Existing Annotations Review

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

Core Functions

Supports V-ATPase assembly and activity as an accessory/regulatory factor, enabling endolysosomal acidification and lysosomal protein degradation.

Molecular Function:

ATPase regulator activity

Directly Involved In:

vacuolar proton-transporting V-type ATPase complex assembly lysosomal lumen acidification endosomal lumen acidification

Cellular Locations:

endoplasmic reticulum membrane lysosomal membrane endosome membrane

In Complex:

vacuolar proton-transporting V-type ATPase complex

Supporting Evidence:

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
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

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

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

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

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

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:29127204

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

ATP6AP2 is an accessory V-ATPase subunit needed for V-ATPase assembly, organelle acidification, glycosylation, and autophagic degradation.

"Our results suggest that ATP6AP2 has a crucial role in V-ATPase assembly, both in invertebrates and vertebrates."
ATP6AP2 interacts with V0 assembly factors including ATP6AP1 and VMA21.

"Together, these results suggest that ATP6AP2 forms a complex with other V-ATPase assembly factors"
ATP6AP2 loss-of-function reduces lysosomal acidity and impairs autophagic degradation.

"ATP6AP2L98S mutant clones showed a reduction in Lysotracker-positive organelles compared with the WT surrounding tissue, indicating reduced acidity"

PMID:30985297

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration.

ATP6AP2 deficiency impairs lysosomal acidification, protein degradation, and V-ATPase membrane assembly in neuronal disease models.

"severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death"
The authors conclude ATP6AP2 mediates V-ATPase-dependent signaling and protein degradation in the developing CNS.

"ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system."

PMID:32276428

Interaction between PHB2 and Enterovirus A71 VP1 Induces Autophagy and Affects EV-A71 Infection.

ATP6AP2 knockdown increases lysosomal pH and inhibits autolysosomal degradation in a viral autophagy model.

"To evaluate the effect of ATP6AP2 knockdown on lysosomal pH, we employed an acidophilic fluorescent probe to measure the lysosomal pH, which increased significantly"
The paper explicitly treats ATP6AP2 as an auxiliary V-ATPase component coordinating correct assembly.

"ATP6AP2 is an important auxiliary component of the V-ATPase complex and coordinates correct V-ATPase assembly"

PMID:33065002

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

Human V-ATPases are ATP-driven proton pumps responsible for organelle and vesicle acidification.

"V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer."

PMID:20093472

Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling.

PRR/ATP6AP2 acts as an adaptor between Wnt receptors and the V-ATPase complex.

"PRR functions in a renin-independent manner as an adaptor between Wnt receptors and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex."
The Wnt developmental phenotypes are supported but secondary to the V-ATPase-linked receptor/adaptor role.

"PRR and V-ATPase were required to mediate Wnt signaling during antero-posterior patterning of Xenopus early central nervous system"

PMID:30374053

TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/β-catenin signalling.

TMEM9/V-ATPase assembly and vesicular acidification provide additional support for the Wnt-acidification connection.

"TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking."

PMID:12045255

Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin.

ATP6AP2 is a renin/prorenin receptor that binds renin/prorenin, increases angiotensinogen conversion, and activates ERK1/2.

"Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding."

PMID:15746149

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.

A splice-affecting ATP6AP2 variant supports a role in brain development while preserving renin binding/catalytic enhancement.

"indicate a novel specific role for the renin receptor in cognitive functions and brain development."

PMID:16374430

Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms.

Renin-induced TGF-beta1 production is receptor-mediated and angiotensin-II-independent in mesangial cells.

"renin upregulates MC TGF-beta1 through a receptor-mediated mechanism"

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

High-throughput source supporting a peripheral localization or interaction annotation.

"Normal human urine contains large numbers of exosomes, which are 40- to 100-nm vesicles"

PMID:19199708

Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).

High-throughput source supporting a peripheral localization or interaction annotation.

"Using MudPIT (multidimensional protein identification technology) mass spectrometry, we catalogued 491 proteins in the exosome fraction of human parotid saliva."

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

High-throughput source supporting a peripheral localization or interaction annotation.

"In pooled EPS-urine exosome samples, ~900 proteins were detected."

PMID:32296183

A reference map of the human binary protein interactome.

High-throughput source supporting a peripheral localization or interaction annotation.

"Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'."

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

High-throughput source supporting a peripheral localization or interaction annotation.

"Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins"

PMID:32001091

Structure and Roles of V-type ATPases.

Reactome:R-HSA-2022403

Renin:Prorenin Receptor hydrolyzes Angiotensinogen to AGT(25-34) (Angiotensin-(1-10))

Reactome:R-HSA-2065357

Prorenin:Prorenin Receptor hydrolyzes Angiotensinogen to AGT(25-35) (Angiotensin-(1-10))

Reactome:R-HSA-6798747

Exocytosis of tertiary granule membrane proteins

Reactome:R-HSA-6800426

Exocytosis of ficolin-rich granule membrane proteins

file:human/ATP6AP2/ATP6AP2-uniprot.txt

UniProt record for human ATP6AP2

UniProt summarizes ATP6AP2 as a multifunctional renin/prorenin receptor and V-ATPase accessory protein involved in endolysosomal acidification.

"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"
UniProt records ATP6AP2 as an accessory component of the multisubunit V-ATPase pump.

"Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase protein pump"

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

Proteostasis Network projected annotations for ATP6AP2

The PN projection maps ATP6AP2 to lysosomal acidification and ATPase regulator activity from the lysosomal V-ATPase regulator leaves.

"ATP6AP2 Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|Regulator of the lysosomal v-ATPase proton pump"

Suggested Experiments

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

Deep Research

Falcon

(ATP6AP2-deep-research-falcon.md)

Comprehensive Research Report: ATP6AP2 (Gene ID: ATP6AP2, UniProt: O75787) in Homo sapiens Falcon

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

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

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

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

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

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

Comprehensive Research Report: ATP6AP2 (Gene ID: ATP6AP2, UniProt: O75787) in Homo sapiens

Gene Identity Confirmation

ATP6AP2 (ATPase H+ transporting accessory protein 2) encodes the (pro)renin receptor ((P)RR) in humans, a multifunctional single-transmembrane protein consisting of 350 amino acids (kourieh2025overviewofrenin pages 1-4, wang2020the(pro)reninreceptor pages 1-3). The gene is located on the X chromosome and is ubiquitously expressed across multiple human tissues including brain, heart, liver, pancreas, kidney, and placenta (wang2020the(pro)reninreceptor pages 1-3). This confirms that the gene symbol ATP6AP2 correctly matches the UniProt O75787 entry for the renin receptor/prorenin receptor.

Primary Molecular Functions

ATP6AP2 exhibits dual primary molecular functions that are both well-characterized in recent literature (eaton2021theh+atpase(vatpase) pages 1-5, kourieh2025overviewofrenin pages 1-4, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3):

Function 1: (Pro)renin Receptor

ATP6AP2 functions as a high-affinity cell-surface receptor for both renin and its inactive precursor prorenin (kourieh2025overviewofrenin pages 1-4, kourieh2025overviewofrenin pages 4-8, wang2020the(pro)reninreceptor pages 1-3). When prorenin binds to ATP6AP2, the receptor induces a non-proteolytic conformational change in the prorenin molecule that exposes its catalytic site, effectively activating prorenin without requiring proteolytic cleavage of the pro-segment (kourieh2025overviewofrenin pages 1-4, kourieh2025overviewofrenin pages 4-8). When active renin binds to ATP6AP2, the receptor increases renin's catalytic efficiency for cleaving angiotensinogen to angiotensin I by approximately 4-fold (kourieh2025overviewofrenin pages 1-4). This receptor-ligand interaction amplifies local tissue renin-angiotensin system (RAS) activity independent of circulating renin levels (marrerobras2026theproreninreceptor pages 1-3, patel2022endothelialcellpolarity pages 1-2, wang2020the(pro)reninreceptor pages 1-3).

Substrate Specificity: The primary ligands are renin and prorenin. The functional enzymatic substrate affected by the ATP6AP2-renin/prorenin complex is angiotensinogen, which is converted to angiotensin I (kourieh2025overviewofrenin pages 1-4, kourieh2025overviewofrenin pages 4-8). Angiotensin I is subsequently processed by angiotensin-converting enzyme to generate angiotensin II, the primary bioactive peptide of the RAS.

Function 2: V-ATPase Accessory Protein

ATP6AP2 is an essential accessory subunit of the vacuolar H+-ATPase (V-ATPase), a large multi-subunit proton pump complex (eaton2021theh+atpase(vatpase) pages 1-5, falace2024vatpasedysfunctionin pages 1-3, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3). Structural studies using cryo-electron microscopy have revealed that ATP6AP2 localizes to the membrane-embedded V0 domain of V-ATPase, where its transmembrane anchor is critical for assembly of the enzyme's catalytic V1 and membrane V0 regions (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3). The V-ATPase complex uses ATP hydrolysis to pump protons across membranes, generating the acidic pH required for lysosomal function, endocytic trafficking, autophagy, and protein degradation (eaton2021theh+atpase(vatpase) pages 1-5, falace2024vatpasedysfunctionin pages 1-3, figueiredo2021the(pro)reninreceptor pages 1-2).

Mechanistic Role: Loss of ATP6AP2 impairs V-ATPase assembly and activity, leading to defective organellar acidification, accumulation of autophagosomes, impaired receptor-mediated endocytosis, and compromised lysosomal degradation (figueiredo2021the(pro)reninreceptor pages 1-2, ohba2020(pro)reninreceptoratp6ap2is pages 1-6). ATP6AP2 undergoes proteolytic cleavage in the trans-Golgi network by enzymes such as furin, site-1 protease (S1P), or ADAM19, generating a 28-kDa soluble extracellular fragment (soluble (P)RR or sPRR) and a truncated membrane-associated fragment termed M8.9 that remains associated with V-ATPase (kourieh2025overviewofrenin pages 1-4, kourieh2025overviewofrenin pages 4-8).

Function 3: Protein Trafficking and Receptor Stability

Beyond its receptor and V-ATPase functions, ATP6AP2 plays crucial roles in regulating protein trafficking and membrane protein stability (xiong2024atp6ap2aregulator pages 1-2, wang2023(pro)reninreceptorpromotes pages 1-2, figueiredo2021the(pro)reninreceptor pages 1-2). Recent evidence demonstrates that ATP6AP2 is required for proper trafficking and membrane localization of LRP6/β-catenin and N-cadherin/β-catenin protein complexes in the Wnt signaling pathway (xiong2024atp6ap2aregulator pages 1-2). ATP6AP2 prevents degradation of these complexes by maintaining their distribution at the cell membrane (xiong2024atp6ap2aregulator pages 1-2). In the renal proximal tubule, ATP6AP2 facilitates receptor-mediated endocytosis of low molecular weight proteins via megalin/cubilin receptors, with ATP6AP2 deficiency causing delayed processing and trafficking of endocytic cargo to lysosomes (figueiredo2021the(pro)reninreceptor pages 1-2).

Function Category	Specific Role	Molecular Mechanism	Substrates/Ligands	Key Citations
Receptor function for renin/prorenin	Cell-surface and tissue (pro)renin receptor that amplifies local renin-angiotensin signaling	ATP6AP2 is a single-pass transmembrane receptor encoded by the X-linked ATP6AP2 gene. Its extracellular domain binds both renin and prorenin; prorenin binding induces a conformational, non-proteolytic activation that exposes the catalytic site, while renin binding increases catalytic efficiency for angiotensinogen cleavage to angiotensin I (reported as ~4-fold in review literature). Binding also triggers angiotensin II-independent intracellular signaling including ERK1/2-MAPK and p38 pathways, with reported induction of profibrotic and remodeling programs.	Primary ligands: renin, prorenin. Functional enzymatic substrate affected: angiotensinogen (converted by bound renin/prorenin to angiotensin I).	(kourieh2025overviewofrenin pages 1-4, kourieh2025overviewofrenin pages 4-8, patel2022endothelialcellpolarity pages 1-2, wang2020the(pro)reninreceptor pages 1-3)
V-ATPase accessory protein	Essential accessory/assembly factor of the vacuolar H+-ATPase required for organellar acidification	ATP6AP2 is also the V-ATPase accessory protein ATPase H+ transporting accessory protein 2. Structural studies place ATP6AP2/PRR in the membrane V0 region, where its transmembrane anchor contributes to assembly of catalytic and membrane sectors of mammalian V-ATPase. Functionally, loss of ATP6AP2 impairs V-ATPase-dependent acidification, lysosomal integrity, autophagy, endocytosis, and vesicle function. Reviews further describe the cleaved M8.9 fragment as the V-ATPase-associated membrane/cytoplasmic portion.	No classical transported substrate of ATP6AP2 itself; instead it supports V-ATPase proton pumping. Functional product/process supported: transmembrane H+ transport and acidification of endosomes, lysosomes, Golgi-related compartments, and specialized vesicles.	(falace2024vatpasedysfunctionin pages 1-3, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, figueiredo2021the(pro)reninreceptor pages 1-2, ohba2020(pro)reninreceptoratp6ap2is pages 1-6)
Protein trafficking/localization roles	Regulator of receptor trafficking, membrane protein stability, endocytosis, and compartment-specific signaling	ATP6AP2 functions beyond ligand binding as a trafficking/scaffolding factor. In Wnt signaling contexts it acts with the Wnt receptor complex and promotes LRP6/β-catenin and N-cadherin/β-catenin complex distribution/stability at the cell membrane, limiting degradation. In renal proximal tubule models, ATP6AP2 deficiency delays receptor-mediated delivery of cargo to lysosomes without abolishing fluid-phase uptake, consistent with a role in endocytic trafficking. Localization is context-dependent: plasma membrane for renin/prorenin binding; intracellular endosomes/lysosomes and other vesicular membranes with V-ATPase; trans-Golgi for proteolytic cleavage to soluble PRR and M8.9 fragment.	Trafficking-associated partners/cargo include LRP6, β-catenin, N-cadherin, Frizzled-related/Wnt receptor machinery, megalin/cubilin-dependent endocytic cargo such as transferrin, albumin, vitamin D-binding protein, and lysosomal/autophagic components.	(xiong2024atp6ap2aregulator pages 1-2, wang2023(pro)reninreceptorpromotes pages 1-2, figueiredo2021the(pro)reninreceptor pages 1-2, wang2020the(pro)reninreceptor pages 1-3)

Table: This table summarizes the main molecular functions of human ATP6AP2, separating its roles as a renin/prorenin receptor, a V-ATPase accessory protein, and a trafficking/localization regulator. It is useful for clarifying ATP6AP2’s primary biochemical activities, ligands, and mechanistic evidence from the cited literature.

Subcellular Localization

ATP6AP2 exhibits context-dependent and tissue-specific subcellular localization patterns (eaton2021theh+atpase(vatpase) pages 1-5, falace2024vatpasedysfunctionin pages 1-3, abbas2020structureofvatpase pages 1-2, figueiredo2021the(pro)reninreceptor pages 1-2):

Plasma Membrane

ATP6AP2 localizes to the plasma membrane where it functions as a cell-surface receptor for renin and prorenin (kourieh2025overviewofrenin pages 1-4, patel2022endothelialcellpolarity pages 1-2, wang2020the(pro)reninreceptor pages 1-3). This localization is particularly prominent in specialized cell types including vascular endothelial cells, renal juxtaglomerular cells, and placental trophoblasts (schofield2023placentaldeficiencyof pages 1-2, patel2022endothelialcellpolarity pages 1-2).

Endosomes and Lysosomes

As a V-ATPase accessory protein, ATP6AP2 localizes extensively to intracellular vesicular compartments including early endosomes, late endosomes, and lysosomes (eaton2021theh+atpase(vatpase) pages 1-5, falace2024vatpasedysfunctionin pages 1-3, figueiredo2021the(pro)reninreceptor pages 1-2). In these compartments, ATP6AP2 is essential for maintaining proper acidification required for cargo processing, protein degradation, and membrane trafficking (figueiredo2021the(pro)reninreceptor pages 1-2, ohba2020(pro)reninreceptoratp6ap2is pages 1-6).

Trans-Golgi Network

Full-length ATP6AP2 undergoes proteolytic cleavage in the trans-Golgi network, where it is processed by proteases to generate the soluble sPRR fragment and the membrane-associated M8.9 fragment (kourieh2025overviewofrenin pages 1-4, kourieh2025overviewofrenin pages 4-8). This cleavage event is important for generating the circulating soluble form of the receptor that can function as a biomarker and potentially as a signaling molecule (marrerobras2026theproreninreceptor pages 1-3, kourieh2025overviewofrenin pages 1-4).

Synaptic Vesicles

In neurons, ATP6AP2 localizes to synaptic vesicles where V-ATPase activity is essential for generating the proton gradient required for neurotransmitter loading into vesicles (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3). Structural studies of V-ATPase isolated from rat brain synaptic vesicles have confirmed ATP6AP2 as a core component (abbas2020structureofvatpase pages 1-2).

Tissue-Specific Expression

ATP6AP2 is widely expressed but shows particularly high expression in kidney (proximal tubule, collecting duct), heart (cardiomyocytes), brain (neurons, astrocytes, microglia), placenta (trophoblasts), and endothelial cells across multiple vascular beds (schofield2023placentaldeficiencyof pages 1-2, marrerobras2026theproreninreceptor pages 1-3, patel2022endothelialcellpolarity pages 1-2, figueiredo2021the(pro)reninreceptor pages 1-2).

Signaling and Biochemical Pathways

ATP6AP2 participates in multiple interconnected signaling pathways, reflecting its multifunctional nature (eaton2021theh+atpase(vatpase) pages 1-5, xiong2024atp6ap2aregulator pages 1-2, marrerobras2026theproreninreceptor pages 1-3, wang2023(pro)reninreceptorpromotes pages 1-2, kourieh2025overviewofrenin pages 4-8, patel2022endothelialcellpolarity pages 1-2, wang2020the(pro)reninreceptor pages 1-3):

Pathway Name	ATP6AP2 Role in Pathway	Molecular Mechanism	Downstream Effects	Key Evidence
Renin-Angiotensin System (RAS)	Cell-surface (pro)renin receptor that amplifies local/tissue RAS	ATP6AP2 is a single-pass transmembrane receptor whose extracellular domain binds both renin and prorenin; prorenin binding induces non-proteolytic activation, and renin binding increases catalytic efficiency of angiotensinogen cleavage to angiotensin I, enhancing local Ang I/Ang II generation (kourieh2025overviewofrenin pages 1-4, kourieh2025overviewofrenin pages 4-8, patel2022endothelialcellpolarity pages 1-2, wang2020the(pro)reninreceptor pages 1-3)	Increased tissue RAS activity; regulation of blood pressure, sodium/water handling, and context-dependent remodeling/fibrotic programs (marrerobras2026theproreninreceptor pages 1-3, patel2022endothelialcellpolarity pages 1-2, wang2020the(pro)reninreceptor pages 1-3)	Ligand binding and angiotensinogen-processing role summarized in recent review/chapter sources; endothelial and cancer reviews also identify ATP6AP2 as a tissue-RAS amplifier (kourieh2025overviewofrenin pages 1-4, kourieh2025overviewofrenin pages 4-8, patel2022endothelialcellpolarity pages 1-2, wang2020the(pro)reninreceptor pages 1-3)
V-ATPase-dependent lysosomal/autophagy pathway	Essential V-ATPase accessory protein required for organellar acidification, lysosomal function, and autophagy	ATP6AP2/PRR is part of the mammalian V0 region of V-ATPase; structural studies place its transmembrane anchor within the membrane sector and show it contributes to assembly of catalytic and membrane regions. Loss of ATP6AP2 impairs acidification, lysosomal integrity, receptor-mediated endocytic trafficking, and autophagic flux (falace2024vatpasedysfunctionin pages 1-3, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, figueiredo2021the(pro)reninreceptor pages 1-2, ohba2020(pro)reninreceptoratp6ap2is pages 1-6)	Defective lysosomal acidification, autophagosome accumulation, impaired cargo degradation/endocytosis, altered cell survival and proliferation, tissue dysfunction (figueiredo2021the(pro)reninreceptor pages 1-2, ohba2020(pro)reninreceptoratp6ap2is pages 1-6)	Cryo-EM studies define structural placement in V-ATPase; renal and lung cancer studies show functional defects in lysosomes/autophagy after ATP6AP2 loss (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, figueiredo2021the(pro)reninreceptor pages 1-2, ohba2020(pro)reninreceptoratp6ap2is pages 1-6)
Wnt/β-catenin signaling	Core regulator/adaptor for Wnt receptor complex and membrane trafficking of Wnt pathway components	ATP6AP2 interacts with Wnt receptor machinery and is required for canonical Wnt signaling. Recent primary work shows ATP6AP2 stabilizes LRP6/β-catenin and N-cadherin/β-catenin complexes at the cell membrane, preventing degradation; prior evidence also links ATP6AP2 to endosomal recycling of Wnt receptors (xiong2024atp6ap2aregulator pages 1-2, wang2023(pro)reninreceptorpromotes pages 1-2, figueiredo2021the(pro)reninreceptor pages 1-2)	Increased β-catenin signaling, osteoblast differentiation/bone formation, cancer-promoting Wnt activity, developmental signaling outputs (xiong2024atp6ap2aregulator pages 1-2, wang2023(pro)reninreceptorpromotes pages 1-2, wang2020the(pro)reninreceptor pages 1-3)	Bone Research 2024 demonstrates LRP6/β-catenin trafficking/stability role; CRC study links ATP6AP2 to Wnt3 accumulation and progression; reviews summarize adaptor role in canonical and non-canonical Wnt (xiong2024atp6ap2aregulator pages 1-2, wang2023(pro)reninreceptorpromotes pages 1-2, wang2020the(pro)reninreceptor pages 1-3)
ERK1/2-MAPK pathway	Angiotensin-independent signaling receptor activating MAPK cascades	Binding of renin/prorenin to ATP6AP2 activates intracellular tyrosine-phosphorylation signaling including ERK1/2 and p38 MAPK independently of classical Ang II generation; in specific systems ATP6AP2-dependent ERK signaling regulates extracellular matrix gene expression and cell behavior (schofield2023placentaldeficiencyof pages 1-2, kourieh2025overviewofrenin pages 4-8, patel2022endothelialcellpolarity pages 1-2, wang2020the(pro)reninreceptor pages 1-3)	Upregulation of collagen, fibronectin, TGF-β1, PAI-1 and related remodeling programs; effects on proliferation, migration, angiogenesis, placentation, and fibrosis (schofield2023placentaldeficiencyof pages 1-2, kourieh2025overviewofrenin pages 4-8, patel2022endothelialcellpolarity pages 1-2)	Placental study cites impaired ERK activation after ATP6AP2 knockdown; endothelial study links ATP6AP2 to angiogenic/ECM regulation via ERK; reviews summarize ERK1/2-MAPK activation downstream of ligand binding (schofield2023placentaldeficiencyof pages 1-2, patel2022endothelialcellpolarity pages 1-2, wang2020the(pro)reninreceptor pages 1-3)
mTOR signaling	Indirect regulator of nutrient sensing and lysosome-linked mTOR activity through V-ATPase	ATP6AP2 supports V-ATPase function, and V-ATPase is a lysosomal signaling hub required for mTORC1 localization/activation through the Ragulator-Rag complex. Reviews note ATP6AP2-dependent lysosomal acidification is coupled to mTOR-regulated autophagy and nutrient sensing; kidney ATP6AP2 loss alters lysosomal/autophagic status even when total mTOR/phospho-mTOR appears grossly preserved in one model (eaton2021theh+atpase(vatpase) pages 1-5, falace2024vatpasedysfunctionin pages 1-3, kourieh2025overviewofrenin pages 4-8, figueiredo2021the(pro)reninreceptor pages 1-2)	Control of autophagy initiation/flux, lysosomal homeostasis, metabolic adaptation, growth signaling (eaton2021theh+atpase(vatpase) pages 1-5, falace2024vatpasedysfunctionin pages 1-3, kourieh2025overviewofrenin pages 4-8)	V-ATPase reviews provide the mechanistic lysosome-mTOR link; kidney ATP6AP2 knockout study connects ATP6AP2 loss to lysosomal dysfunction and autophagy changes in vivo (eaton2021theh+atpase(vatpase) pages 1-5, falace2024vatpasedysfunctionin pages 1-3, kourieh2025overviewofrenin pages 4-8, figueiredo2021the(pro)reninreceptor pages 1-2)
PI3K/Akt pathway	Angiotensin-independent downstream signaling node and feedback-linked pathway	Reviews summarize ATP6AP2 activation as capable of engaging PI3K/Akt signaling; one cited mechanism describes PI3K-p85-dependent signaling downstream of renin/prorenin-ATP6AP2 interaction, with transcriptional feedback on ATP6AP2 expression, while broader reviews place PI3K/Akt among major intracellular programs coordinated by ATP6AP2 (marrerobras2026theproreninreceptor pages 1-3, kourieh2025overviewofrenin pages 4-8, wang2020the(pro)reninreceptor pages 1-3)	Survival, metabolic signaling, proliferation, inflammatory/fibrotic gene regulation, and integration with disease pathways including cancer and cardiorenal remodeling (marrerobras2026theproreninreceptor pages 1-3, kourieh2025overviewofrenin pages 4-8, wang2020the(pro)reninreceptor pages 1-3)	Recent review literature consistently lists PI3K/Akt as an ATP6AP2-associated pathway; chapter source provides specific PI3K-p85 feedback detail (marrerobras2026theproreninreceptor pages 1-3, kourieh2025overviewofrenin pages 4-8, wang2020the(pro)reninreceptor pages 1-3)

Table: This table summarizes the main signaling and biochemical pathways involving human ATP6AP2, emphasizing its dual receptor and V-ATPase-associated functions. It is useful for quickly mapping ATP6AP2 to specific molecular mechanisms, downstream effects, and the strongest supporting evidence from the retrieved sources.

Renin-Angiotensin System (RAS)

ATP6AP2 amplifies local tissue RAS signaling by binding renin and prorenin, increasing the efficiency of angiotensinogen cleavage to angiotensin I (marrerobras2026theproreninreceptor pages 1-3, kourieh2025overviewofrenin pages 1-4, patel2022endothelialcellpolarity pages 1-2, wang2020the(pro)reninreceptor pages 1-3). This function is independent of circulating RAS and contributes to regulation of blood pressure, sodium and water homeostasis, and tissue remodeling responses (marrerobras2026theproreninreceptor pages 1-3). In pathological contexts, excessive ATP6AP2-mediated RAS activation has been implicated in hypertension, cardiac remodeling, renal fibrosis, and preeclampsia (schofield2023placentaldeficiencyof pages 1-2, marrerobras2026theproreninreceptor pages 1-3).

V-ATPase-Dependent Lysosomal and Autophagy Pathway

As an essential V-ATPase accessory protein, ATP6AP2 is critical for lysosomal acidification and autophagy (eaton2021theh+atpase(vatpase) pages 1-5, falace2024vatpasedysfunctionin pages 1-3, figueiredo2021the(pro)reninreceptor pages 1-2, ohba2020(pro)reninreceptoratp6ap2is pages 1-6). Loss of ATP6AP2 in multiple cell types causes accumulation of autophagosomes, impaired autophagosome-lysosome fusion, reduced lysosomal degradative capacity, and cellular dysfunction (figueiredo2021the(pro)reninreceptor pages 1-2, ohba2020(pro)reninreceptoratp6ap2is pages 1-6). In lung adenocarcinoma cells, ATP6AP2 is required for autophagy and regulates cell proliferation (ohba2020(pro)reninreceptoratp6ap2is pages 1-6). In renal proximal tubule cells, ATP6AP2 deficiency leads to proteinuria and delayed receptor-mediated endocytosis (figueiredo2021the(pro)reninreceptor pages 1-2).

Wnt/β-Catenin Signaling

ATP6AP2 functions as a core component and regulator of the canonical Wnt signaling pathway (xiong2024atp6ap2aregulator pages 1-2, wang2023(pro)reninreceptorpromotes pages 1-2, wang2020the(pro)reninreceptor pages 1-3). Recent mechanistic studies demonstrate that ATP6AP2 regulates the trafficking and membrane stability of the Wnt co-receptor LRP6 and its associated β-catenin complexes (xiong2024atp6ap2aregulator pages 1-2). ATP6AP2 prevents degradation of LRP6/β-catenin and N-cadherin/β-catenin protein complexes by maintaining their proper distribution at the cell membrane (xiong2024atp6ap2aregulator pages 1-2). This function is essential for osteoblast-mediated bone formation and has been implicated in cancer progression (xiong2024atp6ap2aregulator pages 1-2, wang2023(pro)reninreceptorpromotes pages 1-2). ATP6AP2 also interacts with Frizzled receptors and regulates endosomal recycling of Wnt receptor machinery (wang2023(pro)reninreceptorpromotes pages 1-2).

ERK1/2-MAPK Pathway

Binding of renin or prorenin to ATP6AP2 activates intracellular ERK1/2 and p38 MAPK signaling cascades independently of angiotensin II generation (schofield2023placentaldeficiencyof pages 1-2, kourieh2025overviewofrenin pages 4-8, patel2022endothelialcellpolarity pages 1-2, wang2020the(pro)reninreceptor pages 1-3). This angiotensin-independent signaling leads to upregulation of extracellular matrix components (collagen, fibronectin), profibrotic mediators (TGF-β1, PAI-1), and cell proliferation/migration responses (schofield2023placentaldeficiencyof pages 1-2, kourieh2025overviewofrenin pages 4-8, patel2022endothelialcellpolarity pages 1-2). In placental trophoblasts, ATP6AP2-dependent ERK activation is required for proliferation, migration, and invasion (schofield2023placentaldeficiencyof pages 1-2). In endothelial cells, ATP6AP2 regulates angiogenesis and extracellular matrix composition via ERK signaling (patel2022endothelialcellpolarity pages 1-2).

mTOR Signaling

ATP6AP2 indirectly regulates mTOR signaling through its role in V-ATPase function (eaton2021theh+atpase(vatpase) pages 1-5, falace2024vatpasedysfunctionin pages 1-3, kourieh2025overviewofrenin pages 4-8). V-ATPase serves as a lysosomal signaling hub required for mTORC1 (mechanistic target of rapamycin complex 1) localization and activation through the Ragulator-Rag protein complex (eaton2021theh+atpase(vatpase) pages 1-5, kourieh2025overviewofrenin pages 4-8). V-ATPase-dependent lysosomal acidification enables nutrient sensing and couples cellular metabolic status to autophagy regulation via mTOR (eaton2021theh+atpase(vatpase) pages 1-5, falace2024vatpasedysfunctionin pages 1-3, kourieh2025overviewofrenin pages 4-8). Loss of ATP6AP2 disrupts this lysosome-mTOR axis, leading to altered autophagy and metabolic dysfunction (kourieh2025overviewofrenin pages 4-8, figueiredo2021the(pro)reninreceptor pages 1-2).

PI3K/Akt Pathway

ATP6AP2 activation engages PI3K/Akt signaling pathways downstream of renin/prorenin binding (marrerobras2026theproreninreceptor pages 1-3, kourieh2025overviewofrenin pages 4-8, wang2020the(pro)reninreceptor pages 1-3). One described mechanism involves PI3K-p85-dependent signaling that regulates nuclear translocation of transcription factors and provides feedback regulation of ATP6AP2 expression (kourieh2025overviewofrenin pages 4-8). This pathway contributes to cell survival, proliferation, metabolic regulation, and inflammatory/fibrotic gene programs in multiple disease contexts including cancer and cardiovascular remodeling (marrerobras2026theproreninreceptor pages 1-3, kourieh2025overviewofrenin pages 4-8, wang2020the(pro)reninreceptor pages 1-3).

Evidence from Structural and Functional Studies

Structural Evidence

High-resolution cryo-EM structures of mammalian V-ATPase from rat brain and human cell lines have definitively placed ATP6AP2 within the V0 membrane domain, revealing how its transmembrane anchor contributes to assembly of the catalytic and membrane regions of the enzyme (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3). These structures define the ATP:H+ ratio of V-ATPase as 3:10 and show that the c-ring encloses the transmembrane anchors for both cleaved ATP6AP1/Ac45 and ATP6AP2/PRR (abbas2020structureofvatpase pages 1-2).

Functional Evidence from Knockout/Knockdown Models

Multiple conditional knockout and knockdown models have demonstrated the essential and tissue-specific functions of ATP6AP2:

Osteoblast-specific deletion: Reduced trabecular bone formation and bone mass due to impaired Wnt/β-catenin signaling and LRP6 stability (xiong2024atp6ap2aregulator pages 1-2)
Placental knockdown: Impaired trophoblast proliferation, migration, and invasion, leading to placental insufficiency (schofield2023placentaldeficiencyof pages 1-2)
Renal proximal tubule deletion: Proteinuria, defective receptor-mediated endocytosis, and lysosomal dysfunction (figueiredo2021the(pro)reninreceptor pages 1-2)
Endothelial cell deletion: Cell migration defects, loss of tip cell polarity, and impaired developmental and pathological angiogenesis (patel2022endothelialcellpolarity pages 1-2)
Lung cancer cells: Suppression of ATP6AP2 reduced cell proliferation and migration through impaired autophagy (ohba2020(pro)reninreceptoratp6ap2is pages 1-6)

Evolutionary and Bioinformatic Evidence

ATP6AP2 is highly conserved across eukaryotes, and homologs lacking renin-binding function exist in organisms without a renin-angiotensin system, supporting the primary importance of its V-ATPase-related functions (falace2024vatpasedysfunctionin pages 1-3, figueiredo2021the(pro)reninreceptor pages 1-2). The presence of ATP6AP2 in species from yeast to humans underscores its fundamental role in cellular homeostasis.

Recent Developments (2023-2024)

Recent literature from 2023-2024 has expanded understanding of ATP6AP2 in several key areas:

Cancer Biology: ATP6AP2 promotes colorectal cancer progression by inhibiting NEDD4L-mediated Wnt3 ubiquitination and modulating gut microbiota (wang2023(pro)reninreceptorpromotes pages 1-2). ATP6AP2 expression is elevated in multiple cancer types and correlates with tumor progression (wang2020the(pro)reninreceptor pages 1-3).
Cardiovascular and Metabolic Diseases: Emerging evidence identifies soluble (P)RR (sPRR) as a circulating biomarker for hypertension, chronic kidney disease, and metabolic disorders (marrerobras2026theproreninreceptor pages 1-3, kourieh2025overviewofrenin pages 1-4). sPRR may function as an endocrine-like factor linking tissue RAS activation to systemic disease (marrerobras2026theproreninreceptor pages 1-3).
Neurological Function: ATP6AP2 is highly expressed in the brain and essential for neuronal V-ATPase function, synaptic vesicle acidification, and neurotransmitter loading (falace2024vatpasedysfunctionin pages 1-3, abbas2020structureofvatpase pages 1-2). Mutations in ATP6AP2 are associated with X-linked intellectual disability and epilepsy (falace2024vatpasedysfunctionin pages 1-3).
Autophagy and Lysosomal Biology: ATP6AP2 has emerged as a critical regulator of autophagy by controlling both lysosomal acidification and autophagosome-lysosome fusion (falace2024vatpasedysfunctionin pages 1-3, ohba2020(pro)reninreceptoratp6ap2is pages 1-6). This dual role positions ATP6AP2 as a key integrator of cellular degradative pathways.

Summary

ATP6AP2 is a multifunctional protein with dual primary roles as the (pro)renin receptor and as an essential V-ATPase accessory protein. It binds renin and prorenin with high affinity, activating prorenin non-proteolytically and enhancing local angiotensin production 4-fold. Simultaneously, ATP6AP2 is critical for V-ATPase assembly and function, enabling lysosomal acidification, autophagy, and endocytic trafficking. ATP6AP2 localizes to plasma membranes, endosomes, lysosomes, trans-Golgi network, and specialized vesicles in a context-dependent manner. It participates in multiple signaling pathways including RAS, V-ATPase-dependent autophagy, Wnt/β-catenin, ERK1/2-MAPK, mTOR, and PI3K/Akt. Recent structural, genetic, and functional studies from 2020-2026 have substantially advanced understanding of ATP6AP2's molecular mechanisms and physiological importance across cardiovascular, renal, metabolic, neurological, and cancer biology contexts.

References

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(abbas2020structureofvatpase pages 1-2): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(wang2020structuresofa pages 1-3): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(kourieh2025overviewofrenin pages 4-8): Lana Kourieh and Ola Arab. Overview of renin, prorenin, and the role of (pro)renin receptor across the organs and potential therapeutic target. Renin-Angiotensin-Aldosterone System - Latest Trends, Jan 2025. URL: https://doi.org/10.5772/intechopen.1008850, doi:10.5772/intechopen.1008850. This article has 0 citations.
(marrerobras2026theproreninreceptor pages 1-3): Andrea S. Marrero-Bras, Sarah E. Thomas, Joshua D. Parquet, Zoe Vallotton, Bolu Adewale, Brianna Crabtree, and Minolfa C. Prieto. The prorenin receptor: multitasking its way through cardiovascular, metabolic, and renal diseases. Unknown journal, Apr 2026. URL: https://doi.org/10.20944/preprints202604.1395.v1, doi:10.20944/preprints202604.1395.v1.
(patel2022endothelialcellpolarity pages 1-2): Nehal R. Patel, Rajan K C, Avery Blanks, Yisu Li, Minolfa C. Prieto, and Stryder M. Meadows. Endothelial cell polarity and extracellular matrix composition require functional atp6ap2 during developmental and pathological angiogenesis. JCI Insight, Oct 2022. URL: https://doi.org/10.1172/jci.insight.154379, doi:10.1172/jci.insight.154379. This article has 20 citations and is from a domain leading peer-reviewed journal.
(falace2024vatpasedysfunctionin pages 1-3): Antonio Falace, Greta Volpedo, Marcello Scala, Federico Zara, Pasquale Striano, and Anna Fassio. V-atpase dysfunction in the brain: genetic insights and therapeutic opportunities. Cells, 13:1441, Aug 2024. URL: https://doi.org/10.3390/cells13171441, doi:10.3390/cells13171441. This article has 22 citations.
(figueiredo2021the(pro)reninreceptor pages 1-2): Marta Figueiredo, Arezoo Daryadel, Gabin Sihn, Dominik N. Müller, Elena Popova, Anthony Rouselle, Genevieve Nguyen, Michael Bader, and Carsten A. Wagner. The (pro)renin receptor (atp6ap2) facilitates receptor-mediated endocytosis and lysosomal function in the renal proximal tubule. Pflugers Archiv, 473:1229-1246, Jul 2021. URL: https://doi.org/10.1007/s00424-021-02598-z, doi:10.1007/s00424-021-02598-z. This article has 18 citations.
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📚 Additional Documentation

Notes

(ATP6AP2-notes.md)

ATP6AP2 notes

Research workflow

Ran just fetch-gene human ATP6AP2, which seeded the UniProt record, GOA file, cached publications, and review YAML.
Falcon deep research has now completed successfully (ATP6AP2-deep-research-falcon.md, 21 citations); see the synthesis section at the end of this file. The original PN-batch attempt timed out before the deep_research_unified tool bugs were fixed.
Used cached UniProt, GOA, publications, and the PN projection artifacts for this review.

Curation synthesis

ATP6AP2 is best treated as a V-ATPase accessory/regulatory protein rather than as a canonical chaperone or protease. UniProt summarizes it as "involved in the assembly of the lysosomal proton-transporting V-type ATPase (V-ATPase) and the acidification of the endo-lysosomal system" [file:human/ATP6AP2/ATP6AP2-uniprot.txt].
The strongest primary evidence comes from ATP6AP2 disease and perturbation studies: missense mutations impair interaction with ATP6AP1 and V-ATPase assembly, with downstream defects in glycosylation and autophagy PMID:29127204.
The neuronal disease paper supports the PN proteostasis angle because ATP6AP2 deficiency caused "severe deficiency in lysosomal acidification and protein degradation" and decreased V-ATPase membrane assembly PMID:30985297.
The EV-A71/autophagy paper provides direct knockdown support for lysosomal pH control: ATP6AP2 was described as an auxiliary V-ATPase component, and ATP6AP2 knockdown significantly increased lysosomal pH PMID:32276428.
The PN projection proposes ATP6AP2 to GO:0060590 ATPase regulator activity from lysosomal V-ATPase regulator leaves and already recognizes GO:0007042 lysosomal lumen acidification as present in GOA [file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv].

PN decision

Accept ATP6AP2 for the Proteostasis PN batch only through the Autophagy-Lysosome Pathway / lysosomal acidification / V-ATPase regulator branch.
Add GO:0060590 ATPase regulator activity conservatively: ATP6AP2 is not the proton-pumping catalytic subunit, but multiple lines of evidence support an accessory/regulatory role in V-ATPase assembly and lysosomal acidification.
Add GO:0070072 vacuolar proton-transporting V-type ATPase complex assembly because the primary literature explicitly supports assembly-factor biology.
Keep Wnt signaling, CNS development, angiotensin maturation, MAPK signaling, TGF-beta production, plasma membrane/external side, and high-throughput exosome/granule localizations as non-core or over-broad where appropriate. These are real or plausible contexts but should not be used to broaden the PN proteostasis projection.

Falcon deep research synthesis (2026-06-21)

The Falcon report (file:human/ATP6AP2/ATP6AP2-deep-research-falcon.md) reinforces
the PN decision above (V-ATPase accessory/assembly is the proteostasis-relevant
core; RAS/Wnt/MAPK are non-core elaborations) and adds three useful points.

Evolutionary argument that the V-ATPase function is ancestral/primary.
ATP6AP2 is conserved from yeast to human, and homologs that lack renin-binding
function exist in organisms with no renin-angiotensin system, indicating the
V-ATPase accessory role is the fundamental, conserved function and the
(pro)renin-receptor/RAS role is a vertebrate-specific elaboration
(falace2024vatpasedysfunctionin; figueiredo2021). This is a strong independent
justification for treating the V-ATPase-assembly / lysosomal-acidification
branch as core and the RAS/angiotensin annotations as non-core.

Proteolytic processing nuance (relevant to which "form" does what). In the
trans-Golgi, ATP6AP2 is cleaved by furin / site-1 protease (S1P) / ADAM19 into a
~28-kDa soluble (pro)renin receptor (sPRR) and a truncated membrane fragment
M8.9 that remains associated with V-ATPase. Reviews describe M8.9 as the
V-ATPase-associated portion — i.e. the proteostasis-relevant activity is carried
by the membrane-retained fragment, while the soluble ectodomain participates in
RAS signaling (kourieh2025overviewofrenin). Worth noting when interpreting
isoform/fragment-specific annotations.

Structural placement (Abbas 2020; Wang 2020). Cryo-EM of mammalian/human
V-ATPase places the ATP6AP2/PRR transmembrane anchor inside the V0 c-ring
alongside the cleaved ATP6AP1/Ac45 anchor (enzyme ATP:H+ ratio 3:10), confirming
ATP6AP2 as a structural/assembly contributor to the membrane sector rather than a
catalytic subunit — consistent with the GO:0070072 V-ATPase-assembly and
GO:0060590 ATPase-regulator calls already made.

Other corroborated (non-core) roles: trafficking/stabilization of
LRP6/β-catenin and N-cadherin/β-catenin at the membrane (Wnt; xiong2024),
megalin/cubilin receptor-mediated endocytosis in renal proximal tubule
(figueiredo2021), and tissue-specific KO phenotypes (osteoblast bone formation,
placental trophoblast invasion, endothelial tip-cell polarity/angiogenesis). No
change to the core call.

Pn Notes

(ATP6AP2-pn-notes.md)

ATP6AP2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: O75787
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1378)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6AP2/ATP6AP2-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6AP2/ATP6AP2-ai-review.html
Gene notes: present - genes/human/ATP6AP2/ATP6AP2-notes.md
GOA TSV: present - genes/human/ATP6AP2/ATP6AP2-goa.tsv
UniProt record: present - genes/human/ATP6AP2/ATP6AP2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6AP2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6AP2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

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

AIGR Review Snapshot

Description: 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.
Existing/core annotation action counts: ACCEPT: 19; KEEP_AS_NON_CORE: 35; MARK_AS_OVER_ANNOTATED: 3; MODIFY: 10; NEW: 2

PN Consistency Summary

Consistency: Consistent. Deep research/notes, review YAML, PN annotation, and PN-node mapping all frame ATP6AP2 as an accessory/regulatory V-ATPase subunit driving endolysosomal acidification. Review ADDED GO:0060590 (ATPase regulator activity) and GO:0070072 (V-ATPase complex assembly) as NEW, and ACCEPTs GO:0007042. No contradictions; receptor/Wnt/RAS roles are correctly held KEEP_AS_NON_CORE.
PN story / NEW pressure: PN asserts a lysosomal V-ATPase regulator MF (GO:0060590) not previously in GOA. Review correctly ADDED it (action: NEW, IMP), supported by assembly-factor interaction and acidification-loss phenotypes (PMID:29127204, 30985297, 32276428). GO:0007042 already captured (ACCEPT). Verdict: PN story correctly captured — one ADD (GO:0060590), one already-captured (GO:0007042), no over-reach.
Evidence alignment: PN cites a single review (V-ATPase in neurodegeneration, biomedcentral). Review draws on primary functional papers (PMID:29127204 glycosylation/autophagy disorder; PMID:30985297 neurodegeneration; PMID:32276428 lysosomal-pH) for the same claims — broader, well-anchored evidence than the PN row, with directional agreement.
Verdict: Consistent; PN regulator-activity projection correctly ADDED (NEW GO:0060590), acidification already captured. No edits required.

Full Consistency Review

UniProt: O75787 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
PN placement: ALP|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|Regulator of the lysosomal v-ATPase proton pump (also ...|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|Regulator...) ; PN-node mapping: subtype mapped→GO:0060590 ATPase regulator activity (new_to_goa); type mapped→GO:0007042 lysosomal lumen acidification (already_in_goa_exact). Both GO terms verified real (OLS).
Consistency: Consistent. Deep research/notes, review YAML, PN annotation, and PN-node mapping all frame ATP6AP2 as an accessory/regulatory V-ATPase subunit driving endolysosomal acidification. Review ADDED GO:0060590 (ATPase regulator activity) and GO:0070072 (V-ATPase complex assembly) as NEW, and ACCEPTs GO:0007042. No contradictions; receptor/Wnt/RAS roles are correctly held KEEP_AS_NON_CORE.
PN story / NEW pressure: PN asserts a lysosomal V-ATPase regulator MF (GO:0060590) not previously in GOA. Review correctly ADDED it (action: NEW, IMP), supported by assembly-factor interaction and acidification-loss phenotypes (PMID:29127204, 30985297, 32276428). GO:0007042 already captured (ACCEPT). Verdict: PN story correctly captured — one ADD (GO:0060590), one already-captured (GO:0007042), no over-reach.
Mapping strategy: Gene supports node mapping. The MF projection (ATPase regulator activity, deliberately broad/safe) is conservative; review even raises whether a narrower "lysosomal V-ATPase accessory" term should exist (suggested_questions). The acidification process projection matches review scope. No TOMM20-style over-broadening.
Evidence alignment: PN cites a single review (V-ATPase in neurodegeneration, biomedcentral). Review draws on primary functional papers (PMID:29127204 glycosylation/autophagy disorder; PMID:30985297 neurodegeneration; PMID:32276428 lysosomal-pH) for the same claims — broader, well-anchored evidence than the PN row, with directional agreement.
Verdict: Consistent; PN regulator-activity projection correctly ADDED (NEW GO:0060590), acidification already captured. No edits required.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ATP6AP2/ATP6AP2-ai-review.yaml
PN workbook rows: 2

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

UniProt: O75787
In branches: ALP
Notes: Adapter protein for v-ATPase and its regulators
PN references (titles):
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|Regulator of the lysosomal v-ATPase proton pump
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0060590 ATPase regulator activity]
  rationale: This PN leaf contains ATP6AP-family regulators of the lysosomal V-ATPase. ATPase regulator activity is the safe shared molecular-function target.
- [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
  status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
  rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

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

UniProt: O75787
In branches: ALP
Notes: Adapter protein for v-ATPase and its regulators
PN references (titles):
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|Regulator of the lysosomal v-ATPase proton pump
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0060590 ATPase regulator activity]
  rationale: This PN subtype is a regulator of the lysosomal V-ATPase proton pump. ATPase regulator activity is the narrowest GO target that preserves the source mechanism without requiring a speculative complex-specific term.
- [type] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0007042 lysosomal lumen acidification]
  rationale: This PN group directly names the lysosomal acidification mechanism. Propagation to the GO lysosomal lumen acidification term is an exact mechanistic match.
- [group] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Lysosomal catabolism
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad lysosomal-degradation container. The subtree includes carbohydrate, lipid, protein, nuclease, phosphatase, sulfatase, and environment-regulation roles, so mapping should occur at the enzyme or process subtype level.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

GO:0060590 ATPase regulator activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|Regulator of the lysosomal v-ATPase proton pump
GO:0007042 lysosomal lumen acidification | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
GO:0060590 ATPase regulator activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|Regulator of the lysosomal v-ATPase proton pump

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: 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

ATP6AP2

Gene Description

Existing Annotations Review

Core Functions

Supports V-ATPase assembly and activity as an accessory/regulatory factor, enabling endolysosomal acidification and lysosomal protein degradation.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: ATP6AP2 (Gene ID: ATP6AP2, UniProt: O75787) in Homo sapiens

Gene Identity Confirmation

Primary Molecular Functions

Function 1: (Pro)renin Receptor

Function 2: V-ATPase Accessory Protein

Function 3: Protein Trafficking and Receptor Stability

Subcellular Localization

Plasma Membrane

Endosomes and Lysosomes

Trans-Golgi Network

Synaptic Vesicles

Tissue-Specific Expression

Signaling and Biochemical Pathways

Renin-Angiotensin System (RAS)

V-ATPase-Dependent Lysosomal and Autophagy Pathway

Wnt/β-Catenin Signaling

ERK1/2-MAPK Pathway

mTOR Signaling

PI3K/Akt Pathway

Evidence from Structural and Functional Studies

Structural Evidence

Functional Evidence from Knockout/Knockdown Models

Evolutionary and Bioinformatic Evidence

Recent Developments (2023-2024)

Summary

📚 Additional Documentation

Notes

ATP6AP2 notes

Research workflow

Curation synthesis

PN decision

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6AP2 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

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

Projected GO annotations (3)

Note

📄 View Raw YAML