Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IBA GO_REF:0000033	ACCEPT	Summary: vacuolar proton-transporting V-type ATPase complex is the correct complex context for ATP6V0A4 as an a4 V0-sector subunit of V-ATPase. 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. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps PMID:33065002 V-ATPases are ATP-driven proton pumps
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IBA GO_REF:0000033	ACCEPT	Summary: ATP6V0A4 contributes to rotational proton-transporting ATPase activity as part of the assembled V-ATPase, rather than acting alone. Reason: The qualifier correctly captures a complex subunit contribution: V1 hydrolyzes ATP and V0 transfers protons, requiring V1/V0 coupling. Supporting Evidence: PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane PMID:18632794 Coupling of proton transport and ATP hydrolysis PMID:33065002 V-ATPases are ATP-driven proton pumps
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Plasma membrane localization is well supported for specialized V-ATPases containing ATP6V0A4, especially renal intercalated-cell apical membranes. Reason: ATP6V0A4 is a multi-pass membrane component of plasma-membrane-targeted proton pumps used for extracellular/urinary acidification. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:33065002 Plasma membrane V-ATPases carry out extracellular acidification file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Localizes to the apical surface of alpha-
GO:0007035 vacuolar acidification	IBA GO_REF:0000033	ACCEPT	Summary: Vacuolar acidification is a core V-ATPase process and is the conservative organellar-acidification term for ATP6V0A4. 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. Supporting Evidence: PMID:32001091 primary source of organellar acidification in all eukaryotes PMID:33065002 pH homeostasis of endosomes and lysosomes file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase)
GO:0051117 ATPase binding	IBA GO_REF:0000033	ACCEPT	Summary: ATPase binding is supported by ATP6V0A4 interactions with V-ATPase V1-sector subunits and is relevant to V1/V0 coupling. Reason: The a4 subunit binds V-ATPase G subunits and participates in the same proton pump, supporting this more informative binding term. Supporting Evidence: PMID:17360703 identified a possible interaction between the G3 subunit and the a4 subunit PMID:17360703 a4 and G3 are component subunits of the same proton pump PMID:17360703 represent a novel link between the V(1) and V(0) domains
GO:0000220 vacuolar proton-transporting V-type ATPase, V0 domain	IEA GO_REF:0000002	ACCEPT	Summary: vacuolar proton-transporting V-type ATPase, V0 domain is supported because ATP6V0A4 is the a4 isoform of the V0 a subunit. Reason: The a subunit is part of the membrane V0 proton-translocation sector, so V0-domain membership is a core cellular-component annotation. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane
GO:0016323 basolateral plasma membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Basolateral plasma membrane localization is plausible for beta-intercalated-cell/orthologous contexts but is not the best-supported human a4 core location. 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. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Localizes to the basolateral surface of PMID:14638902 All types of intercalated cells expressed a4
GO:0016324 apical plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: Apical plasma membrane localization is a primary ATP6V0A4 localization in kidney proton-secreting cells. Reason: Multiple human kidney studies support apical a4 localization in alpha-intercalated cells and related nephron segments. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:12649290 ATP6V0A4 encodes a4, which is expressed apically PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:15800125 co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern
GO:0033179 proton-transporting V-type ATPase, V0 domain	IEA GO_REF:0000002	ACCEPT	Summary: proton-transporting V-type ATPase, V0 domain is supported because ATP6V0A4 is the a4 isoform of the V0 a subunit. Reason: The a subunit is part of the membrane V0 proton-translocation sector, so V0-domain membership is a core cellular-component annotation. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000002	ACCEPT	Summary: The activity term is biologically correct for ATP6V0A4 in the context of the assembled V-ATPase complex. 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. Supporting Evidence: PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane PMID:18632794 Coupling of proton transport and ATP hydrolysis
GO:1902600 proton transmembrane transport	IEA GO_REF:0000002	ACCEPT	Summary: ATP6V0A4 supports proton transmembrane transport as part of V-ATPase-mediated proton pumping. 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. Supporting Evidence: PMID:10973252 vectorial proton transport is required for urinary acidification PMID:10973252 essential role in normal vectorial acid transport into the urine by the kidney PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane PMID:33065002 V-ATPases are ATP-driven proton pumps
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: The underlying interaction is useful context, but GO:0005515 protein binding is too generic for ATP6V0A4 function. 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. Supporting Evidence: PMID:32814053 generated by systematic yeast two-hybrid interaction screening
GO:0005768 endosome	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Endosome localization is plausible for V-ATPase-associated ATP6V0A4 but is less central than the renal apical plasma membrane role. 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. Supporting Evidence: PMID:33065002 pH homeostasis of endosomes and lysosomes Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome
GO:0005903 brush border	IEA GO_REF:0000107	MODIFY	Summary: Brush border is supported for proximal tubule apical localization, but brush border membrane is the more precise term for this membrane protein. Reason: ATP6V0A4 is a multi-pass membrane subunit; the direct annotation to brush border membrane is preferable to the broader brush border structure. Proposed replacements: brush border membrane Supporting Evidence: PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IEA GO_REF:0000107	ACCEPT	Summary: vacuolar proton-transporting V-type ATPase complex is the correct complex context for ATP6V0A4 as an a4 V0-sector subunit of V-ATPase. 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. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps PMID:33065002 V-ATPases are ATP-driven proton pumps
GO:0030672 synaptic vesicle membrane	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Synaptic vesicle membrane is an over-specific projection for ATP6V0A4. Reason: ATP6V0A4 has cochlear/inner-ear disease relevance, but direct evidence for synaptic vesicle membrane localization of the a4 isoform is lacking. Supporting Evidence: PMID:12414817 show ATP6V0A4 expression within the cochlea for the first time PMID:32001091 multiple isoforms that are differentially localized
GO:0045177 apical part of cell	IEA GO_REF:0000120	MODIFY	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. Reason: Use the more specific membrane location supported by ATP6V0A4 kidney localization studies. Proposed replacements: apical plasma membrane Supporting Evidence: PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:10973252 localizes almost exclusively to the apical surface
GO:0097401 synaptic vesicle lumen acidification	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Synaptic vesicle lumen acidification is an over-specific orthology projection for ATP6V0A4. 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. Supporting Evidence: PMID:12414817 show ATP6V0A4 expression within the cochlea for the first time PMID:32001091 multiple isoforms that are differentially localized
GO:0005886 plasma membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: Plasma membrane localization is well supported for specialized V-ATPases containing ATP6V0A4, especially renal intercalated-cell apical membranes. Reason: ATP6V0A4 is a multi-pass membrane component of plasma-membrane-targeted proton pumps used for extracellular/urinary acidification. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:33065002 Plasma membrane V-ATPases carry out extracellular acidification file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Localizes to the apical surface of alpha-
GO:0033176 proton-transporting V-type ATPase complex	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: proton-transporting V-type ATPase complex is the correct complex context for ATP6V0A4 as an a4 V0-sector subunit of V-ATPase. 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. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps PMID:33065002 V-ATPases are ATP-driven proton pumps
GO:0051452 intracellular pH reduction	NAS PMID:32001091 Structure and Roles of V-type ATPases.	MODIFY	Summary: Intracellular pH reduction captures the general V-ATPase effect but is less precise than vacuolar acidification and proton transport. Reason: The relevant mechanism is proton translocation by the V-ATPase into membrane-bounded compartments, not an undifferentiated reduction of intracellular pH. Proposed replacements: vacuolar acidification proton transmembrane transport Supporting Evidence: PMID:32001091 primary source of organellar acidification in all eukaryotes PMID:33065002 pH homeostasis of endosomes and lysosomes
GO:1902600 proton transmembrane transport	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: ATP6V0A4 supports proton transmembrane transport as part of V-ATPase-mediated proton pumping. 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. Supporting Evidence: PMID:10973252 vectorial proton transport is required for urinary acidification PMID:10973252 essential role in normal vectorial acid transport into the urine by the kidney PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane PMID:33065002 V-ATPases are ATP-driven proton pumps
GO:0016323 basolateral plasma membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Basolateral plasma membrane localization is plausible for beta-intercalated-cell/orthologous contexts but is not the best-supported human a4 core location. 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. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Localizes to the basolateral surface of PMID:14638902 All types of intercalated cells expressed a4
GO:0097254 renal tubular secretion	IMP PMID:12414817 Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive...	ACCEPT	Summary: Renal tubular secretion is supported by the disease-defining role of ATP6V0A4 in vectorial acid transport into urine. Reason: Although broad, the term reflects a primary tissue-level ATP6V0A4 function in renal intercalated-cell acid secretion. Supporting Evidence: PMID:10973252 essential role in normal vectorial acid transport into the urine by the kidney PMID:14638902 a4 is regulated by trafficking but not protein expression
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IDA PMID:10973252 Mutations in ATP6N1B, encoding a new kidney vacuolar proton ...	ACCEPT	Summary: vacuolar proton-transporting V-type ATPase complex is the correct complex context for ATP6V0A4 as an a4 V0-sector subunit of V-ATPase. 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. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps PMID:33065002 V-ATPases are ATP-driven proton pumps
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	KEEP AS NON CORE	Summary: Extracellular exosome localization is retained as a non-core high-throughput vesicle-proteomics observation. Reason: Parotid exosome detection is a high-throughput extracellular-vesicle context and should not drive core functional interpretation. Supporting Evidence: PMID:19199708 we catalogued 491 proteins in the exosome fraction of human parotid saliva PMID:19199708 membrane-bound vesicles of endosomal origin within multivesicular endosomes
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: Extracellular exosome localization is retained as a non-core high-throughput vesicle-proteomics observation. Reason: Urinary exosome detection is relevant to renal epithelial membranes but remains a high-throughput vesicle-location observation, not a core ATP6V0A4 function. Supporting Evidence: PMID:19056867 Normal human urine contains large numbers of exosomes
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:17897319 In membranes purified from placental lysosomes, we identified 58 proteins PMID:33065002 pH homeostasis of endosomes and lysosomes PMID:32001091 multiple isoforms that are differentially localized
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-1222516	MARK AS OVER ANNOTATED	Summary: Phagocytic vesicle membrane is a generic Reactome V-ATPase projection and is not well supported for ATP6V0A4 specifically. 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. Supporting Evidence: Reactome:R-HSA-1222516 ATP hydrolysis drives a 120 degree rotation of the rotor PMID:32001091 multiple isoforms that are differentially localized
GO:0010008 endosome membrane	TAS Reactome:R-HSA-5252133	KEEP AS NON CORE	Summary: Endosome membrane is retained as a supported V-ATPase context but not the defining ATP6V0A4 localization. Reason: Reactome events capture V-ATPase-mediated endosome acidification; ATP6V0A4-specific human evidence is stronger for renal apical membranes. Supporting Evidence: Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome PMID:33065002 pH homeostasis of endosomes and lysosomes
GO:0010008 endosome membrane	TAS Reactome:R-HSA-74723	KEEP AS NON CORE	Summary: Endosome membrane is retained as a supported V-ATPase context but not the defining ATP6V0A4 localization. Reason: Reactome events capture V-ATPase-mediated endosome acidification; ATP6V0A4-specific human evidence is stronger for renal apical membranes. Supporting Evidence: Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome PMID:33065002 pH homeostasis of endosomes and lysosomes
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917841	KEEP AS NON CORE	Summary: Endosome membrane is retained as a supported V-ATPase context but not the defining ATP6V0A4 localization. Reason: Reactome events capture V-ATPase-mediated endosome acidification; ATP6V0A4-specific human evidence is stronger for renal apical membranes. Supporting Evidence: Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome PMID:33065002 pH homeostasis of endosomes and lysosomes
GO:0045177 apical part of cell	IDA PMID:14675051 Comparative ontogeny, processing, and segmental distribution...	MODIFY	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. Reason: Use the more specific membrane location supported by ATP6V0A4 kidney localization studies. Proposed replacements: apical plasma membrane Supporting Evidence: PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:10973252 localizes almost exclusively to the apical surface
GO:0005768 endosome	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Endosome localization is plausible for V-ATPase-associated ATP6V0A4 but is less central than the renal apical plasma membrane role. 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. Supporting Evidence: PMID:33065002 pH homeostasis of endosomes and lysosomes Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome
GO:0016324 apical plasma membrane	IDA PMID:15800125 Vacuolar H+-ATPase d2 subunit: molecular characterization, d...	ACCEPT	Summary: Apical plasma membrane localization is a primary ATP6V0A4 localization in kidney proton-secreting cells. Reason: Multiple human kidney studies support apical a4 localization in alpha-intercalated cells and related nephron segments. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:12649290 ATP6V0A4 encodes a4, which is expressed apically PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:15800125 co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern
GO:0005886 plasma membrane	IDA PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an in...	ACCEPT	Summary: Plasma membrane localization is well supported for specialized V-ATPases containing ATP6V0A4, especially renal intercalated-cell apical membranes. Reason: ATP6V0A4 is a multi-pass membrane component of plasma-membrane-targeted proton pumps used for extracellular/urinary acidification. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:33065002 Plasma membrane V-ATPases carry out extracellular acidification file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Localizes to the apical surface of alpha-
GO:0016324 apical plasma membrane	IDA PMID:12649290 The a-subunit of the V-type H+-ATPase interacts with phospho...	ACCEPT	Summary: Apical plasma membrane localization is a primary ATP6V0A4 localization in kidney proton-secreting cells. Reason: Multiple human kidney studies support apical a4 localization in alpha-intercalated cells and related nephron segments. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:12649290 ATP6V0A4 encodes a4, which is expressed apically PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:15800125 co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern
GO:0051117 ATPase binding	IPI PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an in...	ACCEPT	Summary: ATPase binding is supported by ATP6V0A4 interactions with V-ATPase V1-sector subunits and is relevant to V1/V0 coupling. Reason: The a4 subunit binds V-ATPase G subunits and participates in the same proton pump, supporting this more informative binding term. Supporting Evidence: PMID:17360703 identified a possible interaction between the G3 subunit and the a4 subunit PMID:17360703 a4 and G3 are component subunits of the same proton pump PMID:17360703 represent a novel link between the V(1) and V(0) domains
GO:0005515 protein binding	IPI PMID:18632794 Human H+ATPase a4 subunit mutations causing renal tubular ac...	MARK AS OVER ANNOTATED	Summary: The underlying interaction is useful context, but GO:0005515 protein binding is too generic for ATP6V0A4 function. 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. Supporting Evidence: PMID:18632794 PFK-1 in normal proton pump function PMID:12649290 co-immunoprecipitation of a4 with PFK-1 from solubilized human kidney membrane proteins
GO:1902600 proton transmembrane transport	IMP PMID:10973252 Mutations in ATP6N1B, encoding a new kidney vacuolar proton ...	ACCEPT	Summary: ATP6V0A4 supports proton transmembrane transport as part of V-ATPase-mediated proton pumping. 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. Supporting Evidence: PMID:10973252 vectorial proton transport is required for urinary acidification PMID:10973252 essential role in normal vectorial acid transport into the urine by the kidney PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane PMID:33065002 V-ATPases are ATP-driven proton pumps
GO:0001503 ossification	IMP PMID:10973252 Mutations in ATP6N1B, encoding a new kidney vacuolar proton ...	MARK AS OVER ANNOTATED	Summary: Ossification phenotypes in distal renal tubular acidosis are downstream systemic consequences, not evidence that ATP6V0A4 directly participates in ossification. 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. Supporting Evidence: PMID:10973252 essential role in normal vectorial acid transport into the urine by the kidney
GO:0005515 protein binding	IPI PMID:12649290 The a-subunit of the V-type H+-ATPase interacts with phospho...	MARK AS OVER ANNOTATED	Summary: The underlying interaction is useful context, but GO:0005515 protein binding is too generic for ATP6V0A4 function. 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. Supporting Evidence: PMID:12649290 co-immunoprecipitation of a4 with PFK-1 from solubilized human kidney membrane proteins PMID:12649290 direct link between V-type H+-ATPases and glycolysis
GO:0006885 regulation of pH	IMP PMID:10973252 Mutations in ATP6N1B, encoding a new kidney vacuolar proton ...	MODIFY	Summary: Regulation of pH is supported by ATP6V0A4 disease and renal acidification evidence but is too broad for the mechanistic annotation. Reason: The literature supports vectorial proton transport and urinary acidification; proton transmembrane transport is the more informative GO process. Proposed replacements: proton transmembrane transport Supporting Evidence: PMID:10973252 vectorial proton transport is required for urinary acidification PMID:10973252 essential role in normal vectorial acid transport into the urine by the kidney
GO:0007605 sensory perception of sound	IMP PMID:12414817 Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive...	KEEP AS NON CORE	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. Reason: Retain as a non-core tissue phenotype/process because ATP6V0A4 is expressed in the human cochlea and some mutation carriers develop hearing loss. Supporting Evidence: PMID:12414817 several patients with ATP6V0A4 mutations have developed hearing loss PMID:12414817 show ATP6V0A4 expression within the cochlea for the first time file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Found in the inner ear
GO:0016324 apical plasma membrane	IDA PMID:10973252 Mutations in ATP6N1B, encoding a new kidney vacuolar proton ...	ACCEPT	Summary: Apical plasma membrane localization is a primary ATP6V0A4 localization in kidney proton-secreting cells. Reason: Multiple human kidney studies support apical a4 localization in alpha-intercalated cells and related nephron segments. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:12649290 ATP6V0A4 encodes a4, which is expressed apically PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:15800125 co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern
GO:0031526 brush border membrane	IDA PMID:14638902 Localization and regulation of the ATP6V0A4 (a4) vacuolar H+...	ACCEPT	Summary: Brush border membrane localization is supported for ATP6V0A4 in proximal tubule apical compartments. Reason: This is a specific membrane localization consistent with the JASN a4 localization study. Supporting Evidence: PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment
GO:0045177 apical part of cell	IDA PMID:14638902 Localization and regulation of the ATP6V0A4 (a4) vacuolar H+...	MODIFY	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. Reason: Use the more specific membrane location supported by ATP6V0A4 kidney localization studies. Proposed replacements: apical plasma membrane Supporting Evidence: PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:10973252 localizes almost exclusively to the apical surface

Core Functions

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.

Directly Involved In:

proton transmembrane transport vacuolar acidification

In Complex:

vacuolar proton-transporting V-type ATPase complex

Supporting Evidence:

file:human/ATP6V0A4/ATP6V0A4-uniprot.txt
Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase)
PMID:18632794
The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane
PMID:33065002
V-ATPases are ATP-driven proton pumps

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.

Directly Involved In:

renal tubular secretion proton transmembrane transport

Cellular Locations:

apical plasma membrane brush border membrane

In Complex:

vacuolar proton-transporting V-type ATPase complex

Supporting Evidence:

PMID:10973252
essential role in normal vectorial acid transport into the urine by the kidney
PMID:14638902
a4 protein was localized by immunohistochemistry to the apical compartment
PMID:14638902
a4 is regulated by trafficking but not protein expression

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:

ATPase binding

Directly Involved In:

proton transmembrane transport

In Complex:

vacuolar proton-transporting V-type ATPase complex

Supporting Evidence:

PMID:17360703
a4 and G3 are component subunits of the same proton pump
PMID:17360703
represent a novel link between the V(1) and V(0) domains
PMID:18632794
PFK-1 in normal proton pump function

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

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

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

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

GO_REF:0000107

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

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10973252

Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing.

PMID:12414817

Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss.

PMID:12649290

The a-subunit of the V-type H+-ATPase interacts with phosphofructokinase-1 in humans.

PMID:14638902

Localization and regulation of the ATP6V0A4 (a4) vacuolar H+-ATPase subunit defective in an inherited form of distal renal tubular acidosis.

PMID:14675051

Comparative ontogeny, processing, and segmental distribution of the renal chloride channel, ClC-5.

PMID:15800125

Vacuolar H+-ATPase d2 subunit: molecular characterization, developmental regulation, and localization to specialized proton pumps in kidney and bone.

PMID:17360703

V1 and V0 domains of the human H+-ATPase are linked by an interaction between the G and a subunits.

PMID:17897319

Integral and associated lysosomal membrane proteins.

PMID:18632794

Human H+ATPase a4 subunit mutations causing renal tubular acidosis reveal a role for interaction with phosphofructokinase-1.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:19199708

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

PMID:32001091

Structure and Roles of V-type ATPases.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33065002

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

Reactome:R-HSA-1222516

Intraphagosomal pH is lowered to 5 by V-ATPase

Reactome:R-HSA-5252133

ATP6AP1 binds V-ATPase

Reactome:R-HSA-74723

Endosome acidification

Reactome:R-HSA-917841

Acidification of Tf:TfR1 containing endosome

file:human/ATP6V0A4/ATP6V0A4-uniprot.txt

UniProtKB record for human ATP6V0A4/Q9HBG4

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

Proteostasis Network projected candidate additions for ATP6V0A4

file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml

Proteostasis Network autophagy-lysosome pathway GO mappings

Suggested Experiments

Experiment: 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.

Hypothesis: ATP6V0A4 has a context-specific lysosomal role only in cell types where the a4 isoform is targeted to endolysosomal membranes.

Type: cell localization and lysosomal pH assay

Experiment: 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.

Hypothesis: PFK-1 binding modulates ATP6V0A4-containing V-ATPase proton transport by affecting V1/V0 coupling rather than complex targeting.

Type: structure-function rescue assay

Deep Research

Falcon

(ATP6V0A4-deep-research-falcon.md)

Comprehensive Research Report: ATP6V0A4 (V-type Proton ATPase 116 kDa Subunit a4) Falcon

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

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

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

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

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

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

Comprehensive Research Report: ATP6V0A4 (V-type Proton ATPase 116 kDa Subunit a4)

Gene and Protein Identity

ATP6V0A4 (located on chromosome 7q34) encodes the a4 subunit of the V-type H+-ATPase (V-ATPase), a multisubunit proton pump essential for acid-base homeostasis in humans (peng2025againoffunctionmutation pages 1-2, a2023thepathophysiologyof pages 1-5). The protein belongs to the V-ATPase 116 kDa subunit family and contains the V_ATPase_I domain characteristic of this family (indrawinata2023structuralandfunctional pages 1-2). The a4 isoform represents one of four human a-subunit variants (a1-a4), each exhibiting tissue-specific and organelle-specific distribution patterns (tuli2023thecytosolicnterminal pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5).

Protein Structure and Molecular Organization

Domain Architecture

The ATP6V0A4 protein is the largest subunit of the membrane-embedded V0 domain of V-ATPase, consisting of approximately 840 amino acids (peng2025againoffunctionmutation pages 1-2). High-resolution cryo-electron microscopy structures of human V-ATPase (2.9-3.4 Å resolution) have revealed the detailed architecture of the a-subunit (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3). The protein contains two functionally distinct domains:

N-terminal cytoplasmic domain (aNT): This domain extends into the cytosol and serves as a critical bridge connecting the membrane-embedded V0 complex with the cytoplasmic V1 complex, thereby stabilizing the overall V-ATPase structure (tuli2023thecytosolicnterminal pages 1-2, indrawinata2023structuralandfunctional pages 1-2, peng2025againoffunctionmutation pages 2-4).
C-terminal transmembrane domain (aCT): This region contains eight transmembrane helices that form part of the proton translocation pathway across the membrane (indrawinata2023structuralandfunctional pages 1-2, peng2025againoffunctionmutation pages 2-4). Two of these helices are directly involved in proton transport by providing entry and exit hemichannels for protons (indrawinata2023structuralandfunctional pages 1-2).

V-ATPase Complex Organization

V-ATPase functions as a rotary molecular motor composed of two major domains (eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 1-3):

V1 domain (cytoplasmic): Contains subunits A3, B3, C, D, E3, F, G3, and H, responsible for ATP hydrolysis
V0 domain (membrane-embedded): Contains subunits a (including a4), c-ring (typically 8-10 c subunits), c', c'', d, e, and accessory proteins ATP6AP1 and ATP6AP2

The a4 subunit is positioned at the interface between the rotating c-ring and the stationary stator apparatus, enabling it to contribute directly to proton translocation (indrawinata2023structuralandfunctional pages 1-2, abbas2020structureofvatpase pages 1-2).

Primary Function and Catalytic Mechanism

Proton Transport Mechanism

ATP6V0A4 functions as an essential component of the ATP-driven proton pump machinery (peng2025againoffunctionmutation pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5). The mechanistic coupling between ATP hydrolysis and proton transport operates through the following process:

ATP hydrolysis: ATP is hydrolyzed at catalytic sites formed at the interfaces between A and B subunits in the V1 domain (indrawinata2023structuralandfunctional pages 1-2, abbas2020structureofvatpase pages 1-2)
Rotary coupling: Energy from ATP hydrolysis drives rotation of the central rotor complex (consisting of subunits D, F, and the c-ring) (eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 1-3)
Proton translocation: Rotation of the c-ring relative to the stationary a4 subunit enables cycles of proton binding, translocation, and release through hemichannels formed by the a-subunit (indrawinata2023structuralandfunctional pages 1-2, abbas2020structureofvatpase pages 1-2)

The ATP:H+ stoichiometry for mammalian V-ATPase has been determined to be approximately 3:10, meaning that hydrolysis of three ATP molecules drives the translocation of ten protons (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3).

Substrate Specificity

While ATP6V0A4 itself does not possess ATPase activity, it is integral to the V-ATPase complex that utilizes ATP as its energy substrate and transports protons (H+) as its ionic substrate (eaton2021theh+atpase(vatpase) pages 1-5, indrawinata2023structuralandfunctional pages 1-2). The a4 subunit contributes crucial structural elements that determine the efficiency and directionality of proton transport.

Critical Residues and Mechanism

Recent structural and functional studies have identified key conserved residues in the a-subunit essential for proton transport. For example, arginine residues in the transmembrane domain are thought to participate in deprotonating glutamic acid residues on the c-ring subunits during the transport cycle (indrawinata2023structuralandfunctional pages 1-2). The Val512 residue, highly conserved across species, is located in the C-terminal transmembrane region and influences a4 subunit stability and V-ATPase activity (peng2025againoffunctionmutation pages 2-4).

Subcellular Localization and Tissue Distribution

Tissue-Specific Expression

ATP6V0A4 exhibits highly restricted tissue expression compared to other a-subunit isoforms (xu2023identificationofatp6v0a4 pages 1-2). The protein is predominantly expressed in:

Kidney (primary site): Specifically in type A intercalated cells (α-intercalated cells) of the distal nephron
Inner ear: In specialized cells of the cochlea involved in endolymph pH regulation
Epididymis: In epithelial cells contributing to luminal acidification

This tissue-restricted expression pattern reflects the specialized role of a4-containing V-ATPases in plasma membrane proton secretion rather than in general endolysosomal acidification (eaton2021theh+atpase(vatpase) pages 1-5, xu2023identificationofatp6v0a4 pages 1-2).

Subcellular Localization in Kidney

In the kidney, ATP6V0A4-containing V-ATPases are localized to the apical plasma membrane of type A intercalated cells within the collecting duct system, including the distal convoluted tubule (DCT2), connecting tubule, cortical collecting duct (CCD), and medullary collecting duct (a2023thepathophysiologyof pages 1-5, giglio2021distalrenaltubular pages 1-2, a2023thepathophysiologyof pages 5-8). This plasma membrane localization distinguishes a4 from other a-subunit isoforms:

a1: Predominantly in synaptic vesicles and neuronal organelles
a2: Various intracellular organelles
a3: Osteoclast plasma membrane and lysosomes
a4: Apical plasma membrane of intercalated cells, inner ear, and epididymis

The specific apical membrane targeting of a4-containing V-ATPases is essential for their role in urinary acidification (eaton2021theh+atpase(vatpase) pages 1-5, a2023thepathophysiologyof pages 5-8).

Biochemical Pathways and Physiological Role

Renal Acid-Base Homeostasis Pathway

ATP6V0A4 plays a central role in the renal acid-base homeostasis pathway, specifically in type A intercalated cells of the collecting duct (a2023thepathophysiologyof pages 1-5, a2023thepathophysiologyof pages 5-8). The pathway operates as follows:

CO2 hydration: Cytosolic carbonic anhydrase II (CAII) catalyzes the conversion of CO2 and H2O to H2CO3, which spontaneously dissociates into H+ and HCO3- (a2023thepathophysiologyof pages 5-8)
Apical H+ secretion: ATP6V0A4-containing V-ATPases actively transport H+ across the apical membrane into the tubular lumen (urine) (peng2025againoffunctionmutation pages 1-2, a2023thepathophysiologyof pages 1-5, a2023thepathophysiologyof pages 5-8)
Basolateral HCO3- reabsorption: The chloride-bicarbonate exchanger AE1 (SLC4A1) exports HCO3- across the basolateral membrane into the blood (a2023thepathophysiologyof pages 5-8)
Urinary buffering: Secreted H+ combines with urinary buffers, primarily ammonia (NH3) to form ammonium (NH4+), and with phosphate to form titratable acids (a2023thepathophysiologyof pages 1-5, a2023thepathophysiologyof pages 5-8)

This coordinated process accounts for approximately 30 mEq of acid excretion per day under normal physiological conditions, completing the removal and buffering of non-volatile acids generated by normal metabolism (a2023thepathophysiologyof pages 5-8).

Protein-Protein Interactions and Assembly

Proper V-ATPase function requires correct assembly of the V1 and V0 domains (chen2020screeningandfunction pages 1-2, peng2025againoffunctionmutation pages 1-2). ATP6V0A4 physically interacts with the B1 subunit (ATP6V1B1) of the V1 domain, and this interaction is critical for holoenzyme assembly and stability. Disease-associated mutations can disrupt this interaction: the S544L variant showed impaired binding to B1 in co-immunoprecipitation experiments, leading to defective V-ATPase assembly and reduced acidification capacity (chen2020screeningandfunction pages 1-2).

Additional Biological Roles

Beyond renal acid-base balance, recent evidence suggests ATP6V0A4 and related V-ATPase subunits participate in:

Embryonic development: ATP6V0A4 upregulation during blastocyst cavitation facilitates lysosomal acidification and intracellular vacuole formation essential for early mammalian embryogenesis (alsolami2026asinglesmall pages 1-2)
Lysosomal function: While primarily a plasma membrane protein in kidney, V-ATPases containing various a-subunits contribute to lysosomal acidification, autophagy, and mTOR signaling in other cell types (eaton2021theh+atpase(vatpase) pages 1-5)

Disease Associations and Clinical Significance

Loss-of-Function Mutations: Distal Renal Tubular Acidosis

Biallelic loss-of-function mutations in ATP6V0A4 cause autosomal recessive distal renal tubular acidosis (dRTA), one of the canonical monogenic forms of inherited dRTA (peng2025againoffunctionmutation pages 1-2, a2023thepathophysiologyof pages 1-5, giglio2021distalrenaltubular pages 1-2). The clinical phenotype includes:

Metabolic manifestations:
- Hyperchloremic normal anion gap metabolic acidosis
- Hypokalemia
- Inability to acidify urine below pH 5.5 despite systemic acidosis (paradoxically alkaline urine)

Renal complications:
- Nephrocalcinosis (calcium deposition in kidney tissue)
- Nephrolithiasis (kidney stones)
- Potential progression to chronic kidney disease if untreated

Extrarenal manifestations:
- Sensorineural hearing loss (variable penetrance and severity)
- Growth failure and rickets in children
- Osteomalacia in adults

Patients with ATP6V0A4 mutations are typically diagnosed during the first year of life, often presenting with failure to thrive, growth retardation, and electrolyte abnormalities (a2023thepathophysiologyof pages 1-5, giglio2021distalrenaltubular pages 1-2). Compared to ATP6V1B1-associated dRTA, ATP6V0A4 mutations show a more variable hearing phenotype, with some patients developing early-onset sensorineural hearing loss while others maintain normal hearing (giglio2021distalrenaltubular pages 1-2).

Gain-of-Function Mutation: Renal Tubular Alkalosis

A groundbreaking 2025 study by Peng et al. identified the first gain-of-function mutation in ATP6V0A4 (p.V512L), dramatically expanding the phenotypic spectrum of ATP6V0A4-related disorders (peng2025againoffunctionmutation pages 1-2, peng2025againoffunctionmutation pages 2-4). This heterozygous mutation causes a phenotype opposite to classic dRTA:

Hypochloremic metabolic alkalosis (rather than acidosis)
Acidic urine (rather than alkaline urine)
Hypokalemia
Renal insufficiency and hearing loss

The V512L mutation enhances a4 subunit stability by reducing protein degradation, leading to increased V-ATPase abundance and enhanced proton-pumping capacity. This results in excessive H+ secretion into the tubular lumen, causing acidic urine and compensatory metabolic alkalosis (peng2025againoffunctionmutation pages 2-4). The V512 residue is located in the transmembrane region and is highly conserved across species, highlighting its functional importance.

Cancer and Biomarker Potential

Bioinformatic and validation studies have identified downregulation of ATP6V0A4 in clear cell renal cell carcinoma (ccRCC) tissues and cell lines (xu2023identificationofatp6v0a4 pages 1-2). Lower ATP6V0A4 expression correlated with poorer prognosis in ccRCC patients, suggesting potential utility as a prognostic biomarker. However, the functional significance of this downregulation in cancer biology remains to be fully elucidated.

Experimental Evidence and Validation

Structural Studies

High-resolution cryo-EM structures of mammalian V-ATPase complexes (up to 2.9 Å resolution) have provided detailed molecular insights into the organization and mechanism of ATP6V0A4-containing pumps (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3). These structures defined:

The precise arrangement of a-subunit transmembrane helices
The interface between the a-subunit and the c-ring
The ATP:H+ stoichiometry (3:10)
The structural basis for proton hemichannels

AlphaFold structural predictions have complemented experimental structures, enabling modeling of disease-associated variants (peng2025againoffunctionmutation pages 2-4).

Functional Assays

Multiple experimental approaches have validated ATP6V0A4 function:

Cell-based assays: Transfection of wild-type and mutant ATP6V0A4 into HEK293T cells and mouse collecting duct cell lines (M1s) demonstrated altered ATPase activity, proton transport rates, and pH changes in response to mutations (chen2020screeningandfunction pages 1-2, peng2025againoffunctionmutation pages 2-4)
Co-immunoprecipitation: Studies confirmed physical interactions between ATP6V0A4 and ATP6V1B1, with disease mutations disrupting this interaction (chen2020screeningandfunction pages 1-2)
Immunofluorescence: Localization studies demonstrated apical plasma membrane distribution of ATP6V0A4 in kidney intercalated cells, with some mutations causing aberrant intracellular retention or uneven membrane distribution (chen2020screeningandfunction pages 1-2, peng2025againoffunctionmutation pages 2-4)
pH measurements: Lysosomal and cytoplasmic pH measurements using pH-sensitive probes confirmed that ATP6V0A4 mutations impair acidification capacity (chen2020screeningandfunction pages 1-2, peng2025againoffunctionmutation pages 2-4)

Mouse Models

Mouse knockout studies have provided critical in vivo validation of ATP6V0A4 function. Atp6v0a4 knockout mice develop a dRTA phenotype characterized by impaired urinary acidification, metabolic acidosis, and electrolyte abnormalities, recapitulating key features of human disease (eaton2021theh+atpase(vatpase) pages 1-5, a2023thepathophysiologyof pages 1-5). These models have been instrumental in understanding the physiological role of a4 in renal acid-base homeostasis.

Bioinformatic Evidence

Sequence conservation analysis reveals that critical residues in ATP6V0A4, such as Val512, are highly conserved across mammalian species, indicating strong evolutionary constraint and functional importance (peng2025againoffunctionmutation pages 2-4). Pathogenicity prediction tools (MutPred2, PolyPhen-2, Mutation Taster) and CADD scores consistently predict damaging effects for disease-associated variants, supporting their causative role (peng2025againoffunctionmutation pages 2-4).

Summary Table

Property/Feature	Details	Key References
Gene/protein identity	ATP6V0A4 encodes the human V-type proton ATPase 116 kDa subunit a4, a tissue-restricted isoform of the V-ATPase Vo a-subunit family. It is the a4 isoform of the membrane sector that supports proton secretion in specialized epithelia, especially kidney intercalated cells.	(tuli2023thecytosolicnterminal pages 1-2, peng2025againoffunctionmutation pages 1-2, xu2023identificationofatp6v0a4 pages 1-2)
Protein complex context	ATP6V0A4 is part of the Vo membrane sector of the multisubunit V-ATPase. V-ATPase has a cytosolic V1 sector that hydrolyzes ATP and a membrane-embedded Vo sector that translocates protons. The a-subunit is the largest Vo subunit and is essential for coupling ATP hydrolysis to proton movement.	(tuli2023thecytosolicnterminal pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, indrawinata2023structuralandfunctional pages 1-2, wang2020structuresofa pages 1-3)
Domain architecture	The a-subunit has two major regions: an N-terminal cytosolic domain (aNT) that bridges and regulates interactions between V1 and Vo, and a C-terminal membrane domain (aCT) with 8 transmembrane helices that contributes directly to the proton pathway. For ATP6V0A4/a4 specifically, the N-terminus stabilizes V1-Vo association, whereas the C-terminus forms the proton-conducting membrane portion.	(tuli2023thecytosolicnterminal pages 1-2, indrawinata2023structuralandfunctional pages 1-2, peng2025againoffunctionmutation pages 2-4)
Mechanistic role in proton transport	The a4 subunit contributes to the entry/exit hemi-channels for protons in Vo and supports proton translocation coupled to c-ring rotation. ATP hydrolysis in V1 drives rotor rotation, which is converted into vectorial proton movement through Vo. Structural work on mammalian V-ATPase defines an ATP:H+ ratio of ~3:10.	(indrawinata2023structuralandfunctional pages 1-2, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3)
Substrate and energy coupling	ATP6V0A4 is not itself the catalytic ATPase site; instead, it functions within the proton pore machinery. ATP is hydrolyzed at catalytic A/B interfaces in V1, and this energy is transmitted through the central rotor to the Vo sector containing a4, enabling H+ translocation across membranes. The transported substrate is protons (H+).	(eaton2021theh+atpase(vatpase) pages 1-5, indrawinata2023structuralandfunctional pages 1-2, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3)
Isoform-specific biological role	Among mammalian a-subunit isoforms, a4 is specialized for plasma-membrane proton secretion rather than mainly endolysosomal acidification. This isoform specialization helps target V-ATPases to distinct membranes and cell types.	(tuli2023thecytosolicnterminal pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, xu2023identificationofatp6v0a4 pages 1-2)
Tissue distribution	ATP6V0A4 is highly expressed in kidney, inner ear, and epididymis; several sources also note expression in specialized acidifying epithelia. In cancer-expression studies, it is relatively kidney-enriched compared with many other tissues.	(peng2025againoffunctionmutation pages 1-2, xu2023identificationofatp6v0a4 pages 1-2, peng2025againoffunctionmutation pages 2-4)
Subcellular localization	In the kidney, ATP6V0A4-containing V-ATPase localizes predominantly to the apical plasma membrane of type A intercalated cells in the distal nephron/collecting duct, where it secretes H+ into tubular fluid. This plasma membrane localization distinguishes it from other a-subunit isoforms that often mark intracellular organelles.	(eaton2021theh+atpase(vatpase) pages 1-5, giglio2021distalrenaltubular pages 1-2, xu2023identificationofatp6v0a4 pages 1-2, a2023thepathophysiologyof pages 5-8)
Renal physiological pathway	In type A intercalated cells, cytosolic carbonic anhydrase II converts CO2 + H2O to H+ + HCO3-. ATP6V0A4-containing V-ATPase exports H+ apically into urine, while AE1/SLC4A1 returns HCO3- basolaterally to blood. This pathway is central to distal urinary acidification and systemic acid-base homeostasis.	(peng2025againoffunctionmutation pages 1-2, a2023thepathophysiologyof pages 1-5, giglio2021distalrenaltubular pages 1-2, a2023thepathophysiologyof pages 5-8)
Quantitative physiology	Reviews of distal renal acidification indicate that type A intercalated cells account for ~30 mEq acid excretion per day under normal conditions, completing renal net acid elimination; ATP6V0A4 is one of the key V-ATPase subunits enabling this process.	(a2023thepathophysiologyof pages 5-8)
Interaction/assembly evidence	Functional integrity depends on proper V1-Vo assembly and interaction with other subunits such as ATP6V1B1 (B1). A disease-associated ATP6V0A4 mutant (p.S544L) showed impaired binding to B1 in co-immunoprecipitation experiments, supporting a role for a4 in assembly/stability of the holoenzyme.	(chen2020screeningandfunction pages 1-2, peng2025againoffunctionmutation pages 1-2)
Structural evidence	High-resolution mammalian/human cryo-EM structures (up to ~2.9–3.4 Å) resolved overall V-ATPase architecture and defined the a-subunit as a major structural and functional element of Vo. These studies support the conserved rotary mechanism and provide the framework for interpreting ATP6V0A4 pathogenic variants.	(abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3)
Key residue/example variant	Val512 in ATP6V0A4 is located in the C-terminal transmembrane region and is highly conserved across species. Structural modeling and functional data indicate that p.V512L alters a4 stability and increases V-ATPase activity, illustrating how transmembrane residues can tune proton-pump output.	(peng2025againoffunctionmutation pages 2-4)
Loss-of-function disease association	Biallelic or otherwise damaging loss-of-function ATP6V0A4 variants cause primary distal renal tubular acidosis (dRTA), often with variable sensorineural hearing loss. This is one of the canonical monogenic causes of inherited dRTA.	(a2023thepathophysiologyof pages 1-5, giglio2021distalrenaltubular pages 1-2, peng2025againoffunctionmutation pages 1-2)
dRTA clinical phenotype	ATP6V0A4-related dRTA typically presents with hyperchloremic normal-anion-gap metabolic acidosis, hypokalemia, impaired ability to acidify urine, nephrocalcinosis/nephrolithiasis, growth problems, and possible hearing impairment. Reviews note many patients are diagnosed in infancy/early childhood.	(a2023thepathophysiologyof pages 1-5, giglio2021distalrenaltubular pages 1-2, peng2025againoffunctionmutation pages 1-2)
Hearing phenotype	Compared with ATP6V1B1-associated disease, ATP6V0A4 mutations show a more variable hearing phenotype, ranging from early to later-onset or absent sensorineural hearing loss, but hearing involvement remains a recognized extrarenal manifestation.	(giglio2021distalrenaltubular pages 1-2, peng2025againoffunctionmutation pages 1-2)
Gain-of-function disease association	A 2025 study described a gain-of-function ATP6V0A4 mutation, p.V512L, associated with hypochloremic metabolic alkalosis, acidic urine, and hypokalemia—essentially a phenotype opposite to classic dRTA—thereby expanding the ATP6V0A4 disease spectrum beyond loss-of-function.	(peng2025againoffunctionmutation pages 1-2, peng2025againoffunctionmutation pages 2-4)
Functional assay evidence for pathogenicity	In cell-based assays, ATP6V0A4 variants altered ATPase/proton-transport behavior, membrane distribution, protein abundance, and assembly. p.S544L showed weaker early ATPase activity and abnormal membrane distribution; p.V512L increased protein stability/abundance and enhanced acidification capacity.	(chen2020screeningandfunction pages 1-2, peng2025againoffunctionmutation pages 2-4)
Model-system evidence	The ATP6V0A4 literature includes transfected HEK293T cells, mouse collecting duct cell lines, and mouse knockout/physiology studies cited in reviews as evidence that impaired a4 function causes defective urinary acidification and dRTA phenotypes.	(eaton2021theh+atpase(vatpase) pages 1-5, a2023thepathophysiologyof pages 1-5, peng2025againoffunctionmutation pages 2-4)
Broader cell-biological relevance	Although ATP6V0A4’s best-established role is renal proton secretion, recent work also links V-ATPase subunits including ATP6V0A4 to lysosomal acidification during blastocyst cavitation/early embryogenesis, underscoring conserved proton-pump functions outside the kidney.	(alsolami2026asinglesmall pages 1-2)
Cancer/biomarker observations	A 2023 bioinformatics and validation study found ATP6V0A4 downregulated in clear cell renal cell carcinoma (ccRCC); lower expression was associated with poorer prognosis, suggesting biomarker potential, though this is less definitive functionally than the renal acidification evidence.	(xu2023identificationofatp6v0a4 pages 1-2)

Table: This table summarizes the verified identity, structure, proton-pump function, localization, renal physiology, disease associations, and supporting evidence for human ATP6V0A4. It is useful as a compact evidence map for functional annotation of the a4 V-ATPase subunit.

Conclusions

ATP6V0A4 encodes a tissue-specific V-ATPase a-subunit that is essential for renal acid-base homeostasis through its role in apical proton secretion by type A intercalated cells. The protein's dual-domain structure enables it to couple ATP hydrolysis in the cytoplasmic V1 domain to proton translocation through the membrane-embedded V0 domain, with an ATP:H+ stoichiometry of 3:10. Loss-of-function mutations cause distal renal tubular acidosis with variable sensorineural hearing loss, while a novel gain-of-function mutation causes the opposite phenotype of metabolic alkalosis with acidic urine. The protein's critical role in human physiology is supported by extensive structural, functional, and genetic evidence from recent studies (2020-2025), establishing ATP6V0A4 as a key component of renal acid-base regulation.

References

(peng2025againoffunctionmutation pages 1-2): Si-qi Peng, Qian-qian Wu, Wan-yi Wang, Yi-Lin Zhang, Rui-ning Zhou, Jun Liao, Jin-xuan Wei, Yan Yang, Wen Shi, Jun-lan Yang, Xiao-xu Wang, Zhi-yuan Wei, Jia-xuan Sun, Lu Huang, Hong Fan, Hui Cai, Cheng-kun Wang, Xin-hua Li, Ting-song Li, Bi-cheng Liu, Xiao-liang Zhang, and Bin Wang. A gain-of-function mutation in atp6v0a4 drives primary distal renal tubular alkalosis with enhanced v-atpase activity. The Journal of Clinical Investigation, Apr 2025. URL: https://doi.org/10.1172/jci188807, doi:10.1172/jci188807. This article has 10 citations.
(a2023thepathophysiologyof pages 1-5): Carsten A Wagner, Robert Unwin, Sergio C Lopez-Garcia, Robert Kleta, Detlef Bockenhauer, and Stephen Walsh. The pathophysiology of distal renal tubular acidosis. Nature Reviews Nephrology, 19:384-400, Apr 2023. URL: https://doi.org/10.1038/s41581-023-00699-9, doi:10.1038/s41581-023-00699-9. This article has 83 citations and is from a domain leading peer-reviewed journal.
(indrawinata2023structuralandfunctional pages 1-2): Karen Indrawinata, Peter Argiropoulos, and Shuzo Sugita. Structural and functional understanding of disease-associated mutations in v-atpase subunit a1 and other isoforms. Frontiers in Molecular Neuroscience, Jul 2023. URL: https://doi.org/10.3389/fnmol.2023.1135015, doi:10.3389/fnmol.2023.1135015. This article has 16 citations.
(tuli2023thecytosolicnterminal pages 1-2): Farzana Tuli and Patricia M. Kane. The cytosolic n-terminal domain of v-atpase a-subunits is a regulatory hub targeted by multiple signals. Frontiers in Molecular Biosciences, Jun 2023. URL: https://doi.org/10.3389/fmolb.2023.1168680, doi:10.3389/fmolb.2023.1168680. This article has 10 citations.
(eaton2021theh+atpase(vatpase) pages 1-5): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h⁺-atpase (v-atpase): from proton pump to signaling complex in health and disease. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.
(abbas2020structureofvatpase pages 1-2): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(wang2020structuresofa pages 1-3): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(peng2025againoffunctionmutation pages 2-4): Si-qi Peng, Qian-qian Wu, Wan-yi Wang, Yi-Lin Zhang, Rui-ning Zhou, Jun Liao, Jin-xuan Wei, Yan Yang, Wen Shi, Jun-lan Yang, Xiao-xu Wang, Zhi-yuan Wei, Jia-xuan Sun, Lu Huang, Hong Fan, Hui Cai, Cheng-kun Wang, Xin-hua Li, Ting-song Li, Bi-cheng Liu, Xiao-liang Zhang, and Bin Wang. A gain-of-function mutation in atp6v0a4 drives primary distal renal tubular alkalosis with enhanced v-atpase activity. The Journal of Clinical Investigation, Apr 2025. URL: https://doi.org/10.1172/jci188807, doi:10.1172/jci188807. This article has 10 citations.
(xu2023identificationofatp6v0a4 pages 1-2): Jinming Xu, Jiahao Jiang, Cong Yin, Yan Wang, and Bentao Shi. Identification of atp6v0a4 as a potential biomarker in renal cell carcinoma using integrated bioinformatics analysis. Oncology Letters, Jul 2023. URL: https://doi.org/10.3892/ol.2023.13952, doi:10.3892/ol.2023.13952. This article has 1 citations and is from a peer-reviewed journal.
(giglio2021distalrenaltubular pages 1-2): Sabrina Giglio, Giovanni Montini, Francesco Trepiccione, Giovanni Gambaro, and Francesco Emma. Distal renal tubular acidosis: a systematic approach from diagnosis to treatment. Journal of Nephrology, 34:2073-2083, Mar 2021. URL: https://doi.org/10.1007/s40620-021-01032-y, doi:10.1007/s40620-021-01032-y. This article has 98 citations and is from a peer-reviewed journal.
(a2023thepathophysiologyof pages 5-8): Carsten A Wagner, Robert Unwin, Sergio C Lopez-Garcia, Robert Kleta, Detlef Bockenhauer, and Stephen Walsh. The pathophysiology of distal renal tubular acidosis. Nature Reviews Nephrology, 19:384-400, Apr 2023. URL: https://doi.org/10.1038/s41581-023-00699-9, doi:10.1038/s41581-023-00699-9. This article has 83 citations and is from a domain leading peer-reviewed journal.
(chen2020screeningandfunction pages 1-2): Li Chen, Han-Lu Wang, Yao-Bin Zhu, Zhao Jin, Jian-Bin Huang, Xin-Fu Lin, Jie-Wei Luo, and Zhu-Ting Fang. Screening and function discussion of a hereditary renal tubular acidosis family pathogenic gene. Cell Death & Disease, Mar 2020. URL: https://doi.org/10.1038/s41419-020-2354-y, doi:10.1038/s41419-020-2354-y. This article has 15 citations and is from a peer-reviewed journal.
(alsolami2026asinglesmall pages 1-2): Samhan Alsolami, Arun Pandian Chandrasekaran, Yiqing Jin, Yibo Wang, Ling Zhang, Ismail M. Shakir, Yingzi Zhang, Aisha Siddique, Gerardo Ramos-Mandujano, Baolei Yuan, Maya Ayach, Alfonso Saera-Vila, Zejun Fan, Siyi Fu, Huoming Zhang, Saige Xin, Kholoud Khalid AlDakhil, Juan Carlos Izpisua Belmonte, Jin Zhang, Yang Yu, and Mo Li. A single small molecule-based human embryo model reveals v-atpase requirement in mammalian blastocyst cavitation. Cell Research, Apr 2026. URL: https://doi.org/10.1038/s41422-026-01239-3, doi:10.1038/s41422-026-01239-3. This article has 0 citations and is from a domain leading peer-reviewed journal.

📚 Additional Documentation

Notes

(ATP6V0A4-notes.md)

ATP6V0A4 Gene Review Notes

2026-06-03 - Proteostasis PN review

just fetch-gene human ATP6V0A4 created the local scaffold, UniProt record, GOA table, publication cache, and PANTHER family data. GOA seeded 47 review rows, dominated by V-ATPase complex/V0-domain membership, proton transport and acidification, kidney apical membrane localization, endosomal/lysosomal/exosome locations, and broad binding rows.

Falcon deep research has now completed successfully (ATP6V0A4-deep-research-falcon.md, 22 citations); see the synthesis section at the end of this file. The original PN-batch attempt timed out before the deep_research_unified tool bugs were fixed. The review used the local UniProt record, GOA, cached publications, Reactome records, and PN projection files, now supplemented by the Falcon report.

Core functional synthesis: ATP6V0A4 encodes the a4 isoform of the V-ATPase V0 a subunit. It is a membrane-integral V0-sector component that contributes to the assembled V-ATPase rotational proton-pump activity, especially in kidney proton-secreting cells. Human disease and localization evidence support apical plasma membrane targeting in renal intercalated cells and a role in vectorial acid transport into urine [PMID:10973252, "vectorial proton transport is required for urinary acidification"; PMID:10973252, "essential role in normal vectorial acid transport into the urine by the kidney"]. ATP6V0A4 is also expressed in the cochlea, and ATP6V0A4 mutations can be associated with later-onset hearing loss [PMID:12414817, "several patients with ATP6V0A4 mutations have developed hearing loss"; PMID:12414817, "show ATP6V0A4 expression within the cochlea for the first time"].

Subunit-coupling evidence supports retaining V-ATPase/V0-domain and ATPase-binding annotations. The a4 subunit interacts with V1-sector G subunits, supporting V1/V0 coupling [PMID:17360703, "a4 and G3 are component subunits of the same proton pump"]. Disease-variant and yeast rescue experiments support a functional role for a4/PFK-1 interaction in proton-pump coupling rather than generic protein binding [PMID:18632794, "PFK-1 in normal proton pump function"].

Structural support: the current UniProt record lists human V-ATPase structures that include ATP6V0A4, including PDB:9DET and PDB:7UNF [file:human/ATP6V0A4/ATP6V0A4-uniprot.txt, "PDB; 9DET"]. These are useful future support for V0-domain structural annotations, but they do not by themselves resolve the PN lysosomal-specific projection question.

Generic GO:0005515 protein binding rows were marked over-annotated. The PFK-1 and V-ATPase subunit interactions are real, but generic protein binding is less informative than V-ATPase complex membership, ATPase binding, and proton-pump coupling. The high-throughput APOE interaction row from the neurodegenerative-disease interactome was also treated as non-core/uninformative [PMID:32814053, "generated by systematic yeast two-hybrid interaction screening"].

PN curation conclusion: the PN projection lists ATP6V0A4 as a candidate for GO:0007042 lysosomal lumen acidification and GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain under the autophagy-lysosome pathway [file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv, "ATP6V0A4"]. This is plausible at the generic V-ATPase-family level, but conservative gene-level review does not justify adding either projection as a new ATP6V0A4 core annotation. Existing evidence supports broad GO:0007035 vacuolar acidification, V0-domain membership, and a high-throughput GO:0005765 lysosomal membrane row, but the best ATP6V0A4-specific human biology is renal apical plasma membrane acid secretion rather than direct lysosomal lumen acidification. The YAML keeps the lysosomal membrane row as non-core and records a suggested expert question about whether the PN lysosomal projection should be applied to a4 or restricted to better-supported lysosomal a-subunit contexts.

Several vesicle-location annotations were retained cautiously or marked over-annotated. Endosome/endosome membrane rows are kept as non-core because Reactome and V-ATPase biology support endosomal acidification generally, but they are less ATP6V0A4-specific than the renal membrane literature. Synaptic-vesicle and phagocytic-vesicle projections were marked over-annotated because they over-specify a4 isoform localization from broad V-ATPase/orthology contexts.

Falcon deep research synthesis (2026-06-21)

The Falcon report (file:human/ATP6V0A4/ATP6V0A4-deep-research-falcon.md) strongly
supports the gene-level conclusion above: the best-supported a4-specific biology
is renal/cochlear apical-membrane H+ secretion, not lysosomal-lumen
acidification, so the PN lysosomal projection (GO:0007042, GO:0046610) stays
unaccepted for a4 and the lysosomal-membrane row stays non-core.

New gain-of-function evidence pins a4 to proton-pump capacity (Peng et al.
2025). The first GOF variant, p.V512L, causes the mirror-image phenotype of
classic dRTA — hypochloremic metabolic alkalosis with acidic urine,
hypokalemia, renal insufficiency and hearing loss. V512 (conserved, C-terminal
TM) stabilizes a4 against degradation; V512L raises a4 abundance → more V-ATPase →
excessive luminal H+ secretion. Together with the many loss-of-function dRTA
variants, this bidirectional genetics directly ties ATP6V0A4 dosage to vectorial
proton transport, reinforcing the core renal acid-secretion MF/BP calls.

Corroborated (no change to calls): a4 isoform of the V0 a-subunit forming the
proton-conduction path (same arginine/c-ring-glutamate mechanism as a1); apical
plasma membrane of renal α-intercalated cells; expression in cochlea;
loss-of-function → distal renal tubular acidosis ± sensorineural hearing loss;
V1/V0 coupling via G-subunit interaction. A reported ccRCC downregulation/
prognostic-biomarker association (Xu 2023) is non-core. Net: no change to the
core call; renal apical acid secretion remains the a4-specific core, lysosomal
projection remains over-specified.

Pn Notes

(ATP6V0A4-pn-notes.md)

ATP6V0A4 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9HBG4
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1387)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V0A4/ATP6V0A4-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V0A4/ATP6V0A4-ai-review.html
Gene notes: present - genes/human/ATP6V0A4/ATP6V0A4-notes.md
GOA TSV: present - genes/human/ATP6V0A4/ATP6V0A4-goa.tsv
UniProt record: present - genes/human/ATP6V0A4/ATP6V0A4-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V0A4.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V0A4.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

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

AIGR Review Snapshot

Description: 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/core annotation action counts: ACCEPT: 23; KEEP_AS_NON_CORE: 11; MARK_AS_OVER_ANNOTATED: 7; MODIFY: 6

PN Consistency Summary

Consistency: Deep research/notes, review, and PN diverge in emphasis. ATP6V0A4 is the a4 V0 a-subunit whose best-supported human biology is renal apical-plasma-membrane urinary acidification and inner-ear function (dRTA, hearing loss; PMID:10973252, PMID:14638902, PMID:12414817), NOT primarily lysosomal. The review does NOT add GO:0046610 or GO:0007042; it keeps lysosomal membrane KEEP_AS_NON_CORE (HDA, PMID:17897319) and explicitly questions the PN lysosomal projection.
PN story / NEW pressure: PN projects the same lysosomal V0/acidification terms it gives the c''/d2 subunits, but a4 lacks direct isoform-specific lysosomal-acidification evidence. The review's restraint is correct: the lysosomal projection over-reaches for a4 (the a-subunit isoforms are differentially targeted; a4 → apical PM, not lysosome). proposed_new_terms empty; lysosomal terms NOT added. Over-reaches / correctly declined in review.
Evidence alignment: PN cites generic V-ATPase/mTORC1 titles (none a4-specific); review cites a rich a4-specific renal/inner-ear literature (PMID:10973252, 12649290, 14638902, 17360703, 12414817) entirely absent from the PN row. Clear divergence; review is far better sourced.
Verdict: PN LYSOSOMAL PROJECTION OVER-REACHES for a4 (renal-apical, not lysosomal); review correctly declined. Recommended edits: [MAP] flag GO:0046610 + GO:0007042 leaf/type projections as not_for_propagation to ATP6V0A4 (no a4-specific lysosomal evidence; isoform is apical-PM targeted); keep GO:0033179 (V0 domain, already in GOA).

Full Consistency Review

UniProt: Q9HBG4 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
PN placement: two ALP leaves "V0 lysosomal v-ATPase proton pump component". PN-node mapping: leaf→GO:0046610 (more_specific_than_existing_goa); leaf→GO:0033179 (already_in_goa_exact); type→GO:0007042 lysosomal lumen acidification (more_specific_than_existing_goa).
Consistency: Deep research/notes, review, and PN diverge in emphasis. ATP6V0A4 is the a4 V0 a-subunit whose best-supported human biology is renal apical-plasma-membrane urinary acidification and inner-ear function (dRTA, hearing loss; PMID:10973252, PMID:14638902, PMID:12414817), NOT primarily lysosomal. The review does NOT add GO:0046610 or GO:0007042; it keeps lysosomal membrane KEEP_AS_NON_CORE (HDA, PMID:17897319) and explicitly questions the PN lysosomal projection.
PN story / NEW pressure: PN projects the same lysosomal V0/acidification terms it gives the c''/d2 subunits, but a4 lacks direct isoform-specific lysosomal-acidification evidence. The review's restraint is correct: the lysosomal projection over-reaches for a4 (the a-subunit isoforms are differentially targeted; a4 → apical PM, not lysosome). proposed_new_terms empty; lysosomal terms NOT added. Over-reaches / correctly declined in review.
Mapping strategy: This gene should change the node treatment: ATP6V0A4 is a weak/contraindicated member of the "lysosomal V0 component" leaf. GO:0046610/GO:0007042 are narrower than what a4 evidence supports and risk a false lysosome-specific claim — the TOMM20/RAB7A "leaf doesn't fit this member" pattern. The leaf mapping is fine for c''/d2 but should be flagged not-for-propagation to a4.
Evidence alignment: PN cites generic V-ATPase/mTORC1 titles (none a4-specific); review cites a rich a4-specific renal/inner-ear literature (PMID:10973252, 12649290, 14638902, 17360703, 12414817) entirely absent from the PN row. Clear divergence; review is far better sourced.
Verdict: PN LYSOSOMAL PROJECTION OVER-REACHES for a4 (renal-apical, not lysosomal); review correctly declined. Recommended edits: [MAP] flag GO:0046610 + GO:0007042 leaf/type projections as not_for_propagation to ATP6V0A4 (no a4-specific lysosomal evidence; isoform is apical-PM targeted); keep GO:0033179 (V0 domain, already in GOA).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ATP6V0A4/ATP6V0A4-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V0 lysosomal v-ATPase proton pump component

UniProt: Q9HBG4
In branches: ALP
Notes: Subunit of the V0 (lysosomal membrane bound) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V0 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain]
  rationale: This PN leaf is restricted to V0-sector lysosomal V-ATPase components. The GO lysosomal V0-domain component term is the direct target.
- [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
  status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
  rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Lysosomal catabolism | Regulation of lysosomal environment | Lysosomal acidification | V0 lysosomal v-ATPase proton pump component

UniProt: Q9HBG4
In branches: ALP
Notes: Subunit of the V0 (lysosomal membrane bound) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0033179 proton-transporting V-type ATPase, V0 domain]
  rationale: This PN subtype denotes the V0-sector component of the lysosomal V-type ATPase. The GO V0-domain component term is the appropriate propagation target.
- [type] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0007042 lysosomal lumen acidification]
  rationale: This PN group directly names the lysosomal acidification mechanism. Propagation to the GO lysosomal lumen acidification term is an exact mechanistic match.
- [group] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Lysosomal catabolism
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad lysosomal-degradation container. The subtree includes carbohydrate, lipid, protein, nuclease, phosphatase, sulfatase, and environment-regulation roles, so mapping should occur at the enzyme or process subtype level.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V0 lysosomal v-ATPase proton pump component
GO:0007042 lysosomal lumen acidification | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
GO:0033179 proton-transporting V-type ATPase, V0 domain | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component

Note

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

📄 View Raw YAML

id: 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

ATP6V0A4

Gene Description

Existing Annotations Review

Core Functions

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.

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: ATP6V0A4 (V-type Proton ATPase 116 kDa Subunit a4)

Gene and Protein Identity

Protein Structure and Molecular Organization

Domain Architecture

V-ATPase Complex Organization

Primary Function and Catalytic Mechanism

Proton Transport Mechanism

Substrate Specificity

Critical Residues and Mechanism

Subcellular Localization and Tissue Distribution

Tissue-Specific Expression

Subcellular Localization in Kidney

Biochemical Pathways and Physiological Role

Renal Acid-Base Homeostasis Pathway

Protein-Protein Interactions and Assembly

Additional Biological Roles

Disease Associations and Clinical Significance

Loss-of-Function Mutations: Distal Renal Tubular Acidosis

Gain-of-Function Mutation: Renal Tubular Alkalosis

Cancer and Biomarker Potential

Experimental Evidence and Validation

Structural Studies

Functional Assays

Mouse Models

Bioinformatic Evidence

Summary Table

Conclusions

📚 Additional Documentation

Notes

ATP6V0A4 Gene Review Notes

2026-06-03 - Proteostasis PN review

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6V0A4 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V0 lysosomal v-ATPase proton pump component

PN row 2: Autophagy-Lysosome Pathway | Lysosomal catabolism | Regulation of lysosomal environment | Lysosomal acidification | V0 lysosomal v-ATPase proton pump component

Projected GO annotations (3)

Note

📄 View Raw YAML