Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IBA GO_REF:0000033	ACCEPT	Summary: Supported core ATP6V0D1 annotation: vacuolar proton-transporting V-type ATPase complex. Reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase structural evidence support V-ATPase complex membership and V0-domain placement as core annotations. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:18752060 These data indicate that the d subunit in man is centrally located within the pump and is thus important in its rotary mechanism PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md ATP6V0D1 encodes V-type proton ATPase subunit d 1, also called V-ATPase AC39/p39
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IBA GO_REF:0000033	ACCEPT	Summary: ATP6V0D1 contributes to the assembled V-ATPase proton-pump activity: proton-transporting ATPase activity, rotational mechanism. Reason: The d1 subunit is not the independent catalytic ATPase, but the IBA annotation already uses the contributes_to qualifier. This accurately represents ATP6V0D1 as a V0 subunit contributing to the assembled V-ATPase rotary proton-pump activity. Supporting Evidence: PMID:18752060 human d1 and d2 are able to directly interact with the D and F subunits PMID:18752060 the d subunit in man is centrally located within the pump PMID:33065002 human V-ATPase in three rotational states
GO:0005769 early endosome	IBA GO_REF:0000033	ACCEPT	Summary: Supported endolysosomal V-ATPase location: early endosome. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the lysosomal surface, the site of mTORC1 activation PMID:28296633 V-ATPase, the key proton pump for endo-lysosomal acidification
GO:0007034 vacuolar transport	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Vacuolar transport is plausible as a downstream V-ATPase/endolysosomal trafficking context but is not the most specific ATP6V0D1 function. Reason: The conserved primary role is proton-pump complex function and compartment acidification. Vacuolar transport depends on acidic endolysosomal compartments, but this term is broader than the direct ATP6V0D1 mechanism. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:33065002 supporting intracellular membrane trafficking and protein degradation
GO:0007035 vacuolar acidification	IBA GO_REF:0000033	ACCEPT	Summary: Core V-ATPase proton transport/acidification process: vacuolar acidification. Reason: ATP6V0D1 functions in the V-ATPase complex that translocates protons and acidifies intracellular compartments. This is the principal biological process supported for the d1 subunit. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:18752060 These data indicate that the d subunit in man is centrally located within the pump and is thus important in its rotary mechanism PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md ATP6V0D1 encodes V-type proton ATPase subunit d 1, also called V-ATPase AC39/p39
GO:0033181 plasma membrane proton-transporting V-type ATPase complex	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Plasma membrane V-ATPase localization is supported in specialized cells but is not the dominant ATP6V0D1/d1 context. Reason: UniProt notes that V-ATPase can be targeted to the plasma membrane in some cell types. For ubiquitous ATP6V0D1/d1, the better-supported core locations are lysosomal and endosomal V-ATPase complexes. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt in some cell types, is targeted to the plasma membrane PMID:33065002 Plasma membrane V-ATPases carry out extracellular acidification in specialized organs
GO:0005765 lysosomal membrane	IEA GO_REF:0000044	ACCEPT	Summary: Supported endolysosomal V-ATPase location: lysosomal membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the lysosomal surface, the site of mTORC1 activation PMID:28296633 V-ATPase, the key proton pump for endo-lysosomal acidification
GO:0016020 membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Membrane localization is true but too general for ATP6V0D1. Reason: ATP6V0D1 is a peripheral membrane-associated V0-sector subunit. The informative locations are the V-ATPase complex and lysosomal/endosomal membranes rather than the parent membrane term. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Membrane PMID:18752060 The vacuolar H+-ATPase d subunit is known to associate with the integral membrane V0 domain
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IEA GO_REF:0000117	ACCEPT	Summary: Supported core ATP6V0D1 annotation: vacuolar proton-transporting V-type ATPase complex. Reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase structural evidence support V-ATPase complex membership and V0-domain placement as core annotations. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:18752060 These data indicate that the d subunit in man is centrally located within the pump and is thus important in its rotary mechanism PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md ATP6V0D1 encodes V-type proton ATPase subunit d 1, also called V-ATPase AC39/p39
GO:0030665 clathrin-coated vesicle membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Context-specific vesicle membrane localization for V-ATPase: clathrin-coated vesicle membrane. Reason: V-ATPases acidify several specialized vesicle classes, including clathrin-coated and phagocytic vesicles. These locations are plausible and supported, but lysosomal/endosomal V-ATPase function is the primary ATP6V0D1 role. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Cytoplasmic vesicle, clathrin-coated vesicle membrane
GO:0030670 phagocytic vesicle membrane	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Context-specific vesicle membrane localization for V-ATPase: phagocytic vesicle membrane. Reason: V-ATPases acidify several specialized vesicle classes, including clathrin-coated and phagocytic vesicles. These locations are plausible and supported, but lysosomal/endosomal V-ATPase function is the primary ATP6V0D1 role. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Cytoplasmic vesicle, clathrin-coated vesicle membrane
GO:0033179 proton-transporting V-type ATPase, V0 domain	IEA GO_REF:0000120	ACCEPT	Summary: Supported core ATP6V0D1 annotation: proton-transporting V-type ATPase, V0 domain. Reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase structural evidence support V-ATPase complex membership and V0-domain placement as core annotations. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:18752060 These data indicate that the d subunit in man is centrally located within the pump and is thus important in its rotary mechanism PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md ATP6V0D1 encodes V-type proton ATPase subunit d 1, also called V-ATPase AC39/p39
GO:0042592 homeostatic process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Homeostatic process is overly broad for ATP6V0D1. Reason: The specific supported homeostatic roles are endolysosomal acidification, proton transmembrane transport, and context-specific iron/HIF regulation. The generic parent term loses the actual function. Proposed replacements: vacuolar acidification proton transmembrane transport intracellular iron ion homeostasis Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:28296633 disrupting the V-ATPase results in intracellular iron depletion
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000120	MODIFY	Summary: ATP6V0D1 contributes to the assembled V-ATPase proton-pump activity: proton-transporting ATPase activity, rotational mechanism. Reason: The term is biologically appropriate for ATP6V0D1-containing V-ATPase complexes, but the GOA qualifier should be changed from enables to contributes_to. The d1 subunit is not the independent catalytic ATPase; it contributes to the rotary V-ATPase mechanism that couples ATP hydrolysis in V1 to proton transfer through V0. Proposed replacements: proton-transporting ATPase activity, rotational mechanism Supporting Evidence: PMID:18752060 human d1 and d2 are able to directly interact with the D and F subunits PMID:18752060 the d subunit in man is centrally located within the pump PMID:33065002 human V-ATPase in three rotational states
GO:0098793 presynapse	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: Presynapse is an inferred neuronal context from synaptic vesicle acidification, not core ATP6V0D1 biology. Reason: V-ATPases acidify synaptic vesicles, but the reviewed evidence for ATP6V0D1/d1 is broader endolysosomal V-ATPase function. Presynapse should remain a context-specific location. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:18752060 acidification of diverse intracellular compartments in eukaryotic cells, including endosomes, lysosomes, clathrin-coated and synaptic vesicles
GO:1902600 proton transmembrane transport	IEA GO_REF:0000002	ACCEPT	Summary: Core V-ATPase proton transport/acidification process: proton transmembrane transport. Reason: ATP6V0D1 functions in the V-ATPase complex that translocates protons and acidifies intracellular compartments. This is the principal biological process supported for the d1 subunit. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:18752060 These data indicate that the d subunit in man is centrally located within the pump and is thus important in its rotary mechanism PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md ATP6V0D1 encodes V-type proton ATPase subunit d 1, also called V-ATPase AC39/p39
GO:0005515 protein binding	IPI PMID:16713569 A protein-protein interaction network for human inherited at...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to represent ATP6V0D1 function. Reason: These interaction-map annotations are useful context but do not identify a specific ATP6V0D1 activity. Proposed replacements: vacuolar proton-transporting V-type ATPase complex proton-transporting ATPase activity, rotational mechanism Supporting Evidence: PMID:16713569 We identified 770 mostly novel protein-protein interactions using a stringent yeast two-hybrid screen PMID:32296183 The dataset, versioned HI-III-20 (Human Interactome obtained from screening Space III, published in 2020), contains 52,569 verified PPIs involving 8,275 proteins PMID:32814053 connects ∼5,000 human proteins via ∼30,000 candidate interactions
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to represent ATP6V0D1 function. Reason: These interaction-map annotations are useful context but do not identify a specific ATP6V0D1 activity. Proposed replacements: vacuolar proton-transporting V-type ATPase complex proton-transporting ATPase activity, rotational mechanism Supporting Evidence: PMID:16713569 We identified 770 mostly novel protein-protein interactions using a stringent yeast two-hybrid screen PMID:32296183 The dataset, versioned HI-III-20 (Human Interactome obtained from screening Space III, published in 2020), contains 52,569 verified PPIs involving 8,275 proteins PMID:32814053 connects ∼5,000 human proteins via ∼30,000 candidate interactions
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to represent ATP6V0D1 function. Reason: These interaction-map annotations are useful context but do not identify a specific ATP6V0D1 activity. Proposed replacements: vacuolar proton-transporting V-type ATPase complex proton-transporting ATPase activity, rotational mechanism Supporting Evidence: PMID:16713569 We identified 770 mostly novel protein-protein interactions using a stringent yeast two-hybrid screen PMID:32296183 The dataset, versioned HI-III-20 (Human Interactome obtained from screening Space III, published in 2020), contains 52,569 verified PPIs involving 8,275 proteins PMID:32814053 connects ∼5,000 human proteins via ∼30,000 candidate interactions
GO:0005769 early endosome	IEA GO_REF:0000107	ACCEPT	Summary: Supported endolysosomal V-ATPase location: early endosome. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the lysosomal surface, the site of mTORC1 activation PMID:28296633 V-ATPase, the key proton pump for endo-lysosomal acidification
GO:0015078 proton transmembrane transporter activity	IEA GO_REF:0000107	ACCEPT	Summary: ATP6V0D1 contributes to the assembled V-ATPase proton-pump activity: proton transmembrane transporter activity. Reason: The d1 subunit is not the independent catalytic ATPase, but it is centrally positioned in the rotary V-ATPase mechanism and contributes to coupling ATP hydrolysis in V1 to proton transfer through V0. Supporting Evidence: PMID:18752060 human d1 and d2 are able to directly interact with the D and F subunits PMID:18752060 the d subunit in man is centrally located within the pump PMID:33065002 human V-ATPase in three rotational states
GO:0033176 proton-transporting V-type ATPase complex	IEA GO_REF:0000107	ACCEPT	Summary: Supported core ATP6V0D1 annotation: proton-transporting V-type ATPase complex. Reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase structural evidence support V-ATPase complex membership and V0-domain placement as core annotations. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:18752060 These data indicate that the d subunit in man is centrally located within the pump and is thus important in its rotary mechanism PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md ATP6V0D1 encodes V-type proton ATPase subunit d 1, also called V-ATPase AC39/p39
GO:0097401 synaptic vesicle lumen acidification	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Synaptic vesicle lumen acidification is plausible for V-ATPase but context-specific for ATP6V0D1. Reason: The V-ATPase family acidifies synaptic vesicles, but ATP6V0D1/d1 is not uniquely a synaptic-vesicle factor. Keep as a non-core inferred location/process context. Supporting Evidence: PMID:18752060 acidification of diverse intracellular compartments in eukaryotic cells, including endosomes, lysosomes, clathrin-coated and synaptic vesicles
GO:0071230 cellular response to amino acid stimulus	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	KEEP AS NON CORE	Summary: Directly supported lysosomal amino-acid/mTORC1 signaling context: cellular response to amino acid stimulus. Reason: The mTORC1 work supports V-ATPase, including V0 d1, as part of lysosomal amino-acid sensing through Ragulator/Rag signaling. This is a real signaling output but secondary to the core proton-pump/acidification function. Supporting Evidence: PMID:22053050 the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1 PMID:22053050 Ragulator provides a physical and functional link between the v-ATPase and the Rag GTPases PMID:22053050 direct interaction between the V0 component d1 and p18
GO:0160124 guanyl nucleotide exchange factor activator activity	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	KEEP AS NON CORE	Summary: Directly supported lysosomal amino-acid/mTORC1 signaling context: guanyl nucleotide exchange factor activator activity. Reason: The mTORC1 work supports V-ATPase, including V0 d1, as part of lysosomal amino-acid sensing through Ragulator/Rag signaling. This is a real signaling output but secondary to the core proton-pump/acidification function. Supporting Evidence: PMID:22053050 the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1 PMID:22053050 Ragulator provides a physical and functional link between the v-ATPase and the Rag GTPases PMID:22053050 direct interaction between the V0 component d1 and p18
GO:0005765 lysosomal membrane	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	ACCEPT	Summary: Supported endolysosomal V-ATPase location: lysosomal membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the lysosomal surface, the site of mTORC1 activation PMID:28296633 V-ATPase, the key proton pump for endo-lysosomal acidification
GO:0046611 lysosomal proton-transporting V-type ATPase complex	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	ACCEPT	Summary: Supported core ATP6V0D1 annotation: lysosomal proton-transporting V-type ATPase complex. Reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase structural evidence support V-ATPase complex membership and V0-domain placement as core annotations. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:18752060 These data indicate that the d subunit in man is centrally located within the pump and is thus important in its rotary mechanism PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md ATP6V0D1 encodes V-type proton ATPase subunit d 1, also called V-ATPase AC39/p39
GO:1904263 positive regulation of TORC1 signaling	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	KEEP AS NON CORE	Summary: Directly supported lysosomal amino-acid/mTORC1 signaling context: positive regulation of TORC1 signaling. Reason: The mTORC1 work supports V-ATPase, including V0 d1, as part of lysosomal amino-acid sensing through Ragulator/Rag signaling. This is a real signaling output but secondary to the core proton-pump/acidification function. Supporting Evidence: PMID:22053050 the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1 PMID:22053050 Ragulator provides a physical and functional link between the v-ATPase and the Rag GTPases PMID:22053050 direct interaction between the V0 component d1 and p18
GO:0000220 vacuolar proton-transporting V-type ATPase, V0 domain	ISS GO_REF:0000024	ACCEPT	Summary: Supported core ATP6V0D1 annotation: vacuolar proton-transporting V-type ATPase, V0 domain. Reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase structural evidence support V-ATPase complex membership and V0-domain placement as core annotations. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:18752060 These data indicate that the d subunit in man is centrally located within the pump and is thus important in its rotary mechanism PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md ATP6V0D1 encodes V-type proton ATPase subunit d 1, also called V-ATPase AC39/p39
GO:0005515 protein binding	IPI PMID:30374053 TMEM9 promotes intestinal tumorigenesis through vacuolar-ATP...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to represent ATP6V0D1 function. Reason: TMEM9/ATP6AP2 interactions are V-ATPase assembly/signaling context; generic protein binding should not define ATP6V0D1 function. Proposed replacements: vacuolar proton-transporting V-type ATPase complex proton-transporting ATPase activity, rotational mechanism Supporting Evidence: PMID:30374053 TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase)
GO:0005515 protein binding	IPI PMID:29644770 TMEM55B contributes to lysosomal homeostasis and amino acid-...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to represent ATP6V0D1 function. Reason: TMEM55B interaction supports lysosomal V-ATPase/mTORC1 context, but protein binding remains too generic. Proposed replacements: vacuolar proton-transporting V-type ATPase complex proton-transporting ATPase activity, rotational mechanism Supporting Evidence: PMID:29644770 TMEM55B interacts with many proteins that participate in mTORC1 activation including components of the vacuolar-type proton ATPase (V-ATPase)
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9639286	ACCEPT	Summary: Supported endolysosomal V-ATPase location: lysosomal membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: Reactome:R-HSA-9645608 Hydrolysis of ATP by the v-ATPase complex is also required for recruitment of mTORC1 file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640167	ACCEPT	Summary: Supported endolysosomal V-ATPase location: lysosomal membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: Reactome:R-HSA-9645608 Hydrolysis of ATP by the v-ATPase complex is also required for recruitment of mTORC1 file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640168	ACCEPT	Summary: Supported endolysosomal V-ATPase location: lysosomal membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: Reactome:R-HSA-9645608 Hydrolysis of ATP by the v-ATPase complex is also required for recruitment of mTORC1 file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640175	ACCEPT	Summary: Supported endolysosomal V-ATPase location: lysosomal membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: Reactome:R-HSA-9645608 Hydrolysis of ATP by the v-ATPase complex is also required for recruitment of mTORC1 file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640195	ACCEPT	Summary: Supported endolysosomal V-ATPase location: lysosomal membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: Reactome:R-HSA-9645608 Hydrolysis of ATP by the v-ATPase complex is also required for recruitment of mTORC1 file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9645598	ACCEPT	Summary: Supported endolysosomal V-ATPase location: lysosomal membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: Reactome:R-HSA-9645608 Hydrolysis of ATP by the v-ATPase complex is also required for recruitment of mTORC1 file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9645608	ACCEPT	Summary: Supported endolysosomal V-ATPase location: lysosomal membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: Reactome:R-HSA-9645608 Hydrolysis of ATP by the v-ATPase complex is also required for recruitment of mTORC1 file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9646468	ACCEPT	Summary: Supported endolysosomal V-ATPase location: lysosomal membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: Reactome:R-HSA-9645608 Hydrolysis of ATP by the v-ATPase complex is also required for recruitment of mTORC1 file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9858932	ACCEPT	Summary: Supported endolysosomal V-ATPase location: lysosomal membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the lysosomal surface, the site of mTORC1 activation PMID:28296633 V-ATPase, the key proton pump for endo-lysosomal acidification
GO:0006879 intracellular iron ion homeostasis	IMP PMID:28296633 The vacuolar-ATPase complex and assembly factors, TMEM199 an...	KEEP AS NON CORE	Summary: Supported but non-core ATP6V0D1 context: intracellular iron ion homeostasis. Reason: ATP6V0D1 disruption was identified in a V-ATPase/HIF screen and linked to intracellular iron depletion. This is a downstream consequence of endolysosomal V-ATPase function, not the primary evolved activity of the d1 subunit. Supporting Evidence: PMID:28296633 five V-ATPase subunits: ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1 PMID:28296633 disrupting the V-ATPase results in intracellular iron depletion
GO:0036295 cellular response to increased oxygen levels	IMP PMID:28296633 The vacuolar-ATPase complex and assembly factors, TMEM199 an...	MARK AS OVER ANNOTATED	Summary: The HIF/aerobic-response evidence is real but the GO term is an over-specific downstream readout for ATP6V0D1. Reason: PMID:28296633 shows ATP6V0D1/V-ATPase disruption stabilizes HIF1A in aerobic conditions via iron depletion. That supports iron/HIF homeostasis context, but not a direct ATP6V0D1 role in cellular response to increased oxygen levels. Proposed replacements: intracellular iron ion homeostasis Supporting Evidence: PMID:28296633 five V-ATPase subunits: ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1 PMID:28296633 disrupting the V-ATPase results in intracellular iron depletion
GO:0016241 regulation of macroautophagy	NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	MARK AS OVER ANNOTATED	Summary: Regulation of macroautophagy is over-annotated for ATP6V0D1 based on the cited lipofuscin study. Reason: The cited paper discusses macroautophagy and lysosomal uptake of lipofuscin but does not establish ATP6V0D1 as a specific macroautophagy regulator. In the PN context, ATP6V0D1 should be represented through lysosomal V-ATPase acidification rather than a broad macroautophagy-regulatory claim. Proposed replacements: vacuolar acidification Supporting Evidence: PMID:22982048 macroautophagy is responsible for the uptake of lipofuscin into the lysosomes file:human/ATP6V0D1/ATP6V0D1-notes.md The `regulation of macroautophagy` row from the lipofuscin paper is not strong direct evidence for ATP6V0D1 as a macroautophagy regulator
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: Extracellular exosome detection is supported by high-throughput proteomics but is not core ATP6V0D1 function. Reason: ATP6V0D1 can be detected in exosome proteomics datasets, consistent with endomembrane origin and vesicle biology. These HDA rows should not drive functional interpretation. Supporting Evidence: PMID:19056867 LC-MS/MS to profile the proteome of human urinary exosomes PMID:19199708 we catalogued 491 proteins in the exosome fraction of human parotid saliva PMID:23533145 In pooled EPS-urine exosome samples, ~900 proteins were detected
GO:0005515 protein binding	IPI PMID:20093472 Requirement of prorenin receptor and vacuolar H+-ATPase-medi...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to represent ATP6V0D1 function. Reason: The PRR/ATP6AP2 Wnt paper supports a V-ATPase signaling/adaptor context, not a specific ATP6V0D1 molecular function beyond V-ATPase complex function. Proposed replacements: vacuolar proton-transporting V-type ATPase complex proton-transporting ATPase activity, rotational mechanism Supporting Evidence: PMID:20093472 PRR functions in a renin-independent manner as an adaptor between Wnt receptors and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	KEEP AS NON CORE	Summary: Extracellular exosome detection is supported by high-throughput proteomics but is not core ATP6V0D1 function. Reason: ATP6V0D1 can be detected in exosome proteomics datasets, consistent with endomembrane origin and vesicle biology. These HDA rows should not drive functional interpretation. Supporting Evidence: PMID:19056867 LC-MS/MS to profile the proteome of human urinary exosomes PMID:19199708 we catalogued 491 proteins in the exosome fraction of human parotid saliva PMID:23533145 In pooled EPS-urine exosome samples, ~900 proteins were detected
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: Extracellular exosome detection is supported by high-throughput proteomics but is not core ATP6V0D1 function. Reason: ATP6V0D1 can be detected in exosome proteomics datasets, consistent with endomembrane origin and vesicle biology. These HDA rows should not drive functional interpretation. Supporting Evidence: PMID:19056867 LC-MS/MS to profile the proteome of human urinary exosomes PMID:19199708 we catalogued 491 proteins in the exosome fraction of human parotid saliva PMID:23533145 In pooled EPS-urine exosome samples, ~900 proteins were detected
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	ACCEPT	Summary: Supported endolysosomal V-ATPase location: lysosomal membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the lysosomal surface, the site of mTORC1 activation PMID:28296633 V-ATPase, the key proton pump for endo-lysosomal acidification
GO:0060271 cilium assembly	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Cilium assembly is a supported V-ATPase/SNX10 trafficking context but not the core ATP6V0D1 function. Reason: The SNX10 study supports V-ATPase-dependent ciliogenesis and centrosomal targeting, but ATP6V0D1 is best curated primarily as a V-ATPase proton-pump subunit. Supporting Evidence: PMID:21844891 SNX10 interacts with V-ATPase complex and targets it to the centrosome PMID:21844891 Like SNX10, V-ATPase regulates ciliogenesis in vitro and in vivo
GO:0005813 centrosome	IDA PMID:21844891 A SNX10/V-ATPase pathway regulates ciliogenesis in vitro and...	KEEP AS NON CORE	Summary: Centrosome colocalization is supported in the SNX10/V-ATPase ciliogenesis context but is not core. Reason: The cited paper places SNX10/V-ATPase at the centrosome during ciliogenesis. This is a context-specific colocalization rather than the primary ATP6V0D1 location. Supporting Evidence: PMID:21844891 SNX10 interacts with V-ATPase complex and targets it to the centrosome PMID:21844891 Like SNX10, V-ATPase regulates ciliogenesis in vitro and in vivo
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-1222516	KEEP AS NON CORE	Summary: Context-specific vesicle membrane localization for V-ATPase: phagocytic vesicle membrane. Reason: V-ATPases acidify several specialized vesicle classes, including clathrin-coated and phagocytic vesicles. These locations are plausible and supported, but lysosomal/endosomal V-ATPase function is the primary ATP6V0D1 role. Supporting Evidence: Reactome:R-HSA-1222516 When pumping, ATP hydrolysis drives a 120 degree rotation of the rotor which leads to movement of three protons into the phagosome
GO:0010008 endosome membrane	TAS Reactome:R-HSA-1791184	ACCEPT	Summary: Supported endolysosomal V-ATPase location: endosome membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome
GO:0010008 endosome membrane	TAS Reactome:R-HSA-5252133	ACCEPT	Summary: Supported endolysosomal V-ATPase location: endosome membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: Reactome:R-HSA-5252133 Vacuolar-type H+-ATPases (V-ATPases) are proton pumps that acidify intracellular cargos file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the lysosomal surface, the site of mTORC1 activation PMID:28296633 V-ATPase, the key proton pump for endo-lysosomal acidification
GO:0010008 endosome membrane	TAS Reactome:R-HSA-74723	ACCEPT	Summary: Supported endolysosomal V-ATPase location: endosome membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. 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 file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the lysosomal surface, the site of mTORC1 activation PMID:28296633 V-ATPase, the key proton pump for endo-lysosomal acidification
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917841	ACCEPT	Summary: Supported endolysosomal V-ATPase location: endosome membrane. Reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where they acidify organelle lumens. These are core cellular locations for the d1 subunit. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Lysosome membrane PMID:22053050 the lysosomal surface, the site of mTORC1 activation PMID:28296633 V-ATPase, the key proton pump for endo-lysosomal acidification
GO:0005515 protein binding	IPI PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic to represent ATP6V0D1 function. Reason: PMID:18752060 provides meaningful evidence for d1 interaction with V1 D and F subunits, but the curatable function is V-ATPase rotary coupling/complex membership rather than generic protein binding. Proposed replacements: vacuolar proton-transporting V-type ATPase complex proton-transporting ATPase activity, rotational mechanism Supporting Evidence: PMID:18752060 human d1 and d2 are able to directly interact with the D and F subunits PMID:18752060 the d subunit in man is centrally located within the pump PMID:33065002 human V-ATPase in three rotational states
GO:0016020 membrane	IDA PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	KEEP AS NON CORE	Summary: Membrane localization is true but too general for ATP6V0D1. Reason: ATP6V0D1 is a peripheral membrane-associated V0-sector subunit. The informative locations are the V-ATPase complex and lysosomal/endosomal membranes rather than the parent membrane term. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Membrane PMID:18752060 The vacuolar H+-ATPase d subunit is known to associate with the integral membrane V0 domain
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IDA PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	ACCEPT	Summary: Supported core ATP6V0D1 annotation: vacuolar proton-transporting V-type ATPase complex. Reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase structural evidence support V-ATPase complex membership and V0-domain placement as core annotations. Supporting Evidence: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments PMID:18752060 These data indicate that the d subunit in man is centrally located within the pump and is thus important in its rotary mechanism PMID:33065002 V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md ATP6V0D1 encodes V-type proton ATPase subunit d 1, also called V-ATPase AC39/p39
GO:0016471 vacuolar proton-transporting V-type ATPase complex	NAS PMID:11118322 Structure of the VPATPD gene encoding subunit D of the human...	ACCEPT	Summary: Supported core ATP6V0D1 annotation: vacuolar proton-transporting V-type ATPase complex. Reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase structural evidence support V-ATPase complex membership and V0-domain placement as core annotations. Supporting Evidence: PMID:11118322 Structure of the VPATPD gene encoding subunit D of the human vacuolar proton ATPase PMID:11118322 The encoded protein is 99.5% identical to mouse subunit D at the amino acid level file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
GO:1902600 proton transmembrane transport	NAS PMID:11118322 Structure of the VPATPD gene encoding subunit D of the human...	ACCEPT	Summary: The original gene-structure citation is weak alone, but proton transport is supported by the full ATP6V0D1 evidence set. Reason: PMID:11118322 establishes VPATPD/ATP6V0D1 as the gene encoding human vacuolar proton ATPase subunit D; later biochemical and structural evidence supports the proton-transport annotation through V-ATPase complex function. Supporting Evidence: PMID:11118322 Structure of the VPATPD gene encoding subunit D of the human vacuolar proton ATPase PMID:11118322 The encoded protein is 99.5% identical to mouse subunit D at the amino acid level file:human/ATP6V0D1/ATP6V0D1-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) file:human/ATP6V0D1/ATP6V0D1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments

Core Functions

ATP6V0D1 functions as the d1 subunit of the V0 sector of the V-ATPase, helping couple the V1 ATP-hydrolysis motor to V0 proton translocation and thereby acidifying lysosomal, endosomal, and related intracellular compartments.

Directly Involved In:

proton transmembrane transport vacuolar acidification

Cellular Locations:

lysosomal membrane endosome membrane early endosome

In Complex:

vacuolar proton-transporting V-type ATPase complex

Supporting Evidence:

file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase)
file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
PMID:18752060
These data indicate that the d subunit in man is centrally located within the pump and is thus important in its rotary mechanism
PMID:33065002
V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer
PMID:18752060
human d1 and d2 are able to directly interact with the D and F subunits
PMID:18752060
the d subunit in man is centrally located within the pump

References

file:human/ATP6V0D1/ATP6V0D1-uniprot.txt

UniProt record for human ATP6V0D1 (P61421)

ATP6V0D1 is a V0-sector V-ATPase subunit that supports proton translocation and acidification of intracellular compartments.

file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md

Manual deep research fallback for ATP6V0D1

Falcon timed out and the configured fallback failed; manual evidence synthesis supports conservative V-ATPase-centered curation.

file:human/ATP6V0D1/ATP6V0D1-notes.md

Local curation notes for ATP6V0D1

Local PN synthesis treats ATP6V0D1 as a lysosomal/endosomal V-ATPase subunit with proteostasis relevance through organelle acidification, not as a direct chaperone/proteasome factor.

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:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11118322

Structure of the VPATPD gene encoding subunit D of the human vacuolar proton ATPase.

PMID:16713569

A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.

PMID:17897319

Integral and associated lysosomal membrane proteins.

PMID:18752060

The d subunit plays a central role in human vacuolar H(+)-ATPases.

Human d1/d2 subunits interact directly with V1 D and F subunits and occupy a central rotary position in the V-ATPase.

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:20093472

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

PMID:21844891

A SNX10/V-ATPase pathway regulates ciliogenesis in vitro and in vivo.

SNX10/V-ATPase regulates ciliogenesis through a vesicular trafficking and centrosome-targeting pathway.

PMID:22053050

mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase.

V-ATPase, including V0 d1, links lysosomal amino-acid sensing to Ragulator/Rag-dependent mTORC1 activation.

PMID:22982048

Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.

Lipofuscin uptake involves macroautophagy, but the paper does not directly establish ATP6V0D1 as a macroautophagy regulator.

PMID:23533145

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

PMID:28296633

The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels.

ATP6V0D1/V-ATPase disruption affects HIF1A regulation through intracellular iron depletion and impaired PHD activity.

PMID:29644770

TMEM55B contributes to lysosomal homeostasis and amino acid-induced mTORC1 activation.

PMID:30374053

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

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

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

Reactome:R-HSA-1222516

Intraphagosomal pH is lowered to 5 by V-ATPase

Reactome:R-HSA-1791184

Expression of ATP6VOD1

Reactome:R-HSA-5252133

ATP6AP1 binds V-ATPase

Reactome:R-HSA-74723

Endosome acidification

Reactome:R-HSA-917841

Acidification of Tf:TfR1 containing endosome

Reactome:R-HSA-9639286

RRAGC,D exchanges GTP for GDP

Reactome:R-HSA-9640167

RRAGA,B exchanges GDP for GTP

Reactome:R-HSA-9640168

v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates yielding v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine

Reactome:R-HSA-9640175

v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine

Reactome:R-HSA-9640195

RRAGA,B hydrolyzes GTP

Reactome:R-HSA-9645598

RRAGC,D hydrolyzes GTP

Reactome:R-HSA-9645608

v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1

Reactome:R-HSA-9646468

mTORC1 binds RHEB:GTP

Reactome:R-HSA-9858932

MITF-M-dependent ATP6V0D1 gene expression

PMID:33065002

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

Human V-ATPase cryo-EM structures support the assembled V1/Vo proton-pump mechanism and complex-level interpretation of ATP6V0D1.

Suggested Experiments

Experiment: Deplete ATP6V0D1 in human cells and rescue with RNAi-resistant wild-type or V0-interaction-defective mutants while measuring lysosomal pH, EGFR/MHC-I lysosomal degradation, LC3 flux, and accumulation of undegraded protein cargo.

Hypothesis: ATP6V0D1 supports proteostasis phenotypes primarily through endolysosomal acidification rather than a direct macroautophagy-regulatory activity.

Type: loss-of-function rescue with lysosomal acidification and degradation assays

Experiment: Mutate ATP6V0D1 surfaces required for Ragulator p18 interaction and test amino-acid-stimulated mTORC1 lysosomal recruitment and S6K/4E-BP phosphorylation while monitoring V-ATPase assembly and organelle pH.

Hypothesis: The d1-p18/Ragulator interaction contributes to mTORC1 amino-acid sensing independently of bulk lysosomal pH changes.

Type: interaction-mutant signaling assay

Deep Research

Manual

(ATP6V0D1-deep-research-manual.md)

ATP6V0D1 manual deep research fallback Manual

ATP6V0D1 manual deep research fallback

Falcon deep research was attempted for human ATP6V0D1 on 2026-06-03 with perplexity-lite fallback. Falcon timed out after 600 seconds, and the fallback failed because the Perplexity API returned a 401 quota error. This manually written fallback summarizes the local evidence used for curation.

Identity and core role

ATP6V0D1 encodes V-type proton ATPase subunit d 1, also called V-ATPase AC39/p39. UniProt places it in the V-ATPase V0D/AC39 family and describes it as a V0-complex subunit of the vacuolar H(+)-ATPase. The protein is a peripheral membrane component on the cytoplasmic side of endolysosomal membranes and is present in V-ATPase complexes that acidify intracellular compartments [file:human/ATP6V0D1/ATP6V0D1-uniprot.txt, "Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase)"; file:human/ATP6V0D1/ATP6V0D1-uniprot.txt, "V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments"].

The shared d-subunit experimental paper cloned human ATP6V0D1/d1 and ATP6V0D2/d2 and showed that each interacts with V1 central-stalk D and F subunits. The abstract states that d1 and d2 can pull down D and F, that the interactions are direct, and that the d subunit is centrally located in the pump rotary mechanism [PMID:18752060, "human d1 and d2 are able to directly interact with the D and F subunits"; PMID:18752060, "the d subunit in man is centrally located within the pump"].

Cryo-EM structures of complete human V-ATPase support the same interpretation at complex level: V-ATPases are ATP-driven proton pumps with cytoplasmic V1 ATP hydrolysis and membrane-embedded Vo proton transfer sectors, and human structures were solved in multiple rotational states [PMID:33065002, "V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer"; PMID:33065002, "human V-ATPase in three rotational states"].

Signaling and stress-response outputs

V-ATPase has a direct lysosomal amino-acid sensing role upstream of mTORC1. The mTORC1 paper reports that V-ATPase is necessary for amino acids to activate mTORC1, that Ragulator co-immunoprecipitates with endogenous V0 d1 and other V-ATPase subunits, and that purified V0 d1 directly interacts with Ragulator p18 [PMID:22053050, "v-ATPase is necessary for amino acids to activate mTORC1"; PMID:22053050, "direct interaction between the V0 component d1 and p18"]. This supports ATP6V0D1 involvement in amino-acid-stimulated TORC1 signaling as a non-core signaling output of the lysosomal V-ATPase.

ATP6V0D1 is also implicated in HIF1A regulation through V-ATPase-dependent iron handling. A haploid genetic screen identified ATP6V0D1 among five V-ATPase subunits whose disruption increased HIF1A reporter levels, and the paper concludes that V-ATPase disruption causes intracellular iron depletion, impairing PHD activity [PMID:28296633, "five V-ATPase subunits: ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1"; PMID:28296633, "disrupting the V-ATPase results in intracellular iron depletion"]. This supports intracellular iron homeostasis/HIF context as non-core relative to the primary proton-pump role.

PN projection decision

For the Proteostasis PN batch, ATP6V0D1 should be projected conservatively as an endolysosomal V-ATPase subunit that maintains acidic lysosomal/endosomal compartments required for lysosome-dependent degradation and signaling. It should not be treated as a direct protein-folding, chaperone, ubiquitin-proteasome, or general macroautophagy regulator. The existing macroautophagy annotation is weak for ATP6V0D1 specifically and should be marked over-annotated rather than used as the principal PN evidence.

📚 Additional Documentation

Notes

(ATP6V0D1-notes.md)

ATP6V0D1 notes

Local evidence reviewed

just fetch-gene human ATP6V0D1 created the UniProt record, GOA table, review stub, and cached publication set. GOA seeded 60 review entries from 65 fetched annotations.
just deep-research-falcon human ATP6V0D1 --fallback perplexity-lite was run on 2026-06-03. Falcon timed out after 600 seconds. The configured fallback then failed with a Perplexity API 401 quota error, so no provider-generated deep research file was produced.
This manual fallback review uses local UniProt, GOA, cached publications, Reactome entries, and PN-context curation. A separate ATP6V0D1-deep-research-manual.md file summarizes the evidence used for the review.
UniProt describes ATP6V0D1 as V-type proton ATPase subunit d 1, a V0-sector subunit of the V-ATPase that acidifies intracellular compartments [file:human/ATP6V0D1/ATP6V0D1-uniprot.txt, "V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments"].
The human d-subunit paper supports the core complex/mechanism call: human d1 and d2 pull down V1 D and F subunits and the d subunit is centrally located in the pump rotary mechanism [PMID:18752060, "human d1 and d2 are able to directly interact with the D and F subunits"; PMID:18752060, "the d subunit in man is centrally located within the pump"].
Human V-ATPase cryo-EM supports treating ATP6V0D1 as part of the assembled proton pump rather than as an independent enzyme [PMID:33065002, "V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer"].
The mTORC1 amino-acid sensing paper supports a lysosomal signaling output of V-ATPase: the V-ATPase is necessary for amino acids to activate mTORC1 and provides a physical/functional link to Ragulator/Rag GTPases [PMID:22053050, "the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1"; PMID:22053050, "Ragulator provides a physical and functional link between the v-ATPase and the Rag GTPases"].
The HIF/iron paper directly includes ATP6V0D1 among V-ATPase genes whose disruption stabilizes HIF1A in aerobic conditions via intracellular iron depletion [PMID:28296633, "five V-ATPase subunits: ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1"; PMID:28296633, "disrupting the V-ATPase results in intracellular iron depletion"].
The SNX10/ciliogenesis row is supported only as a V-ATPase-dependent trafficking context, not as the core ATP6V0D1 function [PMID:21844891, "SNX10 interacts with V-ATPase complex and targets it to the centrosome"].
High-throughput exosome and binary-interactome rows provide context but should not define ATP6V0D1 function. Generic protein binding rows are over-annotated; the informative biology is V-ATPase V0-sector complex membership and contribution to proton-pump rotational activity.

PN proteostasis synthesis

ATP6V0D1 is appropriate for a conservative proteostasis projection only through lysosomal/endosomal acidification and downstream lysosome-dependent degradation capacity. It is not a chaperone, proteasome component, ubiquitin-system factor, or direct protein-folding machinery component.

The core review should therefore prioritize V-ATPase complex membership, contribution to rotational proton pump activity, and acidification of lysosomal/endosomal/vacuolar compartments. mTORC1 amino-acid sensing, iron/HIF regulation, cilium assembly, phagosome/synaptic vesicle contexts, plasma membrane V-ATPase, and extracellular exosome detection should be retained as non-core or context-specific where supported.

The regulation of macroautophagy row from the lipofuscin paper is not strong direct evidence for ATP6V0D1 as a macroautophagy regulator; it is best treated as an over-annotation in this PN review.

Pn Notes

(ATP6V0D1-pn-notes.md)

ATP6V0D1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: P61421
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1389)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V0D1/ATP6V0D1-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V0D1/ATP6V0D1-ai-review.html
Gene notes: present - genes/human/ATP6V0D1/ATP6V0D1-notes.md
GOA TSV: present - genes/human/ATP6V0D1/ATP6V0D1-goa.tsv
UniProt record: present - genes/human/ATP6V0D1/ATP6V0D1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V0D1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V0D1.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

genes/human/ATP6V0D1/ATP6V0D1-deep-research-manual.md

AIGR Review Snapshot

Description: ATP6V0D1 encodes the ubiquitous d1 isoform of the V0 d subunit of the vacuolar H+-ATPase (V-ATPase). The protein is a peripheral component of the membrane-embedded V0 sector and helps couple the V1 ATP-hydrolysis motor to V0 proton translocation. ATP6V0D1-containing V-ATPase complexes acidify lysosomes, endosomes, phagosomes, synaptic vesicles, and other intracellular compartments, thereby supporting vesicle traffic, lysosomal degradation, nutrient-dependent mTORC1 signaling, and ion homeostasis.
Existing/core annotation action counts: ACCEPT: 31; KEEP_AS_NON_CORE: 18; MARK_AS_OVER_ANNOTATED: 10; MODIFY: 1

PN Consistency Summary

Consistency: Consistent. Notes, deep-research-manual, review, PN row and PN-node mapping all treat ATP6V0D1 as the d1 V0-sector subunit acidifying endolysosomal compartments. The review carries the mTORC1/Ragulator role as directly-evidenced (PMID:22053050, IDA) but KEEP_AS_NON_CORE, matching the PN ancestor no_mapping. No contradictions.
PN story / NEW pressure: Unlike ATP6V0A2, ATP6V0D1 GOA already captures the lysosomal-specific terms: GO:0046611 lysosomal V-ATPase complex (IDA, PMID:22053050, ACCEPT) and GO:0007035 vacuolar acidification (IBA, ACCEPT) plus GO:1902600 proton transport. The two PN projected GO terms GO:0007042/GO:0046610 (both verified real via OLS) are therefore "more_specific" but the gene already has equivalent-or-adjacent coverage — review adds NO NEW terms (proposed_new_terms: []). No NEW pressure; the story is already captured. PN nutrient-sensing context is correctly represented only as non-core mTORC1 signaling, not promoted.
Evidence alignment: Strong primary-evidence base, diverging from PN's review-title citations. Load-bearing PMIDs: 18752060 (d subunit central rotary role), 33065002 (human V-ATPase cryo-EM), 22053050 (mTORC1 amino-acid sensing, V0-d1/p18 interaction), 28296633 (iron/HIF), 11118322 (gene structure, full_text_unavailable flagged). PN's V-ATPase-structure and mTORC1 themes overlap conceptually but cite secondary reviews.
Verdict: Consistent; PN projected terms already captured in GOA (GO:0046611/GO:0007035), so review correctly adds nothing; mTORC1 context kept non-core. No edits required.

Full Consistency Review

UniProt: P61421 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
PN placement: two ALP rows — ALP|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V0 lysosomal v-ATPase proton pump component and ALP|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component ; PN-node mapping: identical to ATP6V0A2 — V0 subtype leaves mapped/ok_for_propagation → GO:0046610, GO:0033179; Lysosomal-acidification type → GO:0007042; mTORC1/nutrient-sensing ancestors no_mapping; Pre-initiation class context_only/too_broad (GO:0010506).
Consistency: Consistent. Notes, deep-research-manual, review, PN row and PN-node mapping all treat ATP6V0D1 as the d1 V0-sector subunit acidifying endolysosomal compartments. The review carries the mTORC1/Ragulator role as directly-evidenced (PMID:22053050, IDA) but KEEP_AS_NON_CORE, matching the PN ancestor no_mapping. No contradictions.
PN story / NEW pressure: Unlike ATP6V0A2, ATP6V0D1 GOA already captures the lysosomal-specific terms: GO:0046611 lysosomal V-ATPase complex (IDA, PMID:22053050, ACCEPT) and GO:0007035 vacuolar acidification (IBA, ACCEPT) plus GO:1902600 proton transport. The two PN projected GO terms GO:0007042/GO:0046610 (both verified real via OLS) are therefore "more_specific" but the gene already has equivalent-or-adjacent coverage — review adds NO NEW terms (proposed_new_terms: []). No NEW pressure; the story is already captured. PN nutrient-sensing context is correctly represented only as non-core mTORC1 signaling, not promoted.
Mapping strategy: No change. The node mapping is shared with ATP6V0A2 and stands; ATP6V0D1 does not push the node broader. Conservative no_mapping ancestors correct.
Evidence alignment: Strong primary-evidence base, diverging from PN's review-title citations. Load-bearing PMIDs: 18752060 (d subunit central rotary role), 33065002 (human V-ATPase cryo-EM), 22053050 (mTORC1 amino-acid sensing, V0-d1/p18 interaction), 28296633 (iron/HIF), 11118322 (gene structure, full_text_unavailable flagged). PN's V-ATPase-structure and mTORC1 themes overlap conceptually but cite secondary reviews.
Verdict: Consistent; PN projected terms already captured in GOA (GO:0046611/GO:0007035), so review correctly adds nothing; mTORC1 context kept non-core. No edits required.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ATP6V0D1/ATP6V0D1-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: P61421
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: P61421
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: P61421
gene_symbol: ATP6V0D1
product_type: PROTEIN
aliases:
- ATP6D
- VPATPD
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ATP6V0D1 encodes the ubiquitous d1 isoform of the V0 d subunit of the vacuolar H+-ATPase
  (V-ATPase). The protein is a peripheral component of the membrane-embedded V0 sector and helps couple
  the V1 ATP-hydrolysis motor to V0 proton translocation. ATP6V0D1-containing V-ATPase complexes acidify
  lysosomes, endosomes, phagosomes, synaptic vesicles, and other intracellular compartments, thereby supporting
  vesicle traffic, lysosomal degradation, nutrient-dependent mTORC1 signaling, and ion homeostasis.
references:
- id: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
  title: UniProt record for human ATP6V0D1 (P61421)
  findings:
  - statement: ATP6V0D1 is a V0-sector V-ATPase subunit that supports proton translocation and acidification
      of intracellular compartments.
- id: file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
  title: Manual deep research fallback for ATP6V0D1
  findings:
  - statement: Falcon timed out and the configured fallback failed; manual evidence synthesis supports
      conservative V-ATPase-centered curation.
- id: file:human/ATP6V0D1/ATP6V0D1-notes.md
  title: Local curation notes for ATP6V0D1
  findings:
  - statement: Local PN synthesis treats ATP6V0D1 as a lysosomal/endosomal V-ATPase subunit with proteostasis
      relevance through organelle acidification, not as a direct chaperone/proteasome factor.
- 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:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11118322
  title: Structure of the VPATPD gene encoding subunit D of the human vacuolar proton ATPase.
  findings: []
- id: PMID:16713569
  title: A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell
    degeneration.
  findings: []
- id: PMID:17897319
  title: Integral and associated lysosomal membrane proteins.
  findings: []
- id: PMID:18752060
  title: The d subunit plays a central role in human vacuolar H(+)-ATPases.
  findings:
  - statement: Human d1/d2 subunits interact directly with V1 D and F subunits and occupy a central rotary
      position in the V-ATPase.
- 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:20093472
  title: Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling.
  findings: []
- id: PMID:21844891
  title: A SNX10/V-ATPase pathway regulates ciliogenesis in vitro and in vivo.
  findings:
  - statement: SNX10/V-ATPase regulates ciliogenesis through a vesicular trafficking and centrosome-targeting
      pathway.
- id: PMID:22053050
  title: mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar
    H(+)-ATPase.
  findings:
  - statement: V-ATPase, including V0 d1, links lysosomal amino-acid sensing to Ragulator/Rag-dependent
      mTORC1 activation.
- id: PMID:22982048
  title: Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced
    prematurely senescent human fibroblasts.
  findings:
  - statement: Lipofuscin uptake involves macroautophagy, but the paper does not directly establish ATP6V0D1
      as a macroautophagy regulator.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
  findings: []
- id: PMID:28296633
  title: The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation
    by regulating cellular iron levels.
  findings:
  - statement: ATP6V0D1/V-ATPase disruption affects HIF1A regulation through intracellular iron depletion
      and impaired PHD activity.
- id: PMID:29644770
  title: TMEM55B contributes to lysosomal homeostasis and amino acid-induced mTORC1 activation.
  findings: []
- id: PMID:30374053
  title: TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/β-catenin signalling.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread
    Protein Aggregation in Affected Brains.
  findings: []
- id: Reactome:R-HSA-1222516
  title: Intraphagosomal pH is lowered to 5 by V-ATPase
  findings: []
- id: Reactome:R-HSA-1791184
  title: Expression of ATP6VOD1
  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: Reactome:R-HSA-9639286
  title: RRAGC,D exchanges GTP for GDP
  findings: []
- id: Reactome:R-HSA-9640167
  title: RRAGA,B exchanges GDP for GTP
  findings: []
- id: Reactome:R-HSA-9640168
  title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates yielding v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP
    and SLC38A9:Arginine
  findings: []
- id: Reactome:R-HSA-9640175
  title: v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine
  findings: []
- id: Reactome:R-HSA-9640195
  title: RRAGA,B hydrolyzes GTP
  findings: []
- id: Reactome:R-HSA-9645598
  title: RRAGC,D hydrolyzes GTP
  findings: []
- id: Reactome:R-HSA-9645608
  title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1
  findings: []
- id: Reactome:R-HSA-9646468
  title: mTORC1 binds RHEB:GTP
  findings: []
- id: Reactome:R-HSA-9858932
  title: MITF-M-dependent ATP6V0D1 gene expression
  findings: []
- id: PMID:33065002
  title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.
  findings:
  - statement: Human V-ATPase cryo-EM structures support the assembled V1/Vo proton-pump mechanism and
      complex-level interpretation of ATP6V0D1.
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: 'Supported core ATP6V0D1 annotation: vacuolar proton-transporting V-type ATPase complex.'
    action: ACCEPT
    reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase
      structural evidence support V-ATPase complex membership and V0-domain placement as core annotations.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: &id002
    - &id016
      reference_id: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
      supporting_text: Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase)
    - &id001
      reference_id: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
      supporting_text: V-ATPase is responsible for acidifying and maintaining the pH of intracellular
        compartments
    - &id019
      reference_id: PMID:18752060
      supporting_text: These data indicate that the d subunit in man is centrally located within the pump
        and is thus important in its rotary mechanism
    - &id020
      reference_id: PMID:33065002
      supporting_text: V-ATPases are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for
        ATP hydrolysis and a membrane-embedded Vo complex for proton transfer
    - reference_id: file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
      supporting_text: ATP6V0D1 encodes V-type proton ATPase subunit d 1, also called V-ATPase AC39/p39
- 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: 'ATP6V0D1 contributes to the assembled V-ATPase proton-pump activity: proton-transporting
      ATPase activity, rotational mechanism.'
    action: ACCEPT
    reason: The d1 subunit is not the independent catalytic ATPase, but the IBA annotation already uses the contributes_to qualifier. This accurately represents ATP6V0D1 as a V0 subunit contributing to the assembled V-ATPase rotary proton-pump activity.
    additional_reference_ids:
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: &id005
    - &id021
      reference_id: PMID:18752060
      supporting_text: human d1 and d2 are able to directly interact with the D and F subunits
    - &id022
      reference_id: PMID:18752060
      supporting_text: the d subunit in man is centrally located within the pump
    - reference_id: PMID:33065002
      supporting_text: human V-ATPase in three rotational states
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: early endosome.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:22053050
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - &id003
      reference_id: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
      supporting_text: Lysosome membrane
    - reference_id: PMID:22053050
      supporting_text: the lysosomal surface, the site of mTORC1 activation
    - reference_id: PMID:28296633
      supporting_text: V-ATPase, the key proton pump for endo-lysosomal acidification
- term:
    id: GO:0007034
    label: vacuolar transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Vacuolar transport is plausible as a downstream V-ATPase/endolysosomal trafficking context
      but is not the most specific ATP6V0D1 function.
    action: KEEP_AS_NON_CORE
    reason: The conserved primary role is proton-pump complex function and compartment acidification.
      Vacuolar transport depends on acidic endolysosomal compartments, but this term is broader than the
      direct ATP6V0D1 mechanism.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id001
    - reference_id: PMID:33065002
      supporting_text: supporting intracellular membrane trafficking and protein degradation
- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: 'Core V-ATPase proton transport/acidification process: vacuolar acidification.'
    action: ACCEPT
    reason: ATP6V0D1 functions in the V-ATPase complex that translocates protons and acidifies intracellular
      compartments. This is the principal biological process supported for the d1 subunit.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id002
- term:
    id: GO:0033181
    label: plasma membrane proton-transporting V-type ATPase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Plasma membrane V-ATPase localization is supported in specialized cells but is not the dominant
      ATP6V0D1/d1 context.
    action: KEEP_AS_NON_CORE
    reason: UniProt notes that V-ATPase can be targeted to the plasma membrane in some cell types. For
      ubiquitous ATP6V0D1/d1, the better-supported core locations are lysosomal and endosomal V-ATPase
      complexes.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - reference_id: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
      supporting_text: in some cell types, is targeted to the plasma membrane
    - reference_id: PMID:33065002
      supporting_text: Plasma membrane V-ATPases carry out extracellular acidification in specialized
        organs
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: lysosomal membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:22053050
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id003
    - reference_id: PMID:22053050
      supporting_text: the lysosomal surface, the site of mTORC1 activation
    - reference_id: PMID:28296633
      supporting_text: V-ATPase, the key proton pump for endo-lysosomal acidification
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Membrane localization is true but too general for ATP6V0D1.
    action: KEEP_AS_NON_CORE
    reason: ATP6V0D1 is a peripheral membrane-associated V0-sector subunit. The informative locations
      are the V-ATPase complex and lysosomal/endosomal membranes rather than the parent membrane term.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:18752060
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - reference_id: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
      supporting_text: Membrane
    - reference_id: PMID:18752060
      supporting_text: The vacuolar H+-ATPase d subunit is known to associate with the integral membrane
        V0 domain
- term:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: 'Supported core ATP6V0D1 annotation: vacuolar proton-transporting V-type ATPase complex.'
    action: ACCEPT
    reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase
      structural evidence support V-ATPase complex membership and V0-domain placement as core annotations.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id002
- term:
    id: GO:0030665
    label: clathrin-coated vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'Context-specific vesicle membrane localization for V-ATPase: clathrin-coated vesicle membrane.'
    action: KEEP_AS_NON_CORE
    reason: V-ATPases acidify several specialized vesicle classes, including clathrin-coated and phagocytic
      vesicles. These locations are plausible and supported, but lysosomal/endosomal V-ATPase function
      is the primary ATP6V0D1 role.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - &id004
      reference_id: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
      supporting_text: Cytoplasmic vesicle, clathrin-coated vesicle membrane
- term:
    id: GO:0030670
    label: phagocytic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: 'Context-specific vesicle membrane localization for V-ATPase: phagocytic vesicle membrane.'
    action: KEEP_AS_NON_CORE
    reason: V-ATPases acidify several specialized vesicle classes, including clathrin-coated and phagocytic
      vesicles. These locations are plausible and supported, but lysosomal/endosomal V-ATPase function
      is the primary ATP6V0D1 role.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id004
- term:
    id: GO:0033179
    label: proton-transporting V-type ATPase, V0 domain
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: 'Supported core ATP6V0D1 annotation: proton-transporting V-type ATPase, V0 domain.'
    action: ACCEPT
    reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase
      structural evidence support V-ATPase complex membership and V0-domain placement as core annotations.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id002
- term:
    id: GO:0042592
    label: homeostatic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Homeostatic process is overly broad for ATP6V0D1.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific supported homeostatic roles are endolysosomal acidification, proton transmembrane
      transport, and context-specific iron/HIF regulation. The generic parent term loses the actual function.
    proposed_replacement_terms:
    - id: GO:0007035
      label: vacuolar acidification
    - id: GO:1902600
      label: proton transmembrane transport
    - id: GO:0006879
      label: intracellular iron ion homeostasis
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id001
    - &id011
      reference_id: PMID:28296633
      supporting_text: disrupting the V-ATPase results in intracellular iron depletion
- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: 'ATP6V0D1 contributes to the assembled V-ATPase proton-pump activity: proton-transporting
      ATPase activity, rotational mechanism.'
    action: MODIFY
    reason: The term is biologically appropriate for ATP6V0D1-containing V-ATPase complexes, but the GOA qualifier should be changed from enables to contributes_to. The d1 subunit is not the independent catalytic ATPase; it contributes to the rotary V-ATPase mechanism that couples ATP hydrolysis in V1 to proton transfer through V0.
    proposed_replacement_terms:
    - id: GO:0046961
      label: proton-transporting ATPase activity, rotational mechanism
    additional_reference_ids:
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id005
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: located_in
  review:
    summary: Presynapse is an inferred neuronal context from synaptic vesicle acidification, not core
      ATP6V0D1 biology.
    action: KEEP_AS_NON_CORE
    reason: V-ATPases acidify synaptic vesicles, but the reviewed evidence for ATP6V0D1/d1 is broader
      endolysosomal V-ATPase function. Presynapse should remain a context-specific location.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:18752060
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id001
    - reference_id: PMID:18752060
      supporting_text: acidification of diverse intracellular compartments in eukaryotic cells, including
        endosomes, lysosomes, clathrin-coated and synaptic vesicles
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: 'Core V-ATPase proton transport/acidification process: proton transmembrane transport.'
    action: ACCEPT
    reason: ATP6V0D1 functions in the V-ATPase complex that translocates protons and acidifies intracellular
      compartments. This is the principal biological process supported for the d1 subunit.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id002
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16713569
  qualifier: enables
  review:
    summary: Protein binding is too generic to represent ATP6V0D1 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: These interaction-map annotations are useful context but do not identify a specific ATP6V0D1
      activity.
    proposed_replacement_terms: &id006
    - id: GO:0016471
      label: vacuolar proton-transporting V-type ATPase complex
    - id: GO:0046961
      label: proton-transporting ATPase activity, rotational mechanism
    additional_reference_ids:
    - PMID:16713569
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: &id007
    - reference_id: PMID:16713569
      supporting_text: We identified 770 mostly novel protein-protein interactions using a stringent yeast
        two-hybrid screen
    - reference_id: PMID:32296183
      supporting_text: The dataset, versioned HI-III-20 (Human Interactome obtained from screening Space
        III, published in 2020), contains 52,569 verified PPIs involving 8,275 proteins
    - reference_id: PMID:32814053
      supporting_text: connects ∼5,000 human proteins via ∼30,000 candidate interactions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Protein binding is too generic to represent ATP6V0D1 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: These interaction-map annotations are useful context but do not identify a specific ATP6V0D1
      activity.
    proposed_replacement_terms: *id006
    additional_reference_ids:
    - PMID:32296183
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id007
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Protein binding is too generic to represent ATP6V0D1 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: These interaction-map annotations are useful context but do not identify a specific ATP6V0D1
      activity.
    proposed_replacement_terms: *id006
    additional_reference_ids:
    - PMID:32814053
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id007
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: early endosome.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:22053050
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id003
    - reference_id: PMID:22053050
      supporting_text: the lysosomal surface, the site of mTORC1 activation
    - reference_id: PMID:28296633
      supporting_text: V-ATPase, the key proton pump for endo-lysosomal acidification
- term:
    id: GO:0015078
    label: proton transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: contributes_to
  review:
    summary: 'ATP6V0D1 contributes to the assembled V-ATPase proton-pump activity: proton transmembrane
      transporter activity.'
    action: ACCEPT
    reason: The d1 subunit is not the independent catalytic ATPase, but it is centrally positioned in
      the rotary V-ATPase mechanism and contributes to coupling ATP hydrolysis in V1 to proton transfer
      through V0.
    additional_reference_ids:
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id005
- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: 'Supported core ATP6V0D1 annotation: proton-transporting V-type ATPase complex.'
    action: ACCEPT
    reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase
      structural evidence support V-ATPase complex membership and V0-domain placement as core annotations.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id002
- 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 plausible for V-ATPase but context-specific for ATP6V0D1.
    action: KEEP_AS_NON_CORE
    reason: The V-ATPase family acidifies synaptic vesicles, but ATP6V0D1/d1 is not uniquely a synaptic-vesicle
      factor. Keep as a non-core inferred location/process context.
    additional_reference_ids:
    - PMID:18752060
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - reference_id: PMID:18752060
      supporting_text: acidification of diverse intracellular compartments in eukaryotic cells, including
        endosomes, lysosomes, clathrin-coated and synaptic vesicles
- term:
    id: GO:0071230
    label: cellular response to amino acid stimulus
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: involved_in
  review:
    summary: 'Directly supported lysosomal amino-acid/mTORC1 signaling context: cellular response to amino
      acid stimulus.'
    action: KEEP_AS_NON_CORE
    reason: The mTORC1 work supports V-ATPase, including V0 d1, as part of lysosomal amino-acid sensing
      through Ragulator/Rag signaling. This is a real signaling output but secondary to the core proton-pump/acidification
      function.
    additional_reference_ids:
    - PMID:22053050
    - Reactome:R-HSA-9645608
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: &id008
    - &id009
      reference_id: PMID:22053050
      supporting_text: the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino
        acids to activate mTORC1
    - reference_id: PMID:22053050
      supporting_text: Ragulator provides a physical and functional link between the v-ATPase and the
        Rag GTPases
    - reference_id: PMID:22053050
      supporting_text: direct interaction between the V0 component d1 and p18
- term:
    id: GO:0160124
    label: guanyl nucleotide exchange factor activator activity
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: contributes_to
  review:
    summary: 'Directly supported lysosomal amino-acid/mTORC1 signaling context: guanyl nucleotide exchange
      factor activator activity.'
    action: KEEP_AS_NON_CORE
    reason: The mTORC1 work supports V-ATPase, including V0 d1, as part of lysosomal amino-acid sensing
      through Ragulator/Rag signaling. This is a real signaling output but secondary to the core proton-pump/acidification
      function.
    additional_reference_ids:
    - PMID:22053050
    - Reactome:R-HSA-9645608
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id008
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: is_active_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: lysosomal membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:22053050
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id003
    - reference_id: PMID:22053050
      supporting_text: the lysosomal surface, the site of mTORC1 activation
    - reference_id: PMID:28296633
      supporting_text: V-ATPase, the key proton pump for endo-lysosomal acidification
- term:
    id: GO:0046611
    label: lysosomal proton-transporting V-type ATPase complex
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: part_of
  review:
    summary: 'Supported core ATP6V0D1 annotation: lysosomal proton-transporting V-type ATPase complex.'
    action: ACCEPT
    reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase
      structural evidence support V-ATPase complex membership and V0-domain placement as core annotations.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id002
- term:
    id: GO:1904263
    label: positive regulation of TORC1 signaling
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: involved_in
  review:
    summary: 'Directly supported lysosomal amino-acid/mTORC1 signaling context: positive regulation of
      TORC1 signaling.'
    action: KEEP_AS_NON_CORE
    reason: The mTORC1 work supports V-ATPase, including V0 d1, as part of lysosomal amino-acid sensing
      through Ragulator/Rag signaling. This is a real signaling output but secondary to the core proton-pump/acidification
      function.
    additional_reference_ids:
    - PMID:22053050
    - Reactome:R-HSA-9645608
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id008
- term:
    id: GO:0000220
    label: vacuolar proton-transporting V-type ATPase, V0 domain
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: 'Supported core ATP6V0D1 annotation: vacuolar proton-transporting V-type ATPase, V0 domain.'
    action: ACCEPT
    reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase
      structural evidence support V-ATPase complex membership and V0-domain placement as core annotations.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id002
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30374053
  qualifier: enables
  review:
    summary: Protein binding is too generic to represent ATP6V0D1 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: TMEM9/ATP6AP2 interactions are V-ATPase assembly/signaling context; generic protein binding
      should not define ATP6V0D1 function.
    proposed_replacement_terms: *id006
    additional_reference_ids:
    - PMID:30374053
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - reference_id: PMID:30374053
      supporting_text: TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29644770
  qualifier: enables
  review:
    summary: Protein binding is too generic to represent ATP6V0D1 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: TMEM55B interaction supports lysosomal V-ATPase/mTORC1 context, but protein binding remains
      too generic.
    proposed_replacement_terms: *id006
    additional_reference_ids:
    - PMID:29644770
    - PMID:22053050
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - reference_id: PMID:29644770
      supporting_text: TMEM55B interacts with many proteins that participate in mTORC1 activation including
        components of the vacuolar-type proton ATPase (V-ATPase)
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9639286
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: lysosomal membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - Reactome:R-HSA-9639286
    - PMID:22053050
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - &id010
      reference_id: Reactome:R-HSA-9645608
      supporting_text: Hydrolysis of ATP by the v-ATPase complex is also required for recruitment of mTORC1
    - *id003
    - *id009
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640167
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: lysosomal membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - Reactome:R-HSA-9640167
    - PMID:22053050
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id010
    - *id003
    - *id009
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640168
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: lysosomal membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - Reactome:R-HSA-9640168
    - PMID:22053050
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id010
    - *id003
    - *id009
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640175
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: lysosomal membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - Reactome:R-HSA-9640175
    - PMID:22053050
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id010
    - *id003
    - *id009
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640195
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: lysosomal membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - Reactome:R-HSA-9640195
    - PMID:22053050
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id010
    - *id003
    - *id009
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645598
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: lysosomal membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - Reactome:R-HSA-9645598
    - PMID:22053050
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id010
    - *id003
    - *id009
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645608
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: lysosomal membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - Reactome:R-HSA-9645608
    - PMID:22053050
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id010
    - *id003
    - *id009
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9646468
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: lysosomal membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - Reactome:R-HSA-9646468
    - PMID:22053050
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id010
    - *id003
    - *id009
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858932
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: lysosomal membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:22053050
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id003
    - reference_id: PMID:22053050
      supporting_text: the lysosomal surface, the site of mTORC1 activation
    - reference_id: PMID:28296633
      supporting_text: V-ATPase, the key proton pump for endo-lysosomal acidification
- term:
    id: GO:0006879
    label: intracellular iron ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:28296633
  qualifier: involved_in
  review:
    summary: 'Supported but non-core ATP6V0D1 context: intracellular iron ion homeostasis.'
    action: KEEP_AS_NON_CORE
    reason: ATP6V0D1 disruption was identified in a V-ATPase/HIF screen and linked to intracellular iron
      depletion. This is a downstream consequence of endolysosomal V-ATPase function, not the primary
      evolved activity of the d1 subunit.
    additional_reference_ids:
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: &id012
    - reference_id: PMID:28296633
      supporting_text: 'five V-ATPase subunits: ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1'
    - *id011
- term:
    id: GO:0036295
    label: cellular response to increased oxygen levels
  evidence_type: IMP
  original_reference_id: PMID:28296633
  qualifier: involved_in
  review:
    summary: The HIF/aerobic-response evidence is real but the GO term is an over-specific downstream
      readout for ATP6V0D1.
    action: MARK_AS_OVER_ANNOTATED
    reason: PMID:28296633 shows ATP6V0D1/V-ATPase disruption stabilizes HIF1A in aerobic conditions via
      iron depletion. That supports iron/HIF homeostasis context, but not a direct ATP6V0D1 role in cellular
      response to increased oxygen levels.
    proposed_replacement_terms:
    - id: GO:0006879
      label: intracellular iron ion homeostasis
    additional_reference_ids:
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id012
- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: NAS
  original_reference_id: PMID:22982048
  qualifier: involved_in
  review:
    summary: Regulation of macroautophagy is over-annotated for ATP6V0D1 based on the cited lipofuscin
      study.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited paper discusses macroautophagy and lysosomal uptake of lipofuscin but does not establish
      ATP6V0D1 as a specific macroautophagy regulator. In the PN context, ATP6V0D1 should be represented
      through lysosomal V-ATPase acidification rather than a broad macroautophagy-regulatory claim.
    proposed_replacement_terms:
    - id: GO:0007035
      label: vacuolar acidification
    additional_reference_ids:
    - PMID:22982048
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    - file:human/ATP6V0D1/ATP6V0D1-notes.md
    supported_by:
    - reference_id: PMID:22982048
      supporting_text: macroautophagy is responsible for the uptake of lipofuscin into the lysosomes
    - reference_id: file:human/ATP6V0D1/ATP6V0D1-notes.md
      supporting_text: The `regulation of macroautophagy` row from the lipofuscin paper is not strong
        direct evidence for ATP6V0D1 as a macroautophagy regulator
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: Extracellular exosome detection is supported by high-throughput proteomics but is not core
      ATP6V0D1 function.
    action: KEEP_AS_NON_CORE
    reason: ATP6V0D1 can be detected in exosome proteomics datasets, consistent with endomembrane origin
      and vesicle biology. These HDA rows should not drive functional interpretation.
    additional_reference_ids:
    - PMID:19056867
    - PMID:19199708
    - PMID:23533145
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: &id013
    - reference_id: PMID:19056867
      supporting_text: LC-MS/MS to profile the proteome of human urinary exosomes
    - reference_id: PMID:19199708
      supporting_text: we catalogued 491 proteins in the exosome fraction of human parotid saliva
    - reference_id: PMID:23533145
      supporting_text: In pooled EPS-urine exosome samples, ~900 proteins were detected
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20093472
  qualifier: enables
  review:
    summary: Protein binding is too generic to represent ATP6V0D1 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The PRR/ATP6AP2 Wnt paper supports a V-ATPase signaling/adaptor context, not a specific ATP6V0D1
      molecular function beyond V-ATPase complex function.
    proposed_replacement_terms: *id006
    additional_reference_ids:
    - PMID:20093472
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - reference_id: PMID:20093472
      supporting_text: PRR functions in a renin-independent manner as an adaptor between Wnt receptors
        and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  qualifier: located_in
  review:
    summary: Extracellular exosome detection is supported by high-throughput proteomics but is not core
      ATP6V0D1 function.
    action: KEEP_AS_NON_CORE
    reason: ATP6V0D1 can be detected in exosome proteomics datasets, consistent with endomembrane origin
      and vesicle biology. These HDA rows should not drive functional interpretation.
    additional_reference_ids:
    - PMID:19056867
    - PMID:19199708
    - PMID:23533145
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id013
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: Extracellular exosome detection is supported by high-throughput proteomics but is not core
      ATP6V0D1 function.
    action: KEEP_AS_NON_CORE
    reason: ATP6V0D1 can be detected in exosome proteomics datasets, consistent with endomembrane origin
      and vesicle biology. These HDA rows should not drive functional interpretation.
    additional_reference_ids:
    - PMID:19056867
    - PMID:19199708
    - PMID:23533145
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id013
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: HDA
  original_reference_id: PMID:17897319
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: lysosomal membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:22053050
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id003
    - reference_id: PMID:22053050
      supporting_text: the lysosomal surface, the site of mTORC1 activation
    - reference_id: PMID:28296633
      supporting_text: V-ATPase, the key proton pump for endo-lysosomal acidification
- term:
    id: GO:0060271
    label: cilium assembly
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Cilium assembly is a supported V-ATPase/SNX10 trafficking context but not the core ATP6V0D1
      function.
    action: KEEP_AS_NON_CORE
    reason: The SNX10 study supports V-ATPase-dependent ciliogenesis and centrosomal targeting, but ATP6V0D1
      is best curated primarily as a V-ATPase proton-pump subunit.
    additional_reference_ids:
    - PMID:21844891
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: &id014
    - reference_id: PMID:21844891
      supporting_text: SNX10 interacts with V-ATPase complex and targets it to the centrosome
    - reference_id: PMID:21844891
      supporting_text: Like SNX10, V-ATPase regulates ciliogenesis in vitro and in vivo
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:21844891
  qualifier: colocalizes_with
  review:
    summary: Centrosome colocalization is supported in the SNX10/V-ATPase ciliogenesis context but is
      not core.
    action: KEEP_AS_NON_CORE
    reason: The cited paper places SNX10/V-ATPase at the centrosome during ciliogenesis. This is a context-specific
      colocalization rather than the primary ATP6V0D1 location.
    additional_reference_ids:
    - PMID:21844891
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id014
- term:
    id: GO:0030670
    label: phagocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1222516
  qualifier: located_in
  review:
    summary: 'Context-specific vesicle membrane localization for V-ATPase: phagocytic vesicle membrane.'
    action: KEEP_AS_NON_CORE
    reason: V-ATPases acidify several specialized vesicle classes, including clathrin-coated and phagocytic
      vesicles. These locations are plausible and supported, but lysosomal/endosomal V-ATPase function
      is the primary ATP6V0D1 role.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - reference_id: Reactome:R-HSA-1222516
      supporting_text: When pumping, ATP hydrolysis drives a 120 degree rotation of the rotor which leads
        to movement of three protons into the phagosome
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1791184
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: endosome membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:22053050
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id001
    - &id015
      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:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252133
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: endosome membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:22053050
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - reference_id: Reactome:R-HSA-5252133
      supporting_text: Vacuolar-type H+-ATPases (V-ATPases) are proton pumps that acidify intracellular
        cargos
    - *id003
    - reference_id: PMID:22053050
      supporting_text: the lysosomal surface, the site of mTORC1 activation
    - reference_id: PMID:28296633
      supporting_text: V-ATPase, the key proton pump for endo-lysosomal acidification
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74723
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: endosome membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:22053050
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id015
    - *id003
    - reference_id: PMID:22053050
      supporting_text: the lysosomal surface, the site of mTORC1 activation
    - reference_id: PMID:28296633
      supporting_text: V-ATPase, the key proton pump for endo-lysosomal acidification
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917841
  qualifier: located_in
  review:
    summary: 'Supported endolysosomal V-ATPase location: endosome membrane.'
    action: ACCEPT
    reason: ATP6V0D1-containing V-ATPase complexes function on lysosomal and endosomal membranes, where
      they acidify organelle lumens. These are core cellular locations for the d1 subunit.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:22053050
    - PMID:28296633
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id003
    - reference_id: PMID:22053050
      supporting_text: the lysosomal surface, the site of mTORC1 activation
    - reference_id: PMID:28296633
      supporting_text: V-ATPase, the key proton pump for endo-lysosomal acidification
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18752060
  qualifier: enables
  review:
    summary: Protein binding is too generic to represent ATP6V0D1 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: PMID:18752060 provides meaningful evidence for d1 interaction with V1 D and F subunits, but
      the curatable function is V-ATPase rotary coupling/complex membership rather than generic protein
      binding.
    proposed_replacement_terms: *id006
    additional_reference_ids:
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id005
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:18752060
  qualifier: located_in
  review:
    summary: Membrane localization is true but too general for ATP6V0D1.
    action: KEEP_AS_NON_CORE
    reason: ATP6V0D1 is a peripheral membrane-associated V0-sector subunit. The informative locations
      are the V-ATPase complex and lysosomal/endosomal membranes rather than the parent membrane term.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:18752060
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - reference_id: file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
      supporting_text: Membrane
    - reference_id: PMID:18752060
      supporting_text: The vacuolar H+-ATPase d subunit is known to associate with the integral membrane
        V0 domain
- term:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
  evidence_type: IDA
  original_reference_id: PMID:18752060
  qualifier: part_of
  review:
    summary: 'Supported core ATP6V0D1 annotation: vacuolar proton-transporting V-type ATPase complex.'
    action: ACCEPT
    reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase
      structural evidence support V-ATPase complex membership and V0-domain placement as core annotations.
    additional_reference_ids:
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - PMID:18752060
    - PMID:33065002
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by: *id002
- term:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
  evidence_type: NAS
  original_reference_id: PMID:11118322
  qualifier: part_of
  review:
    summary: 'Supported core ATP6V0D1 annotation: vacuolar proton-transporting V-type ATPase complex.'
    action: ACCEPT
    reason: ATP6V0D1/d1 is a V0-sector d subunit of the V-ATPase. Biochemical, UniProt, and human V-ATPase
      structural evidence support V-ATPase complex membership and V0-domain placement as core annotations.
    additional_reference_ids:
    - PMID:11118322
    - PMID:18752060
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - &id017
      reference_id: PMID:11118322
      supporting_text: Structure of the VPATPD gene encoding subunit D of the human vacuolar proton ATPase
    - &id018
      reference_id: PMID:11118322
      supporting_text: The encoded protein is 99.5% identical to mouse subunit D at the amino acid level
    - *id016
    - *id001
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: NAS
  original_reference_id: PMID:11118322
  qualifier: involved_in
  review:
    summary: The original gene-structure citation is weak alone, but proton transport is supported by
      the full ATP6V0D1 evidence set.
    action: ACCEPT
    reason: PMID:11118322 establishes VPATPD/ATP6V0D1 as the gene encoding human vacuolar proton ATPase
      subunit D; later biochemical and structural evidence supports the proton-transport annotation through
      V-ATPase complex function.
    additional_reference_ids:
    - PMID:11118322
    - PMID:18752060
    - file:human/ATP6V0D1/ATP6V0D1-uniprot.txt
    - file:human/ATP6V0D1/ATP6V0D1-deep-research-manual.md
    supported_by:
    - *id017
    - *id018
    - *id016
    - *id001
core_functions:
- description: ATP6V0D1 functions as the d1 subunit of the V0 sector of the V-ATPase, helping couple the
    V1 ATP-hydrolysis motor to V0 proton translocation and thereby acidifying lysosomal, endosomal, and
    related intracellular compartments.
  supported_by:
  - *id016
  - *id001
  - *id019
  - *id020
  - *id021
  - *id022
  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
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  - id: GO:0010008
    label: endosome membrane
  - id: GO:0005769
    label: early endosome
  in_complex:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
proposed_new_terms: []
suggested_questions:
- question: Should the ATP6V0D1 mTORC1 amino-acid sensing annotations remain as direct non-core V-ATPase
    signaling outputs, or should GO represent them primarily at the assembled V-ATPase/Ragulator complex
    level?
- question: 'Which ATP6V0D1-containing V-ATPase pools are most relevant to proteostasis phenotypes: lysosomal
    degradation, endosomal trafficking, autophagy-lysosome flux, or nutrient signaling through mTORC1?'
suggested_experiments:
- hypothesis: ATP6V0D1 supports proteostasis phenotypes primarily through endolysosomal acidification
    rather than a direct macroautophagy-regulatory activity.
  description: Deplete ATP6V0D1 in human cells and rescue with RNAi-resistant wild-type or V0-interaction-defective
    mutants while measuring lysosomal pH, EGFR/MHC-I lysosomal degradation, LC3 flux, and accumulation
    of undegraded protein cargo.
  experiment_type: loss-of-function rescue with lysosomal acidification and degradation assays
- hypothesis: The d1-p18/Ragulator interaction contributes to mTORC1 amino-acid sensing independently
    of bulk lysosomal pH changes.
  description: Mutate ATP6V0D1 surfaces required for Ragulator p18 interaction and test amino-acid-stimulated
    mTORC1 lysosomal recruitment and S6K/4E-BP phosphorylation while monitoring V-ATPase assembly and
    organelle pH.
  experiment_type: interaction-mutant signaling assay

ATP6V0D1

Gene Description