id: Q9HBG4 gene_symbol: ATP6V0A4 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: ATP6V0A4 encodes the a4 isoform of the membrane-integral a subunit of the V-type proton ATPase V0 sector. The protein is a multi-pass V-ATPase component that helps couple ATP hydrolysis in the V1 sector to proton translocation through V0. It is especially important in renal acid-base physiology, where a4-containing pumps are targeted to apical membranes of intercalated cells and other nephron segments to support urinary acidification, and it is also expressed in the inner ear where loss of function can contribute to sensorineural hearing loss. Like other V-ATPase a subunits, ATP6V0A4 participates in acidification of membrane-bounded compartments and specialized extracellular-facing membranes, with its best-supported human roles centered on kidney proton secretion and V-ATPase assembly/coupling. existing_annotations: - term: id: GO:0016471 label: vacuolar proton-transporting V-type ATPase complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: vacuolar proton-transporting V-type ATPase complex is the correct complex context for ATP6V0A4 as an a4 V0-sector subunit of V-ATPase. action: ACCEPT reason: ATP6V0A4 is a membrane-integral component of the V0 sector of the V-ATPase holoenzyme; the complex-level annotation is a core representation of its function. supported_by: - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) - reference_id: PMID:32001091 supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps - reference_id: PMID:33065002 supporting_text: V-ATPases are ATP-driven proton pumps - term: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: contributes_to review: summary: ATP6V0A4 contributes to rotational proton-transporting ATPase activity as part of the assembled V-ATPase, rather than acting alone. action: ACCEPT reason: 'The qualifier correctly captures a complex subunit contribution: V1 hydrolyzes ATP and V0 transfers protons, requiring V1/V0 coupling.' supported_by: - reference_id: PMID:18632794 supporting_text: The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane - reference_id: PMID:18632794 supporting_text: Coupling of proton transport and ATP hydrolysis - reference_id: PMID:33065002 supporting_text: V-ATPases are ATP-driven proton pumps - term: id: GO:0005886 label: plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Plasma membrane localization is well supported for specialized V-ATPases containing ATP6V0A4, especially renal intercalated-cell apical membranes. action: ACCEPT reason: ATP6V0A4 is a multi-pass membrane component of plasma-membrane-targeted proton pumps used for extracellular/urinary acidification. supported_by: - reference_id: PMID:10973252 supporting_text: localizes almost exclusively to the apical surface - reference_id: PMID:33065002 supporting_text: Plasma membrane V-ATPases carry out extracellular acidification - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Localizes to the apical surface of alpha- - term: id: GO:0007035 label: vacuolar acidification evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Vacuolar acidification is a core V-ATPase process and is the conservative organellar-acidification term for ATP6V0A4. action: ACCEPT reason: V-ATPases are the primary source of organellar acidification. For ATP6V0A4, this broad term is better supported than forcing a lysosome-specific projection without a4-specific lysosomal functional evidence. supported_by: - reference_id: PMID:32001091 supporting_text: primary source of organellar acidification in all eukaryotes - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) - term: id: GO:0051117 label: ATPase binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: ATPase binding is supported by ATP6V0A4 interactions with V-ATPase V1-sector subunits and is relevant to V1/V0 coupling. action: ACCEPT reason: The a4 subunit binds V-ATPase G subunits and participates in the same proton pump, supporting this more informative binding term. supported_by: - reference_id: PMID:17360703 supporting_text: identified a possible interaction between the G3 subunit and the a4 subunit - reference_id: PMID:17360703 supporting_text: a4 and G3 are component subunits of the same proton pump - reference_id: PMID:17360703 supporting_text: represent a novel link between the V(1) and V(0) domains - term: id: GO:0000220 label: vacuolar proton-transporting V-type ATPase, V0 domain evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: part_of review: summary: vacuolar proton-transporting V-type ATPase, V0 domain is supported because ATP6V0A4 is the a4 isoform of the V0 a subunit. action: ACCEPT reason: The a subunit is part of the membrane V0 proton-translocation sector, so V0-domain membership is a core cellular-component annotation. supported_by: - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) - reference_id: PMID:18632794 supporting_text: The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane - term: id: GO:0016323 label: basolateral plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Basolateral plasma membrane localization is plausible for beta-intercalated-cell/orthologous contexts but is not the best-supported human a4 core location. action: KEEP_AS_NON_CORE reason: The human evidence emphasizes apical localization in alpha-intercalated and proximal tubule cells. Basolateral localization should be retained as non-core/orthology-supported context. supported_by: - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Localizes to the basolateral surface of - reference_id: PMID:14638902 supporting_text: All types of intercalated cells expressed a4 - term: id: GO:0016324 label: apical plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Apical plasma membrane localization is a primary ATP6V0A4 localization in kidney proton-secreting cells. action: ACCEPT reason: Multiple human kidney studies support apical a4 localization in alpha-intercalated cells and related nephron segments. supported_by: - reference_id: PMID:10973252 supporting_text: localizes almost exclusively to the apical surface - reference_id: PMID:12649290 supporting_text: ATP6V0A4 encodes a4, which is expressed apically - reference_id: PMID:14638902 supporting_text: a4 protein was localized by immunohistochemistry to the apical compartment - reference_id: PMID:15800125 supporting_text: co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern - term: id: GO:0033179 label: proton-transporting V-type ATPase, V0 domain evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: part_of review: summary: proton-transporting V-type ATPase, V0 domain is supported because ATP6V0A4 is the a4 isoform of the V0 a subunit. action: ACCEPT reason: The a subunit is part of the membrane V0 proton-translocation sector, so V0-domain membership is a core cellular-component annotation. supported_by: - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) - reference_id: PMID:18632794 supporting_text: The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane - term: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: The activity term is biologically correct for ATP6V0A4 in the context of the assembled V-ATPase complex. action: ACCEPT reason: Retain the term because ATP6V0A4 contributes to V-ATPase rotational proton-pump activity as a V0-sector subunit. The evidence should be interpreted in the complex-subunit context also captured by the IBA contributes_to row. supported_by: - reference_id: PMID:18632794 supporting_text: The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane - reference_id: PMID:18632794 supporting_text: Coupling of proton transport and ATP hydrolysis - term: id: GO:1902600 label: proton transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: ATP6V0A4 supports proton transmembrane transport as part of V-ATPase-mediated proton pumping. action: ACCEPT reason: The a4 V0-sector subunit is required for normal V-ATPase proton translocation and renal urinary acidification; retain as a core process-level annotation. supported_by: - reference_id: PMID:10973252 supporting_text: vectorial proton transport is required for urinary acidification - reference_id: PMID:10973252 supporting_text: essential role in normal vectorial acid transport into the urine by the kidney - reference_id: PMID:18632794 supporting_text: The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane - reference_id: PMID:33065002 supporting_text: V-ATPases are ATP-driven proton pumps - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: The underlying interaction is useful context, but GO:0005515 protein binding is too generic for ATP6V0A4 function. action: MARK_AS_OVER_ANNOTATED reason: The interaction evidence comes from a broad neurodegenerative-disease interactome screen and does not identify a specific ATP6V0A4 molecular function. Generic protein binding is not informative for ATP6V0A4 function. supported_by: - reference_id: PMID:32814053 supporting_text: generated by systematic yeast two-hybrid interaction screening - term: id: GO:0005768 label: endosome evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Endosome localization is plausible for V-ATPase-associated ATP6V0A4 but is less central than the renal apical plasma membrane role. action: KEEP_AS_NON_CORE reason: V-ATPases acidify endosomes and ATP6V0A4 has orthology/Reactome support in endosomal contexts, but direct human a4 evidence is stronger for kidney plasma membrane targeting. supported_by: - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - reference_id: Reactome:R-HSA-74723 supporting_text: The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome - term: id: GO:0005903 label: brush border evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Brush border is supported for proximal tubule apical localization, but brush border membrane is the more precise term for this membrane protein. action: MODIFY reason: ATP6V0A4 is a multi-pass membrane subunit; the direct annotation to brush border membrane is preferable to the broader brush border structure. proposed_replacement_terms: - id: GO:0031526 label: brush border membrane supported_by: - reference_id: PMID:14638902 supporting_text: a4 protein was localized by immunohistochemistry to the apical compartment - term: id: GO:0016471 label: vacuolar proton-transporting V-type ATPase complex evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: part_of review: summary: vacuolar proton-transporting V-type ATPase complex is the correct complex context for ATP6V0A4 as an a4 V0-sector subunit of V-ATPase. action: ACCEPT reason: ATP6V0A4 is a membrane-integral component of the V0 sector of the V-ATPase holoenzyme; the complex-level annotation is a core representation of its function. supported_by: - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) - reference_id: PMID:32001091 supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps - reference_id: PMID:33065002 supporting_text: V-ATPases are ATP-driven proton pumps - term: id: GO:0030672 label: synaptic vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: Synaptic vesicle membrane is an over-specific projection for ATP6V0A4. action: MARK_AS_OVER_ANNOTATED reason: ATP6V0A4 has cochlear/inner-ear disease relevance, but direct evidence for synaptic vesicle membrane localization of the a4 isoform is lacking. supported_by: - reference_id: PMID:12414817 supporting_text: show ATP6V0A4 expression within the cochlea for the first time - reference_id: PMID:32001091 supporting_text: multiple isoforms that are differentially localized - term: id: GO:0045177 label: apical part of cell evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Apical part of cell is true but too broad for a multi-pass V-ATPase subunit with stronger apical plasma membrane/brush-border membrane evidence. action: MODIFY reason: Use the more specific membrane location supported by ATP6V0A4 kidney localization studies. proposed_replacement_terms: - id: GO:0016324 label: apical plasma membrane supported_by: - reference_id: PMID:14638902 supporting_text: a4 protein was localized by immunohistochemistry to the apical compartment - reference_id: PMID:10973252 supporting_text: localizes almost exclusively to the apical surface - 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 an over-specific orthology projection for ATP6V0A4. action: MARK_AS_OVER_ANNOTATED reason: ATP6V0A4 has inner-ear expression, but the local human evidence supports renal/inner-ear specialized V-ATPases rather than a specific synaptic-vesicle acidification role for the a4 isoform. supported_by: - reference_id: PMID:12414817 supporting_text: show ATP6V0A4 expression within the cochlea for the first time - reference_id: PMID:32001091 supporting_text: multiple isoforms that are differentially localized - term: id: GO:0005886 label: plasma membrane evidence_type: NAS original_reference_id: PMID:32001091 qualifier: located_in review: summary: Plasma membrane localization is well supported for specialized V-ATPases containing ATP6V0A4, especially renal intercalated-cell apical membranes. action: ACCEPT reason: ATP6V0A4 is a multi-pass membrane component of plasma-membrane-targeted proton pumps used for extracellular/urinary acidification. supported_by: - reference_id: PMID:10973252 supporting_text: localizes almost exclusively to the apical surface - reference_id: PMID:33065002 supporting_text: Plasma membrane V-ATPases carry out extracellular acidification - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Localizes to the apical surface of alpha- - term: id: GO:0033176 label: proton-transporting V-type ATPase complex evidence_type: NAS original_reference_id: PMID:33065002 qualifier: part_of review: summary: proton-transporting V-type ATPase complex is the correct complex context for ATP6V0A4 as an a4 V0-sector subunit of V-ATPase. action: ACCEPT reason: ATP6V0A4 is a membrane-integral component of the V0 sector of the V-ATPase holoenzyme; the complex-level annotation is a core representation of its function. supported_by: - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) - reference_id: PMID:32001091 supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps - reference_id: PMID:33065002 supporting_text: V-ATPases are ATP-driven proton pumps - term: id: GO:0051452 label: intracellular pH reduction evidence_type: NAS original_reference_id: PMID:32001091 qualifier: involved_in review: summary: Intracellular pH reduction captures the general V-ATPase effect but is less precise than vacuolar acidification and proton transport. action: MODIFY reason: The relevant mechanism is proton translocation by the V-ATPase into membrane-bounded compartments, not an undifferentiated reduction of intracellular pH. proposed_replacement_terms: - id: GO:0007035 label: vacuolar acidification - id: GO:1902600 label: proton transmembrane transport supported_by: - reference_id: PMID:32001091 supporting_text: primary source of organellar acidification in all eukaryotes - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - term: id: GO:1902600 label: proton transmembrane transport evidence_type: NAS original_reference_id: PMID:33065002 qualifier: involved_in review: summary: ATP6V0A4 supports proton transmembrane transport as part of V-ATPase-mediated proton pumping. action: ACCEPT reason: The a4 V0-sector subunit is required for normal V-ATPase proton translocation and renal urinary acidification; retain as a core process-level annotation. supported_by: - reference_id: PMID:10973252 supporting_text: vectorial proton transport is required for urinary acidification - reference_id: PMID:10973252 supporting_text: essential role in normal vectorial acid transport into the urine by the kidney - reference_id: PMID:18632794 supporting_text: The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane - reference_id: PMID:33065002 supporting_text: V-ATPases are ATP-driven proton pumps - term: id: GO:0016323 label: basolateral plasma membrane evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Basolateral plasma membrane localization is plausible for beta-intercalated-cell/orthologous contexts but is not the best-supported human a4 core location. action: KEEP_AS_NON_CORE reason: The human evidence emphasizes apical localization in alpha-intercalated and proximal tubule cells. Basolateral localization should be retained as non-core/orthology-supported context. supported_by: - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Localizes to the basolateral surface of - reference_id: PMID:14638902 supporting_text: All types of intercalated cells expressed a4 - term: id: GO:0097254 label: renal tubular secretion evidence_type: IMP original_reference_id: PMID:12414817 qualifier: involved_in review: summary: Renal tubular secretion is supported by the disease-defining role of ATP6V0A4 in vectorial acid transport into urine. action: ACCEPT reason: Although broad, the term reflects a primary tissue-level ATP6V0A4 function in renal intercalated-cell acid secretion. supported_by: - reference_id: PMID:10973252 supporting_text: essential role in normal vectorial acid transport into the urine by the kidney - reference_id: PMID:14638902 supporting_text: a4 is regulated by trafficking but not protein expression - term: id: GO:0016471 label: vacuolar proton-transporting V-type ATPase complex evidence_type: IDA original_reference_id: PMID:10973252 qualifier: part_of review: summary: vacuolar proton-transporting V-type ATPase complex is the correct complex context for ATP6V0A4 as an a4 V0-sector subunit of V-ATPase. action: ACCEPT reason: ATP6V0A4 is a membrane-integral component of the V0 sector of the V-ATPase holoenzyme; the complex-level annotation is a core representation of its function. supported_by: - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) - reference_id: PMID:32001091 supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps - reference_id: PMID:33065002 supporting_text: V-ATPases are ATP-driven proton pumps - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19199708 qualifier: located_in review: summary: Extracellular exosome localization is retained as a non-core high-throughput vesicle-proteomics observation. action: KEEP_AS_NON_CORE reason: Parotid exosome detection is a high-throughput extracellular-vesicle context and should not drive core functional interpretation. supported_by: - reference_id: PMID:19199708 supporting_text: we catalogued 491 proteins in the exosome fraction of human parotid saliva - reference_id: PMID:19199708 supporting_text: membrane-bound vesicles of endosomal origin within multivesicular endosomes - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 qualifier: located_in review: summary: Extracellular exosome localization is retained as a non-core high-throughput vesicle-proteomics observation. action: KEEP_AS_NON_CORE reason: Urinary exosome detection is relevant to renal epithelial membranes but remains a high-throughput vesicle-location observation, not a core ATP6V0A4 function. supported_by: - reference_id: PMID:19056867 supporting_text: Normal human urine contains large numbers of exosomes - term: id: GO:0005765 label: lysosomal membrane evidence_type: HDA original_reference_id: PMID:17897319 qualifier: located_in review: summary: Lysosomal membrane is supported by high-throughput lysosomal membrane proteomics and general V-ATPase biology, but it should be treated cautiously for the a4 isoform. action: KEEP_AS_NON_CORE reason: The PN projection asks whether ATP6V0A4 should be treated as a lysosomal V-ATPase component. Existing evidence supports possible lysosomal membrane presence, but not a direct a4-specific lysosomal lumen acidification role. supported_by: - reference_id: PMID:17897319 supporting_text: In membranes purified from placental lysosomes, we identified 58 proteins - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - reference_id: PMID:32001091 supporting_text: multiple isoforms that are differentially localized - term: id: GO:0030670 label: phagocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-1222516 qualifier: located_in review: summary: Phagocytic vesicle membrane is a generic Reactome V-ATPase projection and is not well supported for ATP6V0A4 specifically. action: MARK_AS_OVER_ANNOTATED reason: The Reactome event describes V-ATPase proton pumping in phagosomes generally; the a4 isoform is best supported in renal and inner-ear specialized pumps. supported_by: - reference_id: Reactome:R-HSA-1222516 supporting_text: ATP hydrolysis drives a 120 degree rotation of the rotor - reference_id: PMID:32001091 supporting_text: multiple isoforms that are differentially localized - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5252133 qualifier: located_in review: summary: Endosome membrane is retained as a supported V-ATPase context but not the defining ATP6V0A4 localization. action: KEEP_AS_NON_CORE reason: Reactome events capture V-ATPase-mediated endosome acidification; ATP6V0A4-specific human evidence is stronger for renal apical membranes. supported_by: - reference_id: Reactome:R-HSA-74723 supporting_text: The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-74723 qualifier: located_in review: summary: Endosome membrane is retained as a supported V-ATPase context but not the defining ATP6V0A4 localization. action: KEEP_AS_NON_CORE reason: Reactome events capture V-ATPase-mediated endosome acidification; ATP6V0A4-specific human evidence is stronger for renal apical membranes. supported_by: - reference_id: Reactome:R-HSA-74723 supporting_text: The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-917841 qualifier: located_in review: summary: Endosome membrane is retained as a supported V-ATPase context but not the defining ATP6V0A4 localization. action: KEEP_AS_NON_CORE reason: Reactome events capture V-ATPase-mediated endosome acidification; ATP6V0A4-specific human evidence is stronger for renal apical membranes. supported_by: - reference_id: Reactome:R-HSA-74723 supporting_text: The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - term: id: GO:0045177 label: apical part of cell evidence_type: IDA original_reference_id: PMID:14675051 qualifier: located_in review: summary: Apical part of cell is true but too broad for a multi-pass V-ATPase subunit with stronger apical plasma membrane/brush-border membrane evidence. action: MODIFY reason: Use the more specific membrane location supported by ATP6V0A4 kidney localization studies. proposed_replacement_terms: - id: GO:0016324 label: apical plasma membrane supported_by: - reference_id: PMID:14638902 supporting_text: a4 protein was localized by immunohistochemistry to the apical compartment - reference_id: PMID:10973252 supporting_text: localizes almost exclusively to the apical surface - term: id: GO:0005768 label: endosome evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Endosome localization is plausible for V-ATPase-associated ATP6V0A4 but is less central than the renal apical plasma membrane role. action: KEEP_AS_NON_CORE reason: V-ATPases acidify endosomes and ATP6V0A4 has orthology/Reactome support in endosomal contexts, but direct human a4 evidence is stronger for kidney plasma membrane targeting. supported_by: - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - reference_id: Reactome:R-HSA-74723 supporting_text: The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome - term: id: GO:0016324 label: apical plasma membrane evidence_type: IDA original_reference_id: PMID:15800125 qualifier: located_in review: summary: Apical plasma membrane localization is a primary ATP6V0A4 localization in kidney proton-secreting cells. action: ACCEPT reason: Multiple human kidney studies support apical a4 localization in alpha-intercalated cells and related nephron segments. supported_by: - reference_id: PMID:10973252 supporting_text: localizes almost exclusively to the apical surface - reference_id: PMID:12649290 supporting_text: ATP6V0A4 encodes a4, which is expressed apically - reference_id: PMID:14638902 supporting_text: a4 protein was localized by immunohistochemistry to the apical compartment - reference_id: PMID:15800125 supporting_text: co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:17360703 qualifier: located_in review: summary: Plasma membrane localization is well supported for specialized V-ATPases containing ATP6V0A4, especially renal intercalated-cell apical membranes. action: ACCEPT reason: ATP6V0A4 is a multi-pass membrane component of plasma-membrane-targeted proton pumps used for extracellular/urinary acidification. supported_by: - reference_id: PMID:10973252 supporting_text: localizes almost exclusively to the apical surface - reference_id: PMID:33065002 supporting_text: Plasma membrane V-ATPases carry out extracellular acidification - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Localizes to the apical surface of alpha- - term: id: GO:0016324 label: apical plasma membrane evidence_type: IDA original_reference_id: PMID:12649290 qualifier: located_in review: summary: Apical plasma membrane localization is a primary ATP6V0A4 localization in kidney proton-secreting cells. action: ACCEPT reason: Multiple human kidney studies support apical a4 localization in alpha-intercalated cells and related nephron segments. supported_by: - reference_id: PMID:10973252 supporting_text: localizes almost exclusively to the apical surface - reference_id: PMID:12649290 supporting_text: ATP6V0A4 encodes a4, which is expressed apically - reference_id: PMID:14638902 supporting_text: a4 protein was localized by immunohistochemistry to the apical compartment - reference_id: PMID:15800125 supporting_text: co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern - term: id: GO:0051117 label: ATPase binding evidence_type: IPI original_reference_id: PMID:17360703 qualifier: enables review: summary: ATPase binding is supported by ATP6V0A4 interactions with V-ATPase V1-sector subunits and is relevant to V1/V0 coupling. action: ACCEPT reason: The a4 subunit binds V-ATPase G subunits and participates in the same proton pump, supporting this more informative binding term. supported_by: - reference_id: PMID:17360703 supporting_text: identified a possible interaction between the G3 subunit and the a4 subunit - reference_id: PMID:17360703 supporting_text: a4 and G3 are component subunits of the same proton pump - reference_id: PMID:17360703 supporting_text: represent a novel link between the V(1) and V(0) domains - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18632794 qualifier: enables review: summary: The underlying interaction is useful context, but GO:0005515 protein binding is too generic for ATP6V0A4 function. action: MARK_AS_OVER_ANNOTATED reason: The PFK-1 interaction is real and functionally relevant to pump coupling, but GO:0005515 is too generic and should not be treated as a core molecular function. supported_by: - reference_id: PMID:18632794 supporting_text: PFK-1 in normal proton pump function - reference_id: PMID:12649290 supporting_text: co-immunoprecipitation of a4 with PFK-1 from solubilized human kidney membrane proteins - term: id: GO:1902600 label: proton transmembrane transport evidence_type: IMP original_reference_id: PMID:10973252 qualifier: involved_in review: summary: ATP6V0A4 supports proton transmembrane transport as part of V-ATPase-mediated proton pumping. action: ACCEPT reason: The a4 V0-sector subunit is required for normal V-ATPase proton translocation and renal urinary acidification; retain as a core process-level annotation. supported_by: - reference_id: PMID:10973252 supporting_text: vectorial proton transport is required for urinary acidification - reference_id: PMID:10973252 supporting_text: essential role in normal vectorial acid transport into the urine by the kidney - reference_id: PMID:18632794 supporting_text: The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane - reference_id: PMID:33065002 supporting_text: V-ATPases are ATP-driven proton pumps - term: id: GO:0001503 label: ossification evidence_type: IMP original_reference_id: PMID:10973252 qualifier: involved_in review: summary: Ossification phenotypes in distal renal tubular acidosis are downstream systemic consequences, not evidence that ATP6V0A4 directly participates in ossification. action: MARK_AS_OVER_ANNOTATED reason: The cited disease paper mentions disturbed bone physiology and growth as consequences of renal tubular acidosis. ATP6V0A4 is not the osteoclast a-subunit and this annotation overprojects a clinical consequence. supported_by: - reference_id: PMID:10973252 supporting_text: essential role in normal vectorial acid transport into the urine by the kidney - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:12649290 qualifier: enables review: summary: The underlying interaction is useful context, but GO:0005515 protein binding is too generic for ATP6V0A4 function. action: MARK_AS_OVER_ANNOTATED reason: The cited study supports a4 interaction with PFK-1, but generic protein binding is an uninformative over-annotation relative to the mechanistic V-ATPase coupling role. supported_by: - reference_id: PMID:12649290 supporting_text: co-immunoprecipitation of a4 with PFK-1 from solubilized human kidney membrane proteins - reference_id: PMID:12649290 supporting_text: direct link between V-type H+-ATPases and glycolysis - term: id: GO:0006885 label: regulation of pH evidence_type: IMP original_reference_id: PMID:10973252 qualifier: involved_in review: summary: Regulation of pH is supported by ATP6V0A4 disease and renal acidification evidence but is too broad for the mechanistic annotation. action: MODIFY reason: The literature supports vectorial proton transport and urinary acidification; proton transmembrane transport is the more informative GO process. proposed_replacement_terms: - id: GO:1902600 label: proton transmembrane transport supported_by: - reference_id: PMID:10973252 supporting_text: vectorial proton transport is required for urinary acidification - reference_id: PMID:10973252 supporting_text: essential role in normal vectorial acid transport into the urine by the kidney - term: id: GO:0007605 label: sensory perception of sound evidence_type: IMP original_reference_id: PMID:12414817 qualifier: involved_in review: summary: Sensorineural hearing loss in ATP6V0A4 disease and cochlear expression support an inner-ear role, but this is secondary to the renal acidification core function. action: KEEP_AS_NON_CORE reason: Retain as a non-core tissue phenotype/process because ATP6V0A4 is expressed in the human cochlea and some mutation carriers develop hearing loss. supported_by: - reference_id: PMID:12414817 supporting_text: several patients with ATP6V0A4 mutations have developed hearing loss - reference_id: PMID:12414817 supporting_text: show ATP6V0A4 expression within the cochlea for the first time - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Found in the inner ear - term: id: GO:0016324 label: apical plasma membrane evidence_type: IDA original_reference_id: PMID:10973252 qualifier: located_in review: summary: Apical plasma membrane localization is a primary ATP6V0A4 localization in kidney proton-secreting cells. action: ACCEPT reason: Multiple human kidney studies support apical a4 localization in alpha-intercalated cells and related nephron segments. supported_by: - reference_id: PMID:10973252 supporting_text: localizes almost exclusively to the apical surface - reference_id: PMID:12649290 supporting_text: ATP6V0A4 encodes a4, which is expressed apically - reference_id: PMID:14638902 supporting_text: a4 protein was localized by immunohistochemistry to the apical compartment - reference_id: PMID:15800125 supporting_text: co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern - term: id: GO:0031526 label: brush border membrane evidence_type: IDA original_reference_id: PMID:14638902 qualifier: located_in review: summary: Brush border membrane localization is supported for ATP6V0A4 in proximal tubule apical compartments. action: ACCEPT reason: This is a specific membrane localization consistent with the JASN a4 localization study. supported_by: - reference_id: PMID:14638902 supporting_text: a4 protein was localized by immunohistochemistry to the apical compartment - term: id: GO:0045177 label: apical part of cell evidence_type: IDA original_reference_id: PMID:14638902 qualifier: located_in review: summary: Apical part of cell is true but too broad for a multi-pass V-ATPase subunit with stronger apical plasma membrane/brush-border membrane evidence. action: MODIFY reason: Use the more specific membrane location supported by ATP6V0A4 kidney localization studies. proposed_replacement_terms: - id: GO:0016324 label: apical plasma membrane supported_by: - reference_id: PMID:14638902 supporting_text: a4 protein was localized by immunohistochemistry to the apical compartment - reference_id: PMID:10973252 supporting_text: localizes almost exclusively to the apical surface 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:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10973252 title: Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. findings: [] - id: PMID:12414817 title: Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. findings: [] - id: PMID:12649290 title: The a-subunit of the V-type H+-ATPase interacts with phosphofructokinase-1 in humans. findings: [] - id: PMID:14638902 title: Localization and regulation of the ATP6V0A4 (a4) vacuolar H+-ATPase subunit defective in an inherited form of distal renal tubular acidosis. findings: [] - id: PMID:14675051 title: Comparative ontogeny, processing, and segmental distribution of the renal chloride channel, ClC-5. findings: [] - id: PMID:15800125 title: 'Vacuolar H+-ATPase d2 subunit: molecular characterization, developmental regulation, and localization to specialized proton pumps in kidney and bone.' findings: [] - id: PMID:17360703 title: V1 and V0 domains of the human H+-ATPase are linked by an interaction between the G and a subunits. findings: [] - id: PMID:17897319 title: Integral and associated lysosomal membrane proteins. findings: [] - id: PMID:18632794 title: Human H+ATPase a4 subunit mutations causing renal tubular acidosis reveal a role for interaction with phosphofructokinase-1. findings: [] - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: [] - id: PMID:19199708 title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). findings: [] - id: PMID:32001091 title: Structure and Roles of V-type ATPases. findings: [] - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] - id: PMID:33065002 title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly. findings: [] - id: Reactome:R-HSA-1222516 title: Intraphagosomal pH is lowered to 5 by V-ATPase findings: [] - id: Reactome:R-HSA-5252133 title: ATP6AP1 binds V-ATPase findings: [] - id: Reactome:R-HSA-74723 title: Endosome acidification findings: [] - id: Reactome:R-HSA-917841 title: Acidification of Tf:TfR1 containing endosome findings: [] - id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt title: UniProtKB record for human ATP6V0A4/Q9HBG4 findings: [] - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv title: Proteostasis Network projected candidate additions for ATP6V0A4 findings: [] - id: file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml title: Proteostasis Network autophagy-lysosome pathway GO mappings findings: [] core_functions: - description: ATP6V0A4 is the a4 isoform of the membrane-integral V0 a subunit of the V-ATPase. As part of the V0 sector, it contributes to the assembled V-ATPase rotational proton-pump activity, linking ATP hydrolysis by V1 to proton transfer across membranes. contributes_to_molecular_function: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism directly_involved_in: - id: GO:1902600 label: proton transmembrane transport - id: GO:0007035 label: vacuolar acidification in_complex: id: GO:0016471 label: vacuolar proton-transporting V-type ATPase complex supported_by: - reference_id: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) - reference_id: PMID:18632794 supporting_text: The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane - reference_id: PMID:33065002 supporting_text: V-ATPases are ATP-driven proton pumps - description: In kidney, ATP6V0A4-containing V-ATPases are targeted to apical membranes of proton-secreting nephron cells, where they support vectorial acid transport into urine and systemic acid-base homeostasis. contributes_to_molecular_function: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism directly_involved_in: - id: GO:0097254 label: renal tubular secretion - id: GO:1902600 label: proton transmembrane transport locations: - id: GO:0016324 label: apical plasma membrane - id: GO:0031526 label: brush border membrane in_complex: id: GO:0016471 label: vacuolar proton-transporting V-type ATPase complex supported_by: - reference_id: PMID:10973252 supporting_text: essential role in normal vectorial acid transport into the urine by the kidney - reference_id: PMID:14638902 supporting_text: a4 protein was localized by immunohistochemistry to the apical compartment - reference_id: PMID:14638902 supporting_text: a4 is regulated by trafficking but not protein expression - description: ATP6V0A4 helps couple and regulate the V-ATPase through interactions with V1-sector subunits and glycolytic enzyme PFK-1. These interactions support V1/V0 assembly or functional coupling and explain disease mutations that reduce proton transport without simply removing the subunit from the membrane. molecular_function: id: GO:0051117 label: ATPase binding directly_involved_in: - id: GO:1902600 label: proton transmembrane transport in_complex: id: GO:0016471 label: vacuolar proton-transporting V-type ATPase complex supported_by: - reference_id: PMID:17360703 supporting_text: a4 and G3 are component subunits of the same proton pump - reference_id: PMID:17360703 supporting_text: represent a novel link between the V(1) and V(0) domains - reference_id: PMID:18632794 supporting_text: PFK-1 in normal proton pump function proposed_new_terms: [] suggested_questions: - question: Should ATP6V0A4 be annotated to GO:0007042 lysosomal lumen acidification or GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain in human, or should those PN projections be limited to V-ATPase a-subunit isoforms with stronger lysosomal evidence? Existing ATP6V0A4 evidence supports V0 membership, broad organellar/vacuolar acidification, and high-throughput lysosomal membrane detection, but its best-supported isoform-specific biology is renal apical plasma membrane acid secretion. experts: - Karet FE - Wagner CA - Rubinstein JL suggested_experiments: - hypothesis: ATP6V0A4 has a context-specific lysosomal role only in cell types where the a4 isoform is targeted to endolysosomal membranes. description: Use endogenous tagging or isoform-specific antibodies in human kidney intercalated-cell models and inner-ear-relevant cells, combined with LAMP1/RAB7 colocalization and lysosomal pH reporters, to distinguish lysosomal ATP6V0A4 from apical plasma membrane pools. experiment_type: cell localization and lysosomal pH assay - hypothesis: PFK-1 binding modulates ATP6V0A4-containing V-ATPase proton transport by affecting V1/V0 coupling rather than complex targeting. description: Compare wild-type ATP6V0A4 and PFK-binding-defective disease variants in a human epithelial rescue system, measuring V-ATPase assembly, membrane targeting, ATPase activity, and proton transport separately. experiment_type: structure-function rescue assay