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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:12045255 localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery PMID:12045255 Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. |
| GO:0030177 positive regulation of Wnt signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. Reason: The IBA term is biologically plausible, but for PN review it should not be treated as the core proteostasis function. Supporting Evidence: PMID:20093472 PRR functions in a renin-independent manner as an adaptor between Wnt receptors and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex. PMID:20093472 PRR and V-ATPase were required to mediate Wnt signaling during antero-posterior patterning of Xenopus early central nervous system |
| GO:0000421 autophagosome membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Autophagosome-membrane localization is plausible by UniProt similarity and consistent with autophagy phenotypes, but direct human localization evidence is limited. 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. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:29127204 Consistent with decreased autophagic degradation, Ref(2)p was increased in ATP6AP2L98S clones |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Generic cytoplasm is too broad for a single-pass endomembrane protein. 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. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Lysosomal membrane localization is consistent with the UniProt record, V-ATPase accessory role, and lysosomal acidification phenotypes. Reason: This location is central to ATP6AP2 function in the endolysosomal V-ATPase system. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:32276428 ATP6AP2 is an important auxiliary component of the V-ATPase complex and coordinates correct V-ATPase assembly |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: ER membrane localization is supported by ATP6AP2 ER-retrieval/assembly-factor biology. Reason: The V0 sector assembly model places ATP6AP2 among ER-associated V-ATPase assembly factors, and ER retrieval is required for autophagy-related function. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:29127204 Our results suggest that ATP6AP2 has a crucial role in V-ATPase assembly, both in invertebrates and vertebrates. |
| GO:0010008 endosome membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Endosome membrane localization is consistent with the endolysosomal V-ATPase role and orthology-supported UniProt localization. Reason: Endosomal membrane localization is appropriate for a V-ATPase accessory protein that supports endosomal and lysosomal acidification. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:29127204 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. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Generic membrane is true but under-informative for ATP6AP2. Reason: Replace broad membrane with the specific endomembrane/V-ATPase contexts supported by the UniProt record and literature. Proposed replacements: lysosomal membrane endosome membrane endoplasmic reticulum membrane vacuolar proton-transporting V-type ATPase complex Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:29127204 In addition, there are two accessory subunits named ATP6AP1 and ATP6AP2. |
| GO:0030424 axon | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Axonal localization is similarity-based and relevant to neuronal contexts, but it is not the core ATP6AP2 function. Reason: Human disease and mouse data support neuronal dependence on ATP6AP2, yet the primary mechanism remains V-ATPase assembly and lysosomal protein degradation. Supporting Evidence: PMID:30985297 ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system. |
| GO:0030665 clathrin-coated vesicle membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. Reason: Keep as a peripheral localization rather than a core functional assertion. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane |
| GO:0030672 synaptic vesicle membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Synaptic vesicle membrane localization is similarity-based and relevant to neuronal phenotypes, but it is not the central curated function. Reason: The CNS evidence supports V-ATPase-dependent protein degradation and signaling rather than a specific primary synaptic-vesicle role for human ATP6AP2. Supporting Evidence: PMID:30985297 ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system. |
| GO:0032591 dendritic spine membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Dendritic spine membrane localization is similarity-based and consistent with neuronal disease context but non-core. Reason: This should not drive PN proteostasis propagation beyond the stronger endolysosomal V-ATPase evidence. Supporting Evidence: PMID:30985297 ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system. |
| GO:0038023 signaling receptor activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Generic signaling receptor activity is supported by renin/prorenin receptor studies but is biologically distinct from ATP6AP2's endolysosomal V-ATPase role. Reason: Keep as a real but non-core receptor/signaling activity; the stronger PN-relevant molecular function is ATPase regulator/accessory activity. Supporting Evidence: PMID:12045255 Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. PMID:12045255 activation of MAP kinases ERK1 and ERK2 |
| GO:0098588 bounding membrane of organelle | IEA GO_REF:0000117 | MODIFY | Summary: Bounding membrane of organelle is too broad for ATP6AP2. Reason: Specific ER, lysosomal, endosomal, and V-ATPase-complex annotations are more informative and already supported. Proposed replacements: lysosomal membrane endosome membrane endoplasmic reticulum membrane vacuolar proton-transporting V-type ATPase complex Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:29127204 In addition, there are two accessory subunits named ATP6AP1 and ATP6AP2. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: The binary interactome protein-binding annotation is not informative for ATP6AP2 function. Reason: High-throughput interaction data should not be propagated as generic protein binding when mechanistic V-ATPase assembly/regulation evidence is available. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: The 2025 multimodal-map interaction annotation is broad and does not define ATP6AP2 molecular function. Reason: Avoid retaining generic protein binding as a functional endpoint; curated ATP6AP2 roles are V-ATPase accessory/regulator activity and receptor/adaptor signaling. Supporting Evidence: PMID:40205054 Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins |
| GO:0021626 central nervous system maturation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CNS maturation is supported by human and mouse ATP6AP2 deficiency studies but is downstream of the V-ATPase/protein-degradation defect. Reason: Keep as a disease/developmental outcome rather than a core molecular function. Supporting Evidence: PMID:30985297 severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death PMID:30985297 ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system. |
| GO:0030177 positive regulation of Wnt signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of Wnt signaling is supported but context-dependent and secondary to ATP6AP2's endolysosomal V-ATPase role. Reason: ATP6AP2 acts as a Wnt receptor-complex adaptor linked to V-ATPase-mediated acidification; this is a secondary signaling output. Supporting Evidence: PMID:20093472 PRR functions in a renin-independent manner as an adaptor between Wnt receptors and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex. PMID:20093472 PRR and V-ATPase were required to mediate Wnt signaling during antero-posterior patterning of Xenopus early central nervous system |
| GO:0097401 synaptic vesicle lumen acidification | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Synaptic vesicle lumen acidification is similarity-based and plausible in neuronal contexts, but human ATP6AP2 evidence supports broader V-ATPase-dependent endolysosomal acidification. Reason: Keep as non-core; do not use it as the primary PN projection. Supporting Evidence: PMID:30985297 ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system. |
| GO:0005765 lysosomal membrane | EXP PMID:29127204 Mutations in the X-linked ATP6AP2 cause a glycosylation diso... | ACCEPT | Summary: Experimental evidence supports lysosomal membrane localization. Reason: ATP6AP2 is a single-pass membrane protein acting with the V-ATPase in endolysosomal compartments. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:29127204 In addition, there are two accessory subunits named ATP6AP1 and ATP6AP2. |
| GO:0010008 endosome membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Endosome membrane localization by similarity is consistent with ATP6AP2 endolysosomal V-ATPase function. Reason: The term fits the endosomal acidification role supported by V-ATPase biology. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:29127204 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. |
| GO:0000139 Golgi membrane | NAS PMID:32001091 Structure and Roles of V-type ATPases. | KEEP AS NON CORE | 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. Reason: Keep as a non-core location. Supporting Evidence: PMID:29127204 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. |
| GO:0005765 lysosomal membrane | NAS PMID:32001091 Structure and Roles of V-type ATPases. | ACCEPT | Summary: Lysosomal membrane is a supported core location for ATP6AP2. Reason: This localization matches the lysosomal V-ATPase acidification and PN lysosomal-acidification projection. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:32276428 ATP6AP2 is an important auxiliary component of the V-ATPase complex and coordinates correct V-ATPase assembly |
| GO:0005886 plasma membrane | NAS PMID:32001091 Structure and Roles of V-type ATPases. | KEEP AS NON CORE | Summary: Plasma membrane localization is supported by receptor biology and is distinct from ATP6AP2's endolysosomal V-ATPase localization. Reason: Retain as non-core because the cell-surface renin/prorenin role is separate from the endolysosomal V-ATPase role. Supporting Evidence: PMID:12045255 Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. PMID:12045255 localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery |
| GO:0007035 vacuolar acidification | NAS PMID:32001091 Structure and Roles of V-type ATPases. | MODIFY | Summary: Vacuolar acidification is directionally correct but broad. Reason: For ATP6AP2, the best supported acidification outputs are lysosomal, endosomal, and Golgi lumen acidification through V-ATPase assembly/regulation. Proposed replacements: lysosomal lumen acidification endosomal lumen acidification Golgi lumen acidification Supporting Evidence: PMID:29127204 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. PMID:32276428 To evaluate the effect of ATP6AP2 knockdown on lysosomal pH, we employed an acidophilic fluorescent probe to measure the lysosomal pH, which increased significantly |
| GO:0007042 lysosomal lumen acidification | NAS PMID:32001091 Structure and Roles of V-type ATPases. | ACCEPT | Summary: Lysosomal lumen acidification is a core supported ATP6AP2 process. Reason: ATP6AP2 loss impairs lysosomal acidification and autophagic/protein degradation, matching the PN lysosomal-acidification projection. Supporting Evidence: PMID:29127204 ATP6AP2L98S mutant clones showed a reduction in Lysotracker-positive organelles compared with the WT surrounding tissue, indicating reduced acidity PMID:30985297 severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death PMID:32276428 To evaluate the effect of ATP6AP2 knockdown on lysosomal pH, we employed an acidophilic fluorescent probe to measure the lysosomal pH, which increased significantly |
| GO:0007042 lysosomal lumen acidification | NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of... | ACCEPT | Summary: Lysosomal lumen acidification is supported as the functional output of the V-ATPase complex that includes ATP6AP2. Reason: The ComplexPortal structural annotation is consistent with ATP6AP2 V-ATPase complex membership and the direct loss-of-function acidification evidence. Supporting Evidence: PMID:33065002 acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. file:human/ATP6AP2/ATP6AP2-uniprot.txt Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase protein pump PMID:32276428 To evaluate the effect of ATP6AP2 knockdown on lysosomal pH, we employed an acidophilic fluorescent probe to measure the lysosomal pH, which increased significantly |
| GO:0010008 endosome membrane | NAS PMID:32001091 Structure and Roles of V-type ATPases. | ACCEPT | Summary: Endosome membrane localization is consistent with ATP6AP2 as an endolysosomal V-ATPase accessory protein. Reason: Keep as a supported location. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:29127204 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. |
| GO:0016020 membrane | IDA PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of... | MODIFY | Summary: Generic membrane is too broad for the ComplexPortal V-ATPase evidence. Reason: The same evidence should be represented as V-ATPase complex membership and/or specific endolysosomal membrane localization rather than generic membrane. Proposed replacements: proton-transporting V-type ATPase complex vacuolar proton-transporting V-type ATPase complex lysosomal membrane Supporting Evidence: PMID:33065002 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. file:human/ATP6AP2/ATP6AP2-uniprot.txt Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase protein pump |
| GO:0033176 proton-transporting V-type ATPase complex | NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of... | ACCEPT | Summary: ATP6AP2 is part of the proton-transporting V-type ATPase complex. Reason: Complex membership is supported by UniProt and the assembly/interactor literature, and is central to ATP6AP2 function. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase protein pump PMID:29127204 Together, these results suggest that ATP6AP2 forms a complex with other V-ATPase assembly factors |
| GO:0048388 endosomal lumen acidification | NAS PMID:32001091 Structure and Roles of V-type ATPases. | ACCEPT | Summary: Endosomal lumen acidification is a supported V-ATPase-dependent process for ATP6AP2. Reason: ATP6AP2 regulates V-ATPase assembly/activity in the endolysosomal system, so this is an appropriate process-level annotation. Supporting Evidence: PMID:29127204 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. PMID:32276428 ATP6AP2 is an important auxiliary component of the V-ATPase complex and coordinates correct V-ATPase assembly |
| GO:0051452 intracellular pH reduction | NAS PMID:32001091 Structure and Roles of V-type ATPases. | MODIFY | Summary: Intracellular pH reduction is too broad. Reason: Use compartment-specific acidification terms that preserve the V-ATPase/endolysosomal mechanism. Proposed replacements: lysosomal lumen acidification endosomal lumen acidification Golgi lumen acidification Supporting Evidence: PMID:29127204 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. PMID:32276428 To evaluate the effect of ATP6AP2 knockdown on lysosomal pH, we employed an acidophilic fluorescent probe to measure the lysosomal pH, which increased significantly |
| GO:0061795 Golgi lumen acidification | NAS PMID:32001091 Structure and Roles of V-type ATPases. | ACCEPT | Summary: Golgi lumen acidification is a plausible V-ATPase-dependent process for ATP6AP2. Reason: ATP6AP2 participates in V-ATPase assembly/function across secretory and endocytic compartments; this process is credible but less central than lysosomal/endosomal acidification. Supporting Evidence: PMID:29127204 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. |
| GO:1902600 proton transmembrane transport | NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of... | MODIFY | Summary: Proton transmembrane transport is a complex activity and overstates the individual role of ATP6AP2. 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 replacements: vacuolar proton-transporting V-type ATPase complex vacuolar proton-transporting V-type ATPase complex assembly ATPase regulator activity Supporting Evidence: PMID:29127204 Our results suggest that ATP6AP2 has a crucial role in V-ATPase assembly, both in invertebrates and vertebrates. PMID:32276428 ATP6AP2 is an important auxiliary component of the V-ATPase complex and coordinates correct V-ATPase assembly |
| GO:0000220 vacuolar proton-transporting V-type ATPase, V0 domain | ISS GO_REF:0000024 | ACCEPT | Summary: V0-domain membership by similarity fits the conserved ATP6AP2 V-ATPase accessory role. Reason: ATP6AP2 interacts with V0 assembly factors and supports V-ATPase assembly. Supporting Evidence: PMID:29127204 Together, these results suggest that ATP6AP2 forms a complex with other V-ATPase assembly factors PMID:29127204 Our results suggest that ATP6AP2 has a crucial role in V-ATPase assembly, both in invertebrates and vertebrates. |
| GO:0016471 vacuolar proton-transporting V-type ATPase complex | IMP PMID:30985297 ATP6AP2 variant impairs CNS development and neuronal surviva... | ACCEPT | Summary: ATP6AP2 is part of the vacuolar proton-transporting V-type ATPase complex. Reason: The patient-derived neuron and mouse data show ATP6AP2 deficiency decreases V-ATPase membrane assembly, supporting complex membership and functional relevance. Supporting Evidence: PMID:30985297 ATP6AP2 deficiency decreases V-ATPase membrane assembly file:human/ATP6AP2/ATP6AP2-uniprot.txt Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase protein pump |
| GO:0005765 lysosomal membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Lysosomal membrane localization by similarity is consistent with direct human lysosomal/V-ATPase evidence. Reason: Retain as a relevant core location. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:32276428 ATP6AP2 is an important auxiliary component of the V-ATPase complex and coordinates correct V-ATPase assembly |
| GO:0021626 central nervous system maturation | IMP PMID:30985297 ATP6AP2 variant impairs CNS development and neuronal surviva... | KEEP AS NON CORE | Summary: CNS maturation is experimentally supported but reflects a developmental consequence of V-ATPase dysfunction. Reason: Keep as a non-core biological process in the PN context. Supporting Evidence: PMID:30985297 severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death PMID:30985297 ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system. |
| GO:0005515 protein binding | IPI PMID:30374053 TMEM9 promotes intestinal tumorigenesis through vacuolar-ATP... | MODIFY | Summary: Protein binding to TMEM9/V-ATPase components is mechanistically meaningful but should not remain as generic protein binding. Reason: The better functional endpoint for ATP6AP2 is ATPase regulator activity and V-ATPase complex assembly. Proposed replacements: ATPase regulator activity vacuolar proton-transporting V-type ATPase complex assembly Supporting Evidence: PMID:30374053 TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking. PMID:32276428 ATP6AP2 is an important auxiliary component of the V-ATPase complex and coordinates correct V-ATPase assembly |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IMP PMID:30374053 TMEM9 promotes intestinal tumorigenesis through vacuolar-ATP... | KEEP AS NON CORE | Summary: Canonical Wnt signaling regulation is supported through V-ATPase-dependent vesicular acidification but is context-specific. Reason: Keep as a real non-core signaling output rather than a core PN proteostasis annotation. Supporting Evidence: PMID:20093472 PRR functions in a renin-independent manner as an adaptor between Wnt receptors and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex. PMID:30374053 TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking. |
| GO:0007042 lysosomal lumen acidification | IMP PMID:32276428 Interaction between PHB2 and Enterovirus A71 VP1 Induces Aut... | ACCEPT | Summary: ATP6AP2 knockdown directly increased lysosomal pH in the EV-A71 study, supporting lysosomal lumen acidification. Reason: This is direct functional support for the PN lysosomal acidification projection, even though the viral infection phenotype is context-specific. Supporting Evidence: PMID:32276428 ATP6AP2 is an important auxiliary component of the V-ATPase complex and coordinates correct V-ATPase assembly PMID:32276428 To evaluate the effect of ATP6AP2 knockdown on lysosomal pH, we employed an acidophilic fluorescent probe to measure the lysosomal pH, which increased significantly |
| GO:0005515 protein binding | IPI PMID:29127204 Mutations in the X-linked ATP6AP2 cause a glycosylation diso... | MODIFY | Summary: ATP6AP2 interactions with ATP6AP1/VMA21 and V0 factors should not be represented as generic protein binding. Reason: Replace with ATPase regulator activity and V-ATPase complex assembly, which capture the molecular consequence of these interactions. Proposed replacements: ATPase regulator activity vacuolar proton-transporting V-type ATPase complex assembly Supporting Evidence: PMID:29127204 Together, these results suggest that ATP6AP2 forms a complex with other V-ATPase assembly factors PMID:29127204 Our results suggest that ATP6AP2 has a crucial role in V-ATPase assembly, both in invertebrates and vertebrates. |
| GO:0005764 lysosome | IDA PMID:29127204 Mutations in the X-linked ATP6AP2 cause a glycosylation diso... | ACCEPT | Summary: Direct lysosome localization is consistent with ATP6AP2 endolysosomal V-ATPase function. Reason: This is a valid location annotation, though the membrane term is more precise where available. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:29127204 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. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:29127204 Mutations in the X-linked ATP6AP2 cause a glycosylation diso... | ACCEPT | Summary: ER membrane localization is supported and mechanistically important for V0 assembly-factor interaction. Reason: The literature places ATP6AP2 in ER-based V-ATPase assembly and shows ER retrieval is functionally important. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane PMID:29127204 Our results suggest that ATP6AP2 has a crucial role in V-ATPase assembly, both in invertebrates and vertebrates. |
| GO:0016471 vacuolar proton-transporting V-type ATPase complex | IMP PMID:29127204 Mutations in the X-linked ATP6AP2 cause a glycosylation diso... | ACCEPT | Summary: ATP6AP2 is part of the vacuolar proton-transporting V-type ATPase complex. Reason: This is a core cellular-component annotation supported by interaction and deficiency evidence. Supporting Evidence: PMID:29127204 Together, these results suggest that ATP6AP2 forms a complex with other V-ATPase assembly factors PMID:30985297 ATP6AP2 deficiency decreases V-ATPase membrane assembly |
| GO:0070821 tertiary granule membrane | TAS Reactome:R-HSA-6798747 | KEEP AS NON CORE | Summary: Tertiary granule membrane localization from Reactome/neutrophil degranulation may be valid but is peripheral to ATP6AP2 core function. Reason: Retain as non-core; do not use for PN proteostasis projection. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane |
| GO:0101003 ficolin-1-rich granule membrane | TAS Reactome:R-HSA-6800426 | KEEP AS NON CORE | Summary: Ficolin-1-rich granule membrane localization is a peripheral Reactome/neutrophil context. Reason: Keep as non-core because it does not change the core V-ATPase accessory interpretation. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Extracellular exosome detection is high-throughput localization evidence and may reflect vesicle shedding/secretory biology. Reason: Keep as non-core and avoid using it as a core functional annotation. Supporting Evidence: PMID:23533145 In pooled EPS-urine exosome samples, ~900 proteins were detected. |
| GO:0005515 protein binding | IPI PMID:20093472 Requirement of prorenin receptor and vacuolar H+-ATPase-medi... | MODIFY | Summary: Protein binding in the Wnt/V-ATPase receptor-complex paper is mechanistically meaningful but too vague. Reason: Replace with ATPase regulator activity and V-ATPase complex assembly rather than retaining generic binding. Proposed replacements: ATPase regulator activity vacuolar proton-transporting V-type ATPase complex assembly Supporting Evidence: PMID:20093472 PRR functions in a renin-independent manner as an adaptor between Wnt receptors and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex. PMID:29127204 Our results suggest that ATP6AP2 has a crucial role in V-ATPase assembly, both in invertebrates and vertebrates. |
| GO:0021903 rostrocaudal neural tube patterning | IMP PMID:20093472 Requirement of prorenin receptor and vacuolar H+-ATPase-medi... | KEEP AS NON CORE | Summary: Rostrocaudal neural tube patterning is supported in the Wnt/V-ATPase developmental model but is a downstream developmental phenotype. Reason: Keep as non-core in this human PN review. Supporting Evidence: PMID:20093472 PRR and V-ATPase were required to mediate Wnt signaling during antero-posterior patterning of Xenopus early central nervous system |
| GO:0030177 positive regulation of Wnt signaling pathway | IMP PMID:20093472 Requirement of prorenin receptor and vacuolar H+-ATPase-medi... | KEEP AS NON CORE | Summary: Positive regulation of Wnt signaling is supported but secondary to ATP6AP2 V-ATPase/receptor-adaptor function. Reason: The annotation is valid as a context-specific signaling role, not the core PN proteostasis function. Supporting Evidence: PMID:20093472 PRR functions in a renin-independent manner as an adaptor between Wnt receptors and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex. PMID:20093472 PRR and V-ATPase were required to mediate Wnt signaling during antero-posterior patterning of Xenopus early central nervous system |
| GO:0048069 eye pigmentation | IMP PMID:20093472 Requirement of prorenin receptor and vacuolar H+-ATPase-medi... | KEEP AS NON CORE | Summary: Eye pigmentation is an organismal/developmental phenotype from the Wnt/V-ATPase study. Reason: Keep as non-core because it is downstream of signaling/acidification rather than a direct molecular function. Supporting Evidence: PMID:20093472 PRR and V-ATPase were required to mediate Wnt signaling during antero-posterior patterning of Xenopus early central nervous system |
| GO:0060323 head morphogenesis | IMP PMID:20093472 Requirement of prorenin receptor and vacuolar H+-ATPase-medi... | KEEP AS NON CORE | Summary: Head morphogenesis is an organismal/developmental phenotype from the Wnt/V-ATPase study. Reason: Keep as non-core for the same reason as other developmental outputs. Supporting Evidence: PMID:20093472 PRR and V-ATPase were required to mediate Wnt signaling during antero-posterior patterning of Xenopus early central nervous system |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: Parotid exosome detection is high-throughput localization evidence and not a core ATP6AP2 role. Reason: Keep as non-core. Supporting Evidence: PMID:19199708 Using MudPIT (multidimensional protein identification technology) mass spectrometry, we catalogued 491 proteins in the exosome fraction of human parotid saliva. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Urinary exosome detection is high-throughput localization evidence and not a core ATP6AP2 role. Reason: Keep as non-core. Supporting Evidence: PMID:19056867 Normal human urine contains large numbers of exosomes, which are 40- to 100-nm vesicles |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2022403 | KEEP AS NON CORE | Summary: Plasma membrane localization is supported in the renin/prorenin receptor context. Reason: Retain as a non-core receptor-context location distinct from the endolysosomal V-ATPase role. Supporting Evidence: PMID:12045255 Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. PMID:12045255 localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2065357 | KEEP AS NON CORE | Summary: Plasma membrane localization is supported in the prorenin receptor/angiotensinogen context. Reason: Retain as non-core. Supporting Evidence: PMID:12045255 Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. PMID:12045255 localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6798747 | KEEP AS NON CORE | Summary: Plasma membrane localization associated with neutrophil degranulation is peripheral to ATP6AP2 core function. Reason: Keep as non-core. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6800426 | KEEP AS NON CORE | Summary: Plasma membrane localization associated with ficolin-rich granule exocytosis is peripheral to ATP6AP2 core function. Reason: Keep as non-core. Supporting Evidence: file:human/ATP6AP2/ATP6AP2-uniprot.txt Endoplasmic reticulum membrane |
| GO:0032914 positive regulation of transforming growth factor beta1 production | IDA PMID:16374430 Renin increases mesangial cell transforming growth factor-be... | KEEP AS NON CORE | 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. Reason: Keep as non-core; it should not affect the PN projection. Supporting Evidence: PMID:16374430 renin upregulates MC TGF-beta1 through a receptor-mediated mechanism |
| GO:0002003 angiotensin maturation | IDA PMID:15746149 A unique exonic splice enhancer mutation in a family with X-... | KEEP AS NON CORE | Summary: Angiotensin maturation is supported through ATP6AP2/renin binding and reflects receptor/RAS biology rather than ATP6AP2's V-ATPase accessory role. Reason: Retain as a non-core receptor/RAS role. Supporting Evidence: PMID:15746149 the mutated receptor could bind renin and increase renin catalytic activity PMID:12045255 The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I |
| GO:0009897 external side of plasma membrane | IDA PMID:15746149 A unique exonic splice enhancer mutation in a family with X-... | KEEP AS NON CORE | Summary: External side of plasma membrane localization is supported by receptor studies. Reason: Keep as non-core because ATP6AP2 core biology is endolysosomal V-ATPase assembly/acidification. Supporting Evidence: PMID:12045255 localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery PMID:15746149 the mutated receptor could bind renin and increase renin catalytic activity |
| GO:0043408 regulation of MAPK cascade | IDA PMID:15746149 A unique exonic splice enhancer mutation in a family with X-... | KEEP AS NON CORE | Summary: MAPK cascade regulation is supported in the renin/prorenin receptor context and is distinct from ATP6AP2's endolysosomal V-ATPase role. Reason: Retain as non-core signaling. Supporting Evidence: PMID:15746149 modest and reproducible impairment of ERK1/2 activation PMID:12045255 activation of MAP kinases ERK1 and ERK2 |
| GO:0002003 angiotensin maturation | IDA PMID:12045255 Pivotal role of the renin/prorenin receptor in angiotensin I... | KEEP AS NON CORE | Summary: Angiotensin maturation is supported by the original receptor paper and reflects receptor/RAS biology rather than ATP6AP2's V-ATPase accessory role. Reason: Retain as a separate receptor/RAS role. Supporting Evidence: PMID:12045255 Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. PMID:12045255 The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I |
| GO:0005515 protein binding | IPI PMID:12045255 Pivotal role of the renin/prorenin receptor in angiotensin I... | MODIFY | Summary: Renin/prorenin protein binding is real but the generic protein-binding term is uninformative. Reason: Use signaling receptor activity for this receptor role rather than generic protein binding. Proposed replacements: signaling receptor activity Supporting Evidence: PMID:12045255 Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. PMID:12045255 activation of MAP kinases ERK1 and ERK2 |
| GO:0009897 external side of plasma membrane | IDA PMID:12045255 Pivotal role of the renin/prorenin receptor in angiotensin I... | KEEP AS NON CORE | Summary: External side of plasma membrane localization is supported by the original renin/prorenin receptor work. Reason: Keep as a non-core location. Supporting Evidence: PMID:12045255 Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. PMID:12045255 localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery |
| GO:0043408 regulation of MAPK cascade | IDA PMID:12045255 Pivotal role of the renin/prorenin receptor in angiotensin I... | KEEP AS NON CORE | Summary: MAPK cascade regulation is supported by renin/prorenin receptor signaling and is distinct from ATP6AP2's endolysosomal V-ATPase role. Reason: Retain as non-core signaling. Supporting Evidence: PMID:12045255 activation of MAP kinases ERK1 and ERK2 PMID:15746149 modest and reproducible impairment of ERK1/2 activation |
| GO:0060590 ATPase regulator activity | IMP PMID:29127204 Mutations in the X-linked ATP6AP2 cause a glycosylation diso... | NEW | Summary: ATP6AP2 has ATPase regulator activity as an accessory/regulatory factor for lysosomal V-ATPase assembly and acidification. 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. Supporting Evidence: PMID:29127204 Our results suggest that ATP6AP2 has a crucial role in V-ATPase assembly, both in invertebrates and vertebrates. PMID:32276428 ATP6AP2 is an important auxiliary component of the V-ATPase complex and coordinates correct V-ATPase assembly PMID:32276428 To evaluate the effect of ATP6AP2 knockdown on lysosomal pH, we employed an acidophilic fluorescent probe to measure the lysosomal pH, which increased significantly file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv ATP6AP2 Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|Regulator of the lysosomal v-ATPase proton pump |
| GO:0070072 vacuolar proton-transporting V-type ATPase complex assembly | IMP PMID:29127204 Mutations in the X-linked ATP6AP2 cause a glycosylation diso... | NEW | Summary: ATP6AP2 is involved in vacuolar proton-transporting V-type ATPase complex assembly. 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. Supporting Evidence: PMID:29127204 Together, these results suggest that ATP6AP2 forms a complex with other V-ATPase assembly factors PMID:29127204 Our results suggest that ATP6AP2 has a crucial role in V-ATPase assembly, both in invertebrates and vertebrates. PMID:30985297 ATP6AP2 deficiency decreases V-ATPase membrane assembly PMID:32276428 ATP6AP2 is an important auxiliary component of the V-ATPase complex and coordinates correct V-ATPase assembly |
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Download this section (compressed HTML)Q: Would GO benefit from a more specific molecular-function term for lysosomal V-ATPase accessory/regulator activity, narrower than ATPase regulator activity?
Q: Which ATP6AP2 receptor/adaptor activities require the full-length plasma-membrane protein versus the cleaved endomembrane fragments?
Experiment: 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.
Hypothesis: ATP6AP2 regulates lysosomal V-ATPase assembly and acidification independently of its renin/prorenin receptor signaling role.
Type: rescue and structure-function assay
Experiment: 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.
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.
Type: parallel functional phenotyping
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