ATP13A2

Summary: Retain nucleotide binding as part of the transport core.

Reason: The InterPro IPR023299 nucleotide-binding inference agrees with the ATP-dependent catalytic cycle of the established P5B ATPase. Retain this broad biochemical component of the transport core; no second nucleotide-binding core is needed.

Summary: Retain autophagosome membrane as a contextual function or location.

Reason: The SL-0022 mapping is retained as autophagic-compartment context. ATP13A2 acts principally on late endolysosomal membranes; an autophagosome-membrane label does not establish that every mature transporter pool functions there. The mapping is not contradicted by an unexamined target image.

Summary: Retain protein binding as a contextual function or location.

Reason: The original indexed Results of PMID:22645275 explicitly name GAK (O14976) among the seven proteins coexpressed with V5-ATP13A2 in HEK293 cells and confirmed by anti-V5 co-immunoprecipitation. Retain this verified cellular association as non-core. It does not establish purified binary binding or a distinct enzymatic/adaptor function. Complete original Methods and pair-specific figure pixels were not inspected.

Summary: Retain protein binding as a contextual function or location.

Reason: The original indexed Results of PMID:22645275 explicitly name BNIP3L/NIX (O60238) among the seven proteins coexpressed with V5-ATP13A2 in HEK293 cells and confirmed by anti-V5 co-immunoprecipitation. Retain this verified cellular association as non-core. It does not establish purified binary binding or a distinct enzymatic/adaptor function. Complete original Methods and pair-specific figure pixels were not inspected.

Summary: Retain protein binding as a contextual function or location.

Reason: The original indexed Results of PMID:22645275 explicitly name YIF1A (O95070) among the seven proteins coexpressed with V5-ATP13A2 in HEK293 cells and confirmed by anti-V5 co-immunoprecipitation. Retain this verified cellular association as non-core. It does not establish purified binary binding or a distinct enzymatic/adaptor function. Complete original Methods and pair-specific figure pixels were not inspected.

Summary: Retain protein binding as a contextual function or location.

Reason: The original indexed Results of PMID:22645275 explicitly name HSPA8 (P11142) among the seven proteins coexpressed with V5-ATP13A2 in HEK293 cells and confirmed by anti-V5 co-immunoprecipitation. Retain this verified cellular association as non-core. It does not establish purified binary binding or a distinct enzymatic/adaptor function. Complete original Methods and pair-specific figure pixels were not inspected.

Summary: Retain protein binding as a contextual function or location.

Reason: The original indexed Results of PMID:22645275 explicitly name AAK1 (Q2M2I8) among the seven proteins coexpressed with V5-ATP13A2 in HEK293 cells and confirmed by anti-V5 co-immunoprecipitation. Retain this verified cellular association as non-core. It does not establish purified binary binding or a distinct enzymatic/adaptor function. Complete original Methods and pair-specific figure pixels were not inspected.

Summary: Retain protein binding as a contextual function or location.

Reason: The original indexed Results of PMID:22645275 explicitly name SYT11 (Q9BT88) among the seven proteins coexpressed with V5-ATP13A2 in HEK293 cells and confirmed by anti-V5 co-immunoprecipitation. Retain this verified cellular association as non-core. It does not establish purified binary binding or a distinct enzymatic/adaptor function. Complete original Methods and pair-specific figure pixels were not inspected. PMID:27278822 later reports that its blotting did not confirm an obvious ATP13A2–SYT11 association; that context-specific result does not erase the earlier co-IP.

Summary: Retain protein binding as a contextual function or location.

Reason: The original indexed Results of PMID:22645275 explicitly name HDAC6 (Q9UBN7) among the seven proteins coexpressed with V5-ATP13A2 in HEK293 cells and confirmed by anti-V5 co-immunoprecipitation. Retain this verified cellular association as non-core. It does not establish purified binary binding or a distinct enzymatic/adaptor function. Complete original Methods and pair-specific figure pixels were not inspected. The later HDAC6 study supports cellular association and lysosomal recruitment, without demonstrating direct catalytic activation.

Summary: Retain protein binding as a contextual function or location.

Reason: Actual PMID:27278822 Results report endogenous ATP13A2 immunoprecipitation with MYCBP2 and some TSC2, together with proximity-ligation evidence. Retain MYCBP2/O75592 association as non-core; these assays do not establish purified binding or direct ubiquitin-ligase inhibition. The study reports that MYCBP2–TSC2 association was not obviously altered.

Summary: Retain ATP binding as part of the transport core.

Reason: InterPro IPR001757 ATP binding is consistent with measured ATPase/phosphoenzyme chemistry and ATP-dependent polyamine transport. ATP binding is a component of the P-type transport mechanism.

Summary: Retain lysosome as part of the transport core.

Reason: PMID:16964263 describes lysosomal ATP13A2 localization and disease-associated mistargeting. This is a core compartment supported independently by established membrane topology and lysosomal polyamine export. Retain the specific IDA assertion with explicit curatorial deference; the original target localization image was not independently inspected.

Summary: Retain lysosome as part of the transport core.

Reason: The PMID:21542062 abstract places ATP13A2 at lysosomes. This is a core compartment supported independently by established membrane topology and lysosomal polyamine export. Retain the specific IDA assertion with explicit curatorial deference; the original target localization image was not independently inspected.

Summary: Retain lysosome as part of the transport core.

Reason: The PMID:24603074 abstract places ATP13A2 in the endolysosomal/MVB system. This is a core compartment supported independently by established membrane topology and lysosomal polyamine export. Retain the specific IDA assertion with explicit curatorial deference; the original target localization image was not independently inspected.

Summary: Retain lysosome as part of the transport core.

Reason: The PMID:25392495 abstract describes late endosomal/lysosomal ATP13A2 in the vesicular secretion context. This is a core compartment supported independently by established membrane topology and lysosomal polyamine export. Retain the specific IDA assertion with explicit curatorial deference; the original target localization image was not independently inspected.

Summary: Retain lysosomal membrane as part of the transport core.

Reason: The lysosomal-membrane assertion from PMID:21542062 agrees with the membrane-spanning P5B transporter and its directly established lysosomal transport role. The cached abstract was read; complete target images/Methods were not independently reread for this individual source. Retention uses the established target location and curatorial evidence, not a claim that every cited assay was revalidated.

Summary: Retain lysosomal membrane as part of the transport core.

Reason: The lysosomal-membrane assertion from PMID:22186024 agrees with the membrane-spanning P5B transporter and its directly established lysosomal transport role. The cached abstract was read; complete target images/Methods were not independently reread for this individual source. Retention uses the established target location and curatorial evidence, not a claim that every cited assay was revalidated.

Summary: Retain lysosomal membrane as part of the transport core.

Reason: The lysosomal-membrane assertion from PMID:22768177 agrees with the membrane-spanning P5B transporter and its directly established lysosomal transport role. The cached abstract was read; complete target images/Methods were not independently reread for this individual source. Retention uses the established target location and curatorial evidence, not a claim that every cited assay was revalidated.

Summary: Retain lysosomal membrane as part of the transport core.

Reason: The lysosomal-membrane assertion from PMID:24603074 agrees with the membrane-spanning P5B transporter and its directly established lysosomal transport role. The cached abstract was read; complete target images/Methods were not independently reread for this individual source. Retention uses the established target location and curatorial evidence, not a claim that every cited assay was revalidated.

Summary: Retain lysosomal membrane as part of the transport core.

Reason: The lysosomal-membrane assertion from PMID:28137957 agrees with the membrane-spanning P5B transporter and its directly established lysosomal transport role. The cached abstract was read; complete target images/Methods were not independently reread for this individual source. Retention uses the established target location and curatorial evidence, not a claim that every cited assay was revalidated.

Summary: Retain lysosomal membrane as part of the transport core.

Reason: The lysosomal-membrane assertion from PMID:17897319 agrees with the membrane-spanning P5B transporter and its directly established lysosomal transport role. The complete cached abstract describes a lysosomal proteome but does not itself name ATP13A2; the exact target proteomics table was not reread. Retain this location with explicit deference to the HDA curator and independent target topology, without claiming table verification.

Summary: Retain lysosomal membrane as part of the transport core.

Reason: The lysosomal-membrane assertion from PMID:23499937 agrees with the membrane-spanning P5B transporter and its directly established lysosomal transport role. The cached abstract was read; complete target images/Methods were not independently reread for this individual source. Retention uses the established target location and curatorial evidence, not a claim that every cited assay was revalidated.

Summary: Retain lysosomal membrane as part of the transport core.

Reason: The lysosomal-membrane assertion from PMID:26134396 agrees with the membrane-spanning P5B transporter and its directly established lysosomal transport role. Actual selected Results/Methods on human fragments and full-length protein support membrane topology and lipid-dependent endolysosomal targeting; no soluble luminal-enzyme model is implied.

Summary: Retain lysosomal membrane as part of the transport core.

Reason: The lysosomal-membrane assertion from PMID:29505581 agrees with the membrane-spanning P5B transporter and its directly established lysosomal transport role. The cached abstract was read; complete target images/Methods were not independently reread for this individual source. Retention uses the established target location and curatorial evidence, not a claim that every cited assay was revalidated.

Summary: Retain lysosomal membrane as part of the transport core.

Reason: The SL-0157 lysosomal-membrane mapping is concordant with the experimentally supported membrane topology and core transport compartment.

Summary: Retain lysosomal membrane as part of the transport core.

Reason: The lysosomal-membrane assertion from PMID:25548531 agrees with the membrane-spanning P5B transporter and its directly established lysosomal transport role. The cached abstract was read; complete target images/Methods were not independently reread for this individual source. Retention uses the established target location and curatorial evidence, not a claim that every cited assay was revalidated.

Summary: Retain late endosome as part of the transport core.

Reason: PMID:25392495 places ATP13A2 in late endosomes/lysosomes in the secretion study. Retain this core endolysosomal compartment, with original target image details curator-deferred.

Summary: Retain multivesicular body as part of the transport core.

Reason: The complete cached abstract of PMID:24603074 supports the late endosomal/multivesicular-body context. This is part of the transporter’s endolysosomal compartment; retaining location does not make all secretion phenotypes a separate catalytic core. Original subcompartment images were not independently inspected.

Summary: Retain multivesicular body as part of the transport core.

Reason: The complete cached abstract of PMID:25392495 supports the late endosomal/multivesicular-body context. This is part of the transporter’s endolysosomal compartment; retaining location does not make all secretion phenotypes a separate catalytic core. Original subcompartment images were not independently inspected.

Summary: Retain multivesicular body as part of the transport core.

Reason: The complete cached abstract of PMID:25548531 supports the late endosomal/multivesicular-body context. This is part of the transporter’s endolysosomal compartment; retaining location does not make all secretion phenotypes a separate catalytic core. Original subcompartment images were not independently inspected.

Summary: Retain autophagosome as a contextual function or location.

Reason: Retain the PMID:24603074 IDA autophagosome location as a reported vesicular context, with exact target imaging curator-deferred. The synthesis centers on late endolysosomal transport rather than assigning a separate autonomous autophagosome activity.

Summary: Retain intracellular calcium ion homeostasis as a contextual function or location.

Reason: Retain the PTN000643505 ancestral calcium-homeostasis assertion as a secondary homeostatic role, consistent with target evidence in PMID:22186024. The target in WITH/FROM is legitimate descendant evidence, not circularity; the PAINT tree/node placement was not independently reconstructed. This does not identify calcium as an intrinsic transported substrate.

Summary: Retain intracellular calcium ion homeostasis as a contextual function or location.

Reason: PMID:22186024 reports cellular calcium-homeostasis phenotypes in its neuronal ATP13A2 work. Retain that homeostatic involvement as non-core, distinguishing altered cellular calcium from direct ATP13A2 calcium flux. Full original assay/construct details were not reread.

Summary: Retain intracellular iron ion homeostasis as a contextual function or location.

Reason: The complete PMID:26818499 abstract links ATP13A2 loss to iron-related homeostasis/toxicity phenotypes. Retain this context-dependent cellular role with curatorial deference to IMP; neither direct iron transport nor a metal-binding core follows from the phenotype.

Summary: Retain intracellular zinc ion homeostasis as a contextual function or location.

Reason: The ARBA00086919/mouse Q9CTG6 transfer is concordant with independent human ATP13A2 zinc-homeostasis evidence. Retain it as a secondary role; no exact donor assay or ARBA rule audit is claimed.

Summary: Retain intracellular zinc ion homeostasis as a contextual function or location.

Reason: PMID:24334770 includes human patient fibroblasts and separately mouse-neuron depletion/rescue experiments linking ATP13A2 to zinc handling and lysosomal function. Retain zinc homeostasis without converting probe distribution or toxicity rescue into purified zinc transport; the species-specific assays remain distinct.

Summary: Retain intracellular zinc ion homeostasis as a contextual function or location.

Reason: PMID:24603074 reports zinc sensitivity and vesicular zinc changes together with ATP13A2 expression/rescue. Retain cellular zinc homeostasis, while the abstract’s zinc-pump interpretation is not treated as a directly measured purified-protein flux assay.

Summary: Retain autophagy as a contextual function or location.

Reason: The mouse Q9CTG6 orthology transfer is compatible with independent human ATP13A2 autophagy-network and lysosomal studies. Retain a non-core cellular process; this is not evidence that ATP13A2 is itself an autophagy enzyme.

Summary: Retain autophagy as a contextual function or location.

Reason: Actual PMID:27278822 Results connect ATP13A2 perturbation with TFEB/SYT11 signaling and autophagic readouts. Retain this cellular regulatory role as non-core, without assigning direct transcription or an autonomous autophagy catalytic activity.

Summary: Retain lysosomal transport as part of the transport core.

Reason: PMID:31996848 establishes ATP-dependent polyamine movement from the endolysosomal lumen toward cytosol. ATP13A2 performs the transport step rather than merely being a substrate or necessary downstream marker, so lysosomal transport belongs to the core.

Summary: The source-specific support for zinc ion binding remains unresolved.

Reason: PMID:22361905 supplies synthetic yeast YPK9 peptide metal-complex evidence; the explicit ISS donor Q12697 is therefore expected, not a wrong-gene annotation. Conservation of the assayed zinc-binding sites and their function in intact human ATP13A2 has not been established here. The 2012 full paper and complete 2013 Results were not read; selected 2013 Methods/Mn Results and both abstracts were read. A simple absence of exact peptide strings is not an alignment or loss-of-function proof. Retain uncertainty, not REMOVE.

Summary: The source-specific support for zinc ion binding remains unresolved.

Reason: PMID:23202360 supplies synthetic yeast YPK9 peptide metal-complex evidence; the explicit ISS donor Q12697 is therefore expected, not a wrong-gene annotation. Conservation of the assayed zinc-binding sites and their function in intact human ATP13A2 has not been established here. The 2012 full paper and complete 2013 Results were not read; selected 2013 Methods/Mn Results and both abstracts were read. A simple absence of exact peptide strings is not an alignment or loss-of-function proof. Retain uncertainty, not REMOVE.

Summary: Retain positive regulation of gene expression as a contextual function or location.

Reason: PMID:27278822 measures SYT11 expression and TFEB-dependent signaling after ATP13A2 perturbation. TFEB, not ATP13A2, is the promoter-binding factor. Retain the existing positive-regulation process as a secondary cellular role without inventing a DNA-binding/transcription-factor MF.

Summary: Retain regulation of mitochondrion organization as a contextual function or location.

Reason: Retain the PTN002899996 inherited mitochondrial-organization regulation as a non-core homeostatic role, consistent with target perturbation studies. No adverse conclusion is drawn from donor number or the target in WITH/FROM; the exact PAINT node was not reconstructed.

Summary: Retain regulation of mitochondrion organization as a contextual function or location.

Reason: PMID:22186024 reports altered mitochondrial organization in ATP13A2 neuronal experiments. Retain the regulatory phenotype without moving the transporter to mitochondria or asserting direct mitochondrial remodeling.

Summary: Retain regulation of mitochondrion organization as a contextual function or location.

Reason: The ARBA00084914 mouse/rat transfer agrees with target-associated mitochondrial phenotypes. Retain as a secondary process; the exact donor experiments and rule placement were not independently reconstructed.

Summary: Retain regulation of mitochondrion organization as a contextual function or location.

Reason: PMID:22198378 reports mitochondrial/lysosomal alterations after ATP13A2 perturbation. Retain the existing regulation of mitochondrial organization with curatorial deference, distinguishing systemic homeostasis from direct mitochondrial catalysis.

Summary: Retain vesicle membrane as a contextual function or location.

Reason: The mouse-derived vesicle-membrane assertion is compatible with target endolysosomal topology but less informative than the core lysosomal/late-endosomal membrane locations. Retain the broader compartment as non-core.

Summary: Retain polyamine transmembrane transporter activity as part of the transport core.

Reason: PTN000643503 asserts inherited polyamine transport and agrees with direct human ATP13A2 transport evidence. The human target among descendants is appropriate support, not circularity; exact PAINT tree reconstruction is not claimed.

Summary: Retain polyamine transmembrane transporter activity as part of the transport core.

Reason: PMID:31996848 directly supports the principal ATP-dependent polyamine transport role, with spermine preference. Selected original Methods distinguish purified-protein ATPase stimulation from transport in proteoliposomes made using detergent-solubilized yeast membranes; this is not described as flux through purified ATP13A2 alone. Tested human variant 2 does not establish isoform exclusivity.

Summary: Remove the incompatible ABC-type transporter classification.

Reason: The current GO:0015417 term explicitly denotes an ABC-type transporter and has the ABC-type parent GO:0140359. The experimentally studied human ATP13A2 is a P5B P-type ATPase, not an ABC transporter. The source’s polyamine transport result remains accepted in row50; removal concerns the contradicted mechanistic class, not an inaccessible experiment or loss of the measured transport function. No redundant same-paper replacement is proposed.

Summary: Remove the incompatible ABC-type transporter classification.

Reason: ARBA00098143/RHEA:29999 conveys polyamine transport chemistry, but that chemistry does not establish an ABC mechanism. Current GO:0015417 explicitly has an ABC-type parent, whereas ATP13A2 has experimentally supported P-type phosphoenzyme chemistry. Retain polyamine/P-type transport in the other existing rows and remove this mechanistic-class mapping.

Summary: Retain P-type ion transporter activity as part of the transport core.

Reason: Current GO:0015662 has the P-type parent GO:0140358 and refers to ions, not exclusively monoatomic ions. Polyamines are charged substrates; their identity does not contradict this broad P-type ion-transporter classification. InterPro IPR047821 is concordant with the ATP13A2 architecture.

Summary: Retain membrane as a contextual function or location.

Reason: The InterPro membrane inference is correct for the multipass transporter but much broader than its functional lysosomal/late-endosomal membrane locations. Keep the broad context without creating another core.

Summary: Retain membrane as a contextual function or location.

Reason: The PMID:16964263 membrane assertion is compatible with the established target topology; retain this broad NAS location as non-core, with specific compartments represented elsewhere.

Summary: Retain regulation of macroautophagy as a contextual function or location.

Reason: PMID:22198378 reports autophagy/lysosomal perturbation phenotypes. Retain macroautophagy regulation as a secondary cellular function with curatorial deference, not as direct execution of cargo degradation.

Summary: Retain regulation of macroautophagy as a contextual function or location.

Reason: The complete PMID:22885599 commentary describes defective autophagosome clearance after ATP13A2 depletion and restoration with wild-type ATP13A2. Retain this existing regulation of macroautophagy; the citation is a commentary summarizing experiments, not a new independent assay.

Summary: Retain regulation of autophagosome size as a contextual function or location.

Reason: Retain the PTN002899996 ancestral autophagosome-size regulation as non-core, consistent with target neuronal evidence. The rat/target descendant set is not treated as a pairwise score or circularity; no independent ancestral-node reconstruction is claimed.

Summary: Retain regulation of autophagosome size as a contextual function or location.

Reason: PMID:22186024 supports a change in autophagic-vesicle morphology in the ATP13A2 neuronal setting. Retain the curator’s size-regulation assertion as secondary; exact measurements/images were not independently reread.

Summary: Retain regulation of autophagosome size as a contextual function or location.

Reason: The explicit rat F1MAA4 orthology transfer is retained as non-core autophagosome-size regulation, consistent with the target source. No donor-table verification or direct human size-control mechanism is inferred.

Summary: Retain ATP hydrolysis activity as part of the transport core.

Reason: ATP hydrolysis is directly coupled to the P-type transporter cycle. The IPR001757 mapping is supported by target enzyme assays and is core machinery, not a separate ATP-consuming function.

Summary: Retain ATP hydrolysis activity as part of the transport core.

Reason: The broad NAS ATP-hydrolysis assertion in PMID:24252804 is corroborated by subsequent direct ATP13A2 ATPase/phosphoenzyme assays. Retain as core transporter chemistry without claiming that this review article itself performed those experiments.

Summary: Retain the reported potassium-associated transport activity as non-core.

Reason: Retain this InterPro-derived monoatomic-cation activity as non-core in light of the human ATP13A2 study PMID:37080960. Human full-length N-terminally tagged ATP13A2 was studied in HEK293 cells with mock, D513N and knockout/rescue controls. ATPase activity was measured in bulk membrane fractions, and ATP-dependent 86Rb efflux was measured after plasma-membrane permeabilization. These data support a reported potassium-associated activity, while purified intrinsic H+/K+ coupling and stoichiometry remain unresolved. The established polyamine-export activity remains the principal core; neither the family mapping alone nor cellular pH changes establish an independent proton-pump core.

Summary: Retain the reported potassium-associated transport activity as non-core.

Reason: The original Reactome event is a historical probable cation-import model. Retain the broad monoatomic-cation ATPase annotation as non-core using the later target-specific evidence in PMID:37080960, without endorsing the older import direction. Human full-length N-terminally tagged ATP13A2 was studied in HEK293 cells with mock, D513N and knockout/rescue controls. ATPase activity was measured in bulk membrane fractions, and ATP-dependent 86Rb efflux was measured after plasma-membrane permeabilization. These data support a reported potassium-associated activity, while purified intrinsic H+/K+ coupling and stoichiometry remain unresolved.

Summary: Retain intracellular monoatomic cation homeostasis as a contextual function or location.

Reason: PMID:25548531 summarizes ATP13A2-related cation-homeostasis phenotypes. Retain homeostatic involvement as non-core; it does not establish that every altered intracellular metal is an intrinsic transported substrate.

Summary: Retain transport vesicle as a contextual function or location.

Reason: Retain the PMID:22186024 IDA transport-vesicle localization as a cellular context with exact images curator-deferred. The more specific endolysosomal membrane locations define the transport core.

Summary: The source-specific support for manganese ion binding remains unresolved.

Reason: PMID:22361905 supplies synthetic yeast YPK9 peptide metal-complex evidence; the explicit ISS donor Q12697 is therefore expected, not a wrong-gene annotation. Conservation of the assayed manganese-binding sites and their function in intact human ATP13A2 has not been established here. The 2012 full paper and complete 2013 Results were not read; selected 2013 Methods/Mn Results and both abstracts were read. A simple absence of exact peptide strings is not an alignment or loss-of-function proof. Retain uncertainty, not REMOVE.

Summary: The source-specific support for manganese ion binding remains unresolved.

Reason: PMID:23202360 supplies synthetic yeast YPK9 peptide metal-complex evidence; the explicit ISS donor Q12697 is therefore expected, not a wrong-gene annotation. Conservation of the assayed manganese-binding sites and their function in intact human ATP13A2 has not been established here. The 2012 full paper and complete 2013 Results were not read; selected 2013 Methods/Mn Results and both abstracts were read. A simple absence of exact peptide strings is not an alignment or loss-of-function proof. Retain uncertainty, not REMOVE.

Summary: Retain late endosome membrane as part of the transport core.

Reason: The late-endosome membrane is a core ATP13A2 transport compartment. PMID:24603074 is retained as the original source; the complete abstract and independent target topology support this location, while the precise original target image remains curator-deferred.

Summary: Retain late endosome membrane as part of the transport core.

Reason: The late-endosome membrane is a core ATP13A2 transport compartment. PMID:25392495 is retained as the original source; the complete abstract and independent target topology support this location, while the precise original target image remains curator-deferred.

Summary: Retain late endosome membrane as part of the transport core.

Reason: The late-endosome membrane is a core ATP13A2 transport compartment. PMID:26134396 is retained as the original source; selected actual topology/targeting Results and Methods were read.

Summary: Retain late endosome membrane as part of the transport core.

Reason: The PTN000643507 inherited late-endosomal membrane assertion agrees with direct target localization and transport. The target itself in WITH/FROM is legitimate evidence; no independent PAINT-node reconstruction is asserted.

Summary: Retain late endosome membrane as part of the transport core.

Reason: The late-endosome membrane is a core ATP13A2 transport compartment. PMID:29505581 is retained as the original source; the complete abstract and independent target topology support this location, while the precise original target image remains curator-deferred.

Summary: Retain late endosome membrane as part of the transport core.

Reason: ARBA00033481/SL-0151 late-endosomal membrane mapping is concordant with the established target compartment and topology.

Summary: Retain vesicle as a contextual function or location.

Reason: Retain the PMID:24603074 broad vesicle location as non-core context. More specific MVB/late-endosomal membrane assertions convey the functional compartment; no claim is made that all vesicles contain active ATP13A2.

Summary: Retain multivesicular body membrane as part of the transport core.

Reason: The SL-0175 MVB-membrane mapping is consistent with reported ATP13A2 distribution in the late endosomal system. It supplies a core transport compartment, not an independent exosome catalytic mechanism.

Summary: Retain multivesicular body membrane as part of the transport core.

Reason: The PMID:24603074 MVB-membrane assertion is consistent with its reported ATP13A2 localization and target membrane topology. Retain the core compartment with exact images curator-deferred.

Summary: Retain regulation of intracellular protein transport as a contextual function or location.

Reason: PMID:24334770 links ATP13A2 deficiency to lysosomal dysfunction and intracellular handling of alpha-synuclein under zinc stress. Retain the broad existing NAS regulation of protein transport as a secondary cellular role; no direct cargo-translocator or novel trafficking-adaptor MF is inferred.

Summary: Retain the reported potassium-associated transport activity as non-core.

Reason: Retain broad monoatomic-ion transport as a reported non-core activity, supported by the ATP-dependent 86Rb tracer component in human ATP13A2 experiments in PMID:37080960. Human full-length N-terminally tagged ATP13A2 was studied in HEK293 cells with mock, D513N and knockout/rescue controls. ATPase activity was measured in bulk membrane fractions, and ATP-dependent 86Rb efflux was measured after plasma-membrane permeabilization. These data support a reported potassium-associated activity, while purified intrinsic H+/K+ coupling and stoichiometry remain unresolved. This supporting paper does not retroactively validate every reaction or direction in the original Reactome pathway.

Summary: Retain cellular response to oxidative stress as a contextual function or location.

Reason: The ARBA00027632/mouse transfer is consistent with target cytoprotection and lysosomal stress studies. Retain oxidative-stress response as a secondary physiological role; ATP13A2 is not an antioxidant enzyme.

Summary: Retain cellular response to oxidative stress as a contextual function or location.

Reason: PMID:26134396 reports ATP13A2-dependent cellular protection under stress in the lipid-regulation study. Retain the existing IMP stress-response role, distinguishing cellular readouts from direct reactive-oxygen detoxification.

Summary: Retain cellular response to oxidative stress as a contextual function or location.

Reason: The complete PMID:26392192 commentary discusses ATP13A2 protection from oxidative stress in the lipid-regulatory context. Retain the existing TAS response as non-core; this source is commentary, not an independent primary stress experiment.

Summary: Retain neuron projection as a contextual function or location.

Reason: PMID:22186024 places ATP13A2-containing structures in neuronal projections. Retain a contextual cellular location with exact target imaging curator-deferred; this does not imply a projection-specific transport chemistry.

Summary: Retain neuron projection as a contextual function or location.

Reason: The mouse Q9CTG6 transfer for neuron projection is compatible with the target neuronal study. Retain the anatomical cellular context without inferring isoform specificity.

Summary: Retain neuronal cell body as a contextual function or location.

Reason: Retain the PMID:22186024 neuronal-cell-body location as tissue/cellular context, distinct from the specific endolysosomal membrane site of transport.

Summary: Retain neuronal cell body as a contextual function or location.

Reason: The ARBA00027467/mouse neuronal-cell-body mapping is consistent with the target neuronal context and is retained as non-core.

Summary: Correct the compartment or regulatory direction while preserving the source assertion.

Reason: The actual Reactome event explicitly assigns its ATP13A2 physical entity to lysosomal lumen; this is not merely an inference from the event’s output. Direct target topology and the multipass P-type transporter architecture instead support lysosomal membrane. Preserve the original source object and correct the compartment to the existing membrane term; no soluble-lumen enzyme is supported. The linked entity page itself timed out, so the provenance statement is limited to the readable official event page.

Proposed replacements: lysosomal membrane

Summary: Retain regulation of neuron apoptotic process as a contextual function or location.

Reason: The ISS source explicitly identifies medaka H2L3J0. PMID:23499937 reports ATP13A2-related lysosomal/neurodegenerative phenotypes; retain a non-core neuronal survival/apoptosis-regulation transfer with donor species preserved. Neither a direct apoptosis catalyst nor an assayed human construct is inferred from the donor result.

Summary: Retain positive regulation of protein secretion as a contextual function or location.

Reason: PMID:25392495 reports ATP13A2-dependent secretion of alpha-synuclein-containing vesicles/exosomes. Retain the broad positive-regulation process as a secondary function; the transporter is not itself a secreted cargo-processing enzyme.

Summary: Retain lipid homeostasis as a contextual function or location.

Reason: PMID:31132336 explicitly studies human SH-SY5Y ATP13A2 overexpression and lipid/organellar homeostasis. Retain this cellular homeostasis role, without converting lipid changes into demonstrated phospholipid-flippase catalysis.

Summary: Retain protein localization to lysosome as a contextual function or location.

Reason: The mouse Q9CTG6 transfer is concordant with the HDAC6 recruitment mechanism investigated in target cells. Retain protein localization to lysosome as a secondary role, not a new protein-translocation MF.

Summary: Retain protein localization to lysosome as a contextual function or location.

Reason: PMID:30538141 supports lysosomal HDAC6 recruitment, using human cellular association/localization and separately mouse lysosomal fraction evidence. Retain the existing localization process; co-IP and rescue do not establish purified direct binding or direct deacetylase activation.

Summary: Retain autophagosome-lysosome fusion as a contextual function or location.

Reason: Retain the PTN002899996 inherited autophagosome–lysosome fusion role, supported by target experiments. Neither a short donor list nor self-inclusion is a defect; exact PAINT topology was not reconstructed. This is a secondary cellular role rather than a membrane fusogen MF.

Summary: Retain autophagosome-lysosome fusion as a contextual function or location.

Reason: The ARBA00092980/mouse transfer is compatible with human target fusion-pathway evidence. Retain non-core, without assuming the original mouse and human perturbations used identical constructs.

Summary: Retain autophagosome-lysosome fusion as a contextual function or location.

Reason: PMID:30538141 links ATP13A2 to autophagosome–lysosome fusion through HDAC6/cortactin-associated trafficking. Retain this established cellular role; ATP13A2 is not thereby shown to catalyze membrane fusion or directly activate HDAC6.

Summary: Retain phosphatidic acid binding as a contextual function or location.

Reason: Actual PMID:26134396 human N-terminal 1–187 fragment assays show phosphatidic-acid binding in overlays and membrane floatation with GST/mutant controls. Retain a regulatory lipid-binding function; no phospholipid translocation is demonstrated by these binding assays.

Summary: The source-specific support for cellular response to manganese ion remains unresolved.

Reason: Complete cached PMID:22285144 Methods2.1–2.5 and Results describe a cross-sectional human genotype-by-environment study, not a cellular perturbation assay. Two intronic SNPs modify the Mn-exposure/motor association in elderly participants; the authors state their functional effects are unknown and note multiple-comparison limitations. A cellular ATP13A2 response mechanism is unresolved from this source. Preserve the IMP assertion without relabeling its evidence or claiming Mn-response biology is false.

Summary: The source-specific support for cellular response to manganese ion remains unresolved.

Reason: The complete cached PMID:23628791 abstract foregrounds LRRK2/Mn biology; its complete article and exact ATP13A2 discussion were not available in this read. This is insufficient to verify the source-specific TAS ATP13A2 assertion, but is not grounds for a wrong-gene or REMOVE claim.

Summary: Retain cellular response to manganese ion as a contextual function or location.

Reason: The complete PMID:26392192 commentary discusses ATP13A2-associated protection from manganese toxicity. Retain the existing TAS stress-response role as non-core, while its statement that direct heavy-metal transport was unproven remains explicit. The source is commentary, not an independent transport assay.

Summary: Retain cellular response to zinc ion as a contextual function or location.

Reason: The complete PMID:26392192 commentary places ATP13A2 in protection from zinc toxicity, concordant with human/mouse zinc-homeostasis work. Retain a secondary response role, not a direct zinc-binding or transport conclusion.

Summary: Retain phosphatidylinositol-3,5-bisphosphate binding as a contextual function or location.

Reason: Actual PMID:26134396 recombinant human N-tail binding assays support PI(3,5)P2 recognition with lipid/mutant controls. Retain the specific regulatory lipid-binding function; it is not evidence for phosphoinositide translocation.

Summary: Retain extracellular exosome biogenesis as a contextual function or location.

Reason: PMID:25392495 reports ATP13A2 effects on extracellular exosome production. Retain the existing biogenesis process as a non-core cellular role with curatorial deference to the full experiments; the inspected abstract does not establish an autonomous exosome-assembly activity.

Summary: Retain the reported potassium-associated transport activity as non-core.

Reason: Retain this propagated monoatomic-cation transport process as non-core in light of the target-specific potassium-associated study PMID:37080960. Human full-length N-terminally tagged ATP13A2 was studied in HEK293 cells with mock, D513N and knockout/rescue controls. ATPase activity was measured in bulk membrane fractions, and ATP-dependent 86Rb efflux was measured after plasma-membrane permeabilization. These data support a reported potassium-associated activity, while purified intrinsic H+/K+ coupling and stoichiometry remain unresolved. The original propagation source is preserved; no new acidification process or additional transport core is proposed.

Summary: Retain P-type transmembrane transporter activity as part of the transport core.

Reason: The IPR006544 P-type-transporter mapping agrees with direct ATP13A2 phosphoenzyme/ATPase chemistry and polyamine transport. This is the correct transporter class for the core.

Summary: Retain regulation of protein localization to nucleus as a contextual function or location.

Reason: The ARBA00092944/mouse transfer is concordant with ATP13A2-dependent TFEB nuclear distribution. Retain the regulatory process as non-core; ATP13A2 itself is not assigned nuclear residence or DNA binding.

Summary: Retain regulation of protein localization to nucleus as a contextual function or location.

Reason: Actual PMID:27278822 Results measure TFEB nuclear localization after ATP13A2 perturbation via the TSC2/mTORC1 pathway. Retain this secondary regulation of protein localization; the nuclear protein is TFEB, not ATP13A2.

Summary: Retain polyamine transmembrane transport as part of the transport core.

Reason: PTN000643506 inherited polyamine transport agrees with direct human target evidence. Target inclusion among the descendant sources is legitimate, and no uninspected PAINT-node defect is alleged.

Summary: Retain polyamine transmembrane transport as part of the transport core.

Reason: PMID:23205587 uses human ATP13A2 expressed in CHO cells and reports polyamine accumulation in the endolysosomal uptake pathway. Retain polyamine transport; whole-cell uptake in this study does not reverse the later mechanistic lysosome-to-cytosol export direction.

Summary: The source-specific support for cupric ion binding remains unresolved.

Reason: PMID:23202360 supplies synthetic yeast YPK9 peptide metal-complex evidence; the explicit ISS donor Q12697 is therefore expected, not a wrong-gene annotation. Conservation of the assayed cupric ion-binding sites and their function in intact human ATP13A2 has not been established here. The 2012 full paper and complete 2013 Results were not read; selected 2013 Methods/Mn Results and both abstracts were read. A simple absence of exact peptide strings is not an alignment or loss-of-function proof. Retain uncertainty, not REMOVE.

Summary: Retain regulation of autophagy of mitochondrion as a contextual function or location.

Reason: PMID:25548531 discusses autophagy/mitochondrial consequences of ATP13A2 dysfunction. Retain the existing TAS mitophagy-regulation assertion as a non-core homeostatic role with curator deference; a direct mitophagy receptor or enzyme mechanism is not established.

Summary: Retain positive regulation of exosomal secretion as a contextual function or location.

Reason: PMID:24603074 reports ATP13A2-dependent extracellular alpha-synuclein externalization in exosomes. Retain positive exosomal secretion as a secondary cellular role, preserving the distinction between localization, secretion phenotype and intrinsic transport chemistry.

Summary: Retain positive regulation of exosomal secretion as a contextual function or location.

Reason: The ARBA00089029/mouse transfer is compatible with target exosomal secretion studies. Retain it as non-core; the donor source and rule were not independently reconstructed.

Summary: Retain positive regulation of exosomal secretion as a contextual function or location.

Reason: PMID:25392495 reports ATP13A2 regulation of exosome-mediated alpha-synuclein release. Retain the existing IMP secretion process, without making secretion an additional molecular-function core.

Summary: Retain spermine transmembrane transport as part of the transport core.

Reason: PMID:31996848 directly identifies spermine as a favored transported polyamine. Retain the existing substrate-specific process; the core uses the broader polyamine transport process once rather than adding redundant parent/child core processes.

Summary: Retain regulation of chaperone-mediated autophagy as a contextual function or location.

Reason: The complete PMID:22885599 commentary explicitly describes accumulation of CMA substrates when ATP13A2 loss impairs lysosomal proteolysis and rescue by wild-type ATP13A2. Retain this existing TAS regulatory role as non-core, without claiming a CMA-selective translocation assay or direct recognition of CMA cargo. No NEW process is inferred from necessity alone.

Summary: Retain autophagosome organization as a contextual function or location.

Reason: PMID:22186024 reports autophagic-vesicle organization changes in neuronal ATP13A2 experiments. Retain this contextual organization process with curatorial deference; exact target images were not independently reread.

Summary: Retain regulation of lysosomal protein catabolic process as a contextual function or location.

Reason: The ARBA00086818/mouse transfer is compatible with human target lysosomal-proteolysis phenotypes. Retain regulation as a secondary homeostatic role, not protease activity.

Summary: Retain regulation of lysosomal protein catabolic process as a contextual function or location.

Reason: PMID:24334770 links ATP13A2 and zinc-related lysosomal proteolysis, with human patient and separately mouse-neuron experiments. Preserve the explicit mouse Q9CTG6 support in the IGI row and retain the regulation process as non-core, without conflating species or assigning protease activity.

Summary: Retain regulation of lysosomal protein catabolic process as a contextual function or location.

Reason: PMID:23499937 reports ATP13A2 loss-associated lysosomal degradation/neurodegenerative phenotypes. Retain the existing protein-catabolism regulation as a secondary role, preserving the study’s organism/perturbation context and avoiding an intrinsic protease claim.

Summary: Replace the negative-regulation assertion with positive regulation of lysosomal protein catabolism.

Reason: The complete cited commentary PMID:22885599 reports reduced lysosomal substrate degradation in ATP13A2-mutant patient fibroblasts and ATP13A2-depleted human BE-M17 cells, followed by rescue of lysosomal deficits by wild-type ATP13A2. This direction supports GO:1905167, which covers increasing lysosomal protein catabolism, rather than negative regulation. Retain the original TAS source: the commentary summarizes earlier experiments and does not supply an independent Methods section or establish direct protease activity. The positive effect is a contextual lysosomal-homeostasis role, not an additional core function. The three existing GO:1905165 annotations remain valid broader assertions with their own evidence; duplication alone is not the reason for choosing the more specific positive term.

Proposed replacements: positive regulation of lysosomal protein catabolic process