, organelles, and the extracellular milieu
        in eukaryotes.
    - &id016
      reference_id: file:human/ATP6AP2/ATP6AP2-uniprot.txt
      supporting_text: Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase
        protein pump
    - *id015
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: Endosome membrane localization is consistent with ATP6AP2 as an endolysosomal V-ATPase accessory
      protein.
    action: ACCEPT
    reason: Keep as a supported location.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id001
    - *id011
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:33065002
  qualifier: located_in
  review:
    summary: Generic membrane is too broad for the ComplexPortal V-ATPase evidence.
    action: MODIFY
    reason: The same evidence should be represented as V-ATPase complex membership and/or specific endolysosomal
      membrane localization rather than generic membrane.
    proposed_replacement_terms:
    - id: GO:0033176
      label: proton-transporting V-type ATPase complex
    - *id007
    - *id004
    additional_reference_ids:
    - PMID:29127204
    - PMID:33065002
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for
        ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
    - *id016
- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: part_of
  review:
    summary: ATP6AP2 is part of the proton-transporting V-type ATPase complex.
    action: ACCEPT
    reason: Complex membership is supported by UniProt and the assembly/interactor literature, and is
      central to ATP6AP2 function.
    additional_reference_ids:
    - PMID:29127204
    - PMID:33065002
    supported_by:
    - *id016
    - &id021
      reference_id: PMID:29127204
      supporting_text: Together, these results suggest that ATP6AP2 forms a complex with other V-ATPase
        assembly factors
- term:
    id: GO:0048388
    label: endosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Endosomal lumen acidification is a supported V-ATPase-dependent process for ATP6AP2.
    action: ACCEPT
    reason: ATP6AP2 regulates V-ATPase assembly/activity in the endolysosomal system, so this is an appropriate
      process-level annotation.
    additional_reference_ids:
    - PMID:29127204
    - PMID:32276428
    supported_by:
    - *id011
    - *id012
- 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 too broad.
    action: MODIFY
    reason: Use compartment-specific acidification terms that preserve the V-ATPase/endolysosomal mechanism.
    proposed_replacement_terms:
    - *id017
    - *id018
    - *id019
    additional_reference_ids:
    - PMID:29127204
    - PMID:32276428
    supported_by:
    - *id011
    - *id015
- term:
    id: GO:0061795
    label: Golgi lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Golgi lumen acidification is a plausible V-ATPase-dependent process for ATP6AP2.
    action: ACCEPT
    reason: ATP6AP2 participates in V-ATPase assembly/function across secretory and endocytic compartments;
      this process is credible but less central than lysosomal/endosomal acidification.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id011
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: Proton transmembrane transport is a complex activity and overstates the individual role of
      ATP6AP2.
    action: MODIFY
    reason: ATP6AP2 is an accessory/regulatory component, not the proton-pumping catalytic sector itself.
      Replace with V-ATPase complex membership, assembly, and ATPase regulator activity.
    proposed_replacement_terms:
    - *id007
    - &id023
      id: GO:0070072
      label: vacuolar proton-transporting V-type ATPase complex assembly
    - &id022
      id: GO:0060590
      label: ATPase regulator activity
    additional_reference_ids:
    - PMID:29127204
    - PMID:32276428
    supported_by:
    - *id020
    - *id012
- term:
    id: GO:0000220
    label: vacuolar proton-transporting V-type ATPase, V0 domain
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: V0-domain membership by similarity fits the conserved ATP6AP2 V-ATPase accessory role.
    action: ACCEPT
    reason: ATP6AP2 interacts with V0 assembly factors and supports V-ATPase assembly.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id021
    - *id020
- term:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
  evidence_type: IMP
  original_reference_id: PMID:30985297
  qualifier: part_of
  review:
    summary: ATP6AP2 is part of the vacuolar proton-transporting V-type ATPase complex.
    action: ACCEPT
    reason: The patient-derived neuron and mouse data show ATP6AP2 deficiency decreases V-ATPase membrane
      assembly, supporting complex membership and functional relevance.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - &id025
      reference_id: PMID:30985297
      supporting_text: ATP6AP2 deficiency decreases V-ATPase membrane assembly
    - *id016
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Lysosomal membrane localization by similarity is consistent with direct human lysosomal/V-ATPase
      evidence.
    action: ACCEPT
    reason: Retain as a relevant core location.
    additional_reference_ids:
    - PMID:29127204
    - PMID:32276428
    supported_by:
    - *id001
    - *id012
- term:
    id: GO:0021626
    label: central nervous system maturation
  evidence_type: IMP
  original_reference_id: PMID:30985297
  qualifier: involved_in
  review:
    summary: CNS maturation is experimentally supported but reflects a developmental consequence of V-ATPase
      dysfunction.
    action: KEEP_AS_NON_CORE
    reason: Keep as a non-core biological process in the PN context.
    additional_reference_ids:
    - PMID:30985297
    supported_by:
    - *id014
    - *id002
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30374053
  qualifier: enables
  review:
    summary: Protein binding to TMEM9/V-ATPase components is mechanistically meaningful but should not
      remain as generic protein binding.
    action: MODIFY
    reason: The better functional endpoint for ATP6AP2 is ATPase regulator activity and V-ATPase complex
      assembly.
    proposed_replacement_terms:
    - *id022
    - *id023
    additional_reference_ids:
    - PMID:29127204
    - PMID:32276428
    supported_by:
    - &id024
      reference_id: PMID:30374053
      supporting_text: TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), a vacuolar
        proton pump, resulting in enhanced vesicular acidification and trafficking.
    - *id012
- term:
    id: GO:0090263
    label: positive regulation of canonical Wnt signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:30374053
  qualifier: involved_in
  review:
    summary: Canonical Wnt signaling regulation is supported through V-ATPase-dependent vesicular acidification
      but is context-specific.
    action: KEEP_AS_NON_CORE
    reason: Keep as a real non-core signaling output rather than a core PN proteostasis annotation.
    additional_reference_ids:
    - PMID:20093472
    - PMID:30374053
    supported_by:
    - *id009
    - *id024
- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: IMP
  original_reference_id: PMID:32276428
  qualifier: involved_in
  review:
    summary: ATP6AP2 knockdown directly increased lysosomal pH in the EV-A71 study, supporting lysosomal
      lumen acidification.
    action: ACCEPT
    reason: This is direct functional support for the PN lysosomal acidification projection, even though
      the viral infection phenotype is context-specific.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id012
    - *id015
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29127204
  qualifier: enables
  review:
    summary: ATP6AP2 interactions with ATP6AP1/VMA21 and V0 factors should not be represented as generic
      protein binding.
    action: MODIFY
    reason: Replace with ATPase regulator activity and V-ATPase complex assembly, which capture the molecular
      consequence of these interactions.
    proposed_replacement_terms:
    - *id022
    - *id023
    additional_reference_ids:
    - PMID:32276428
    supported_by:
    - *id021
    - *id020
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:29127204
  qualifier: located_in
  review:
    summary: Direct lysosome localization is consistent with ATP6AP2 endolysosomal V-ATPase function.
    action: ACCEPT
    reason: This is a valid location annotation, though the membrane term is more precise where available.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id001
    - *id011
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:29127204
  qualifier: located_in
  review:
    summary: ER membrane localization is supported and mechanistically important for V0 assembly-factor
      interaction.
    action: ACCEPT
    reason: The literature places ATP6AP2 in ER-based V-ATPase assembly and shows ER retrieval is functionally
      important.
    additional_reference_ids:
    - PMID:29127204
    supported_by:
    - *id001
    - *id020
- term:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
  evidence_type: IMP
  original_reference_id: PMID:29127204
  qualifier: part_of
  review:
    summary: ATP6AP2 is part of the vacuolar proton-transporting V-type ATPase complex.
    action: ACCEPT
    reason: This is a core cellular-component annotation supported by interaction and deficiency evidence.
    additional_reference_ids:
    - PMID:29127204
    - PMID:30985297
    supported_by:
    - *id021
    - *id025
- term:
    id: GO:0070821
    label: tertiary granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798747
  qualifier: located_in
  review:
    summary: Tertiary granule membrane localization from Reactome/neutrophil degranulation may be valid
      but is peripheral to ATP6AP2 core function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core; do not use for PN proteostasis projection.
    supported_by:
    - *id001
- term:
    id: GO:0101003
    label: ficolin-1-rich granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800426
  qualifier: located_in
  review:
    summary: Ficolin-1-rich granule membrane localization is a peripheral Reactome/neutrophil context.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core because it does not change the core V-ATPase accessory interpretation.
    supported_by:
    - *id001
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: Extracellular exosome detection is high-throughput localization evidence and may reflect
      vesicle shedding/secretory biology.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core and avoid using it as a core functional annotation.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: In pooled EPS-urine exosome samples, ~900 proteins were detected.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20093472
  qualifier: enables
  review:
    summary: Protein binding in the Wnt/V-ATPase receptor-complex paper is mechanistically meaningful
      but too vague.
    action: MODIFY
    reason: Replace with ATPase regulator activity and V-ATPase complex assembly rather than retaining
      generic binding.
    proposed_replacement_terms:
    - *id022
    - *id023
    additional_reference_ids:
    - PMID:29127204
    - PMID:32276428
    supported_by:
    - *id009
    - *id020
- term:
    id: GO:0021903
    label: rostrocaudal neural tube patterning
  evidence_type: IMP
  original_reference_id: PMID:20093472
  qualifier: involved_in
  review:
    summary: Rostrocaudal neural tube patterning is supported in the Wnt/V-ATPase developmental model
      but is a downstream developmental phenotype.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core in this human PN review.
    additional_reference_ids:
    - PMID:20093472
    supported_by:
    - *id010
- term:
    id: GO:0030177
    label: positive regulation of Wnt signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:20093472
  qualifier: involved_in
  review:
    summary: Positive regulation of Wnt signaling is supported but secondary to ATP6AP2 V-ATPase/receptor-adaptor
      function.
    action: KEEP_AS_NON_CORE
    reason: The annotation is valid as a context-specific signaling role, not the core PN proteostasis
      function.
    additional_reference_ids:
    - PMID:20093472
    - PMID:30374053
    supported_by:
    - *id009
    - *id010
- term:
    id: GO:0048069
    label: eye pigmentation
  evidence_type: IMP
  original_reference_id: PMID:20093472
  qualifier: involved_in
  review:
    summary: Eye pigmentation is an organismal/developmental phenotype from the Wnt/V-ATPase study.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core because it is downstream of signaling/acidification rather than a direct
      molecular function.
    additional_reference_ids:
    - PMID:20093472
    supported_by:
    - *id010
- term:
    id: GO:0060323
    label: head morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:20093472
  qualifier: involved_in
  review:
    summary: Head morphogenesis is an organismal/developmental phenotype from the Wnt/V-ATPase study.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core for the same reason as other developmental outputs.
    additional_reference_ids:
    - PMID:20093472
    supported_by:
    - *id010
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  qualifier: located_in
  review:
    summary: Parotid exosome detection is high-throughput localization evidence and not a core ATP6AP2
      role.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core.
    supported_by:
    - reference_id: PMID:19199708
      supporting_text: Using MudPIT (multidimensional protein identification technology) mass spectrometry,
        we catalogued 491 proteins in the exosome fraction of human parotid saliva.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: Urinary exosome detection is high-throughput localization evidence and not a core ATP6AP2
      role.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: Normal human urine contains large numbers of exosomes, which are 40- to 100-nm
        vesicles
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2022403
  qualifier: located_in
  review:
    summary: Plasma membrane localization is supported in the renin/prorenin receptor context.
    action: KEEP_AS_NON_CORE
    reason: Retain as a non-core receptor-context location distinct from the endolysosomal V-ATPase role.
    additional_reference_ids:
    - PMID:12045255
    supported_by:
    - *id003
    - *id013
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2065357
  qualifier: located_in
  review:
    summary: Plasma membrane localization is supported in the prorenin receptor/angiotensinogen context.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core.
    additional_reference_ids:
    - PMID:12045255
    supported_by:
    - *id003
    - *id013
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798747
  qualifier: located_in
  review:
    summary: Plasma membrane localization associated with neutrophil degranulation is peripheral to ATP6AP2
      core function.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core.
    supported_by:
    - *id001
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800426
  qualifier: located_in
  review:
    summary: Plasma membrane localization associated with ficolin-rich granule exocytosis is peripheral
      to ATP6AP2 core function.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core.
    supported_by:
    - *id001
- term:
    id: GO:0032914
    label: positive regulation of transforming growth factor beta1 production
  evidence_type: IDA
  original_reference_id: PMID:16374430
  qualifier: involved_in
  review:
    summary: Renin-induced TGF-beta1 production is experimentally supported in mesangial cells and reflects
      a receptor-signaling context rather than ATP6AP2's V-ATPase accessory role.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core; it should not affect the PN projection.
    additional_reference_ids:
    - PMID:12045255
    supported_by:
    - reference_id: PMID:16374430
      supporting_text: renin upregulates MC TGF-beta1 through a receptor-mediated mechanism
- term:
    id: GO:0002003
    label: angiotensin maturation
  evidence_type: IDA
  original_reference_id: PMID:15746149
  qualifier: involved_in
  review:
    summary: Angiotensin maturation is supported through ATP6AP2/renin binding and reflects receptor/RAS
      biology rather than ATP6AP2's V-ATPase accessory role.
    action: KEEP_AS_NON_CORE
    reason: Retain as a non-core receptor/RAS role.
    additional_reference_ids:
    - PMID:12045255
    supported_by:
    - &id026
      reference_id: PMID:15746149
      supporting_text: the mutated receptor could bind renin and increase renin catalytic activity
    - &id028
      reference_id: PMID:12045255
      supporting_text: The binding of renin induced a fourfold increase of the catalytic efficiency of
        angiotensinogen conversion to angiotensin I
- term:
    id: GO:0009897
    label: external side of plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:15746149
  qualifier: located_in
  review:
    summary: External side of plasma membrane localization is supported by receptor studies.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core because ATP6AP2 core biology is endolysosomal V-ATPase assembly/acidification.
    additional_reference_ids:
    - PMID:12045255
    supported_by:
    - *id013
    - *id026
- term:
    id: GO:0043408
    label: regulation of MAPK cascade
  evidence_type: IDA
  original_reference_id: PMID:15746149
  qualifier: involved_in
  review:
    summary: MAPK cascade regulation is supported in the renin/prorenin receptor context and is distinct
      from ATP6AP2's endolysosomal V-ATPase role.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core signaling.
    additional_reference_ids:
    - PMID:12045255
    supported_by:
    - &id029
      reference_id: PMID:15746149
      supporting_text: modest and reproducible impairment of ERK1/2 activation
    - *id027
- term:
    id: GO:0002003
    label: angiotensin maturation
  evidence_type: IDA
  original_reference_id: PMID:12045255
  qualifier: involved_in
  review:
    summary: Angiotensin maturation is supported by the original receptor paper and reflects receptor/RAS
      biology rather than ATP6AP2's V-ATPase accessory role.
    action: KEEP_AS_NON_CORE
    reason: Retain as a separate receptor/RAS role.
    additional_reference_ids:
    - PMID:15746149
    supported_by:
    - *id003
    - *id028
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12045255
  qualifier: enables
  review:
    summary: Renin/prorenin protein binding is real but the generic protein-binding term is uninformative.
    action: MODIFY
    reason: Use signaling receptor activity for this receptor role rather than generic protein binding.
    proposed_replacement_terms:
    - id: GO:0038023
      label: signaling receptor activity
    additional_reference_ids:
    - PMID:15746149
    supported_by:
    - *id003
    - *id027
- term:
    id: GO:0009897
    label: external side of plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:12045255
  qualifier: located_in
  review:
    summary: External side of plasma membrane localization is supported by the original renin/prorenin
      receptor work.
    action: KEEP_AS_NON_CORE
    reason: Keep as a non-core location.
    additional_reference_ids:
    - PMID:15746149
    supported_by:
    - *id003
    - *id013
- term:
    id: GO:0043408
    label: regulation of MAPK cascade
  evidence_type: IDA
  original_reference_id: PMID:12045255
  qualifier: involved_in
  review:
    summary: MAPK cascade regulation is supported by renin/prorenin receptor signaling and is distinct
      from ATP6AP2's endolysosomal V-ATPase role.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core signaling.
    additional_reference_ids:
    - PMID:15746149
    supported_by:
    - *id027
    - *id029
- term: *id022
  evidence_type: IMP
  original_reference_id: PMID:29127204
  qualifier: enables
  review:
    summary: ATP6AP2 has ATPase regulator activity as an accessory/regulatory factor for lysosomal V-ATPase
      assembly and acidification.
    action: NEW
    reason: The PN projection proposes GO:0060590 for the lysosomal V-ATPase regulator leaf. This is conservative
      because ATP6AP2 is not annotated as a proton pump subunit with independent transport activity; instead,
      patient, knockdown, interaction, and assembly evidence support a regulator/accessory role.
    additional_reference_ids:
    - PMID:30985297
    - PMID:32276428
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
    supported_by:
    - *id020
    - *id012
    - *id015
    - &id030
      reference_id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
      supporting_text: "ATP6AP2\t\tAutophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal\
        \ environment|Lysosomal acidification|Regulator of the lysosomal v-ATPase proton pump"
- term: *id023
  evidence_type: IMP
  original_reference_id: PMID:29127204
  qualifier: involved_in
  review:
    summary: ATP6AP2 is involved in vacuolar proton-transporting V-type ATPase complex assembly.
    action: NEW
    reason: 'This term captures the clearest mechanistic result from ATP6AP2 disease variants and knockdown/rescue
      studies: impaired ATP6AP2 decreases V-ATPase assembly and downstream lysosomal acidification/autophagic
      degradation.'
    additional_reference_ids:
    - PMID:30985297
    - PMID:32276428
    supported_by:
    - *id021
    - *id020
    - *id025
    - *id012
core_functions:
- description: Supports V-ATPase assembly and activity as an accessory/regulatory factor, enabling endolysosomal
    acidification and lysosomal protein degradation.
  molecular_function: *id022
  directly_involved_in:
  - *id023
  - *id017
  - *id018
  locations:
  - *id006
  - *id004
  - *id005
  in_complex: *id007
  supported_by:
  - *id020
  - *id025
  - *id015
  - *id030
proposed_new_terms: []
suggested_questions:
- question: Would GO benefit from a more specific molecular-function term for lysosomal V-ATPase accessory/regulator
    activity, narrower than ATPase regulator activity?
- question: Which ATP6AP2 receptor/adaptor activities require the full-length plasma-membrane protein
    versus the cleaved endomembrane fragments?
suggested_experiments:
- hypothesis: ATP6AP2 regulates lysosomal V-ATPase assembly and acidification independently of its renin/prorenin
    receptor signaling role.
  description: Compare wild-type ATP6AP2, cleavage-defective mutants, ER-retrieval mutants, and receptor-binding
    mutants in ATP6AP2-null human cells using V-ATPase assembly assays, organelle pH reporters, and lysosomal
    degradation flux readouts.
  experiment_type: rescue and structure-function assay
- hypothesis: The PN ATPase regulator projection is specific to the endolysosomal V-ATPase role and should
    not propagate Wnt or renin signaling annotations as proteostasis core functions.
  description: Measure V-ATPase assembly, lysosomal pH, Wnt reporter output, and ERK activation side by
    side after ATP6AP2 perturbation to separate direct acidification defects from downstream signaling
    phenotypes.
  experiment_type: parallel functional phenotyping