Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0033176 proton-transporting V-type ATPase complex	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that ATP6V1D is part of the V-type ATPase complex. Confirmed by cryo-EM structure and biochemical data. Reason: The D subunit is a core structural and functional component of the V1 sector of the V-type ATPase complex. Multiple lines of evidence including cryo-EM (PMID:33065002) and biochemical pulldowns (PMID:18752060) confirm complex membership. Supporting Evidence: PMID:33065002 Vesicular- or vacuolar-type adenosine triphosphatases (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/ATP6V1D/ATP6V1D-uniprot.txt Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons
GO:0007035 vacuolar acidification	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that ATP6V1D participates in vacuolar acidification. Well-supported by the established role of V-ATPase in acidifying intracellular compartments. Reason: The V-ATPase is the primary driver of organellar acidification in eukaryotes, and subunit D is a core structural component essential for complex function. Vacuolar acidification is the core biological process. Supporting Evidence: PMID:33065002 Vesicular- or vacuolar-type adenosine triphosphatases (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. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps. V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes.
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that subunit D contributes to proton-transporting ATPase activity via rotational mechanism. Supported by the established central rotor function of subunit D in the rotary mechanism. Reason: Subunit D is a core structural component of the V1 central rotor that directly participates in the rotary mechanism. The contributes_to qualifier is appropriate since this is a complex-level activity. Supporting Evidence: PMID:18752060 Energy from this reaction drives the rotation of a central stalk consisting of V1 subunits D and F and this is coupled to rotation of the V0 proteolipid ring made up of c, c′ and c″. PMID:33065002 Vesicular- or vacuolar-type adenosine triphosphatases (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.
GO:0005765 lysosomal membrane	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular location vocabulary mapping. Well-supported by multiple independent HDA and IDA lysosomal membrane annotations. Reason: Lysosomal membrane is the primary functional location of the V-ATPase complex. Supported by HDA proteomics (PMID:17897319) and IDA data (PMID:22053050).
GO:0005813 centrosome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt subcellular location vocabulary mapping based on the centrosome localization reported in PMID:21844891. Reason: Centrosome localization of ATP6V1D (via SNX10 interaction) is supported by IDA evidence (PMID:21844891) but represents a secondary ciliogenesis-related function rather than the core lysosomal proton-pumping role. Supporting Evidence: PMID:21844891 SNX10 interacts with V-ATPase complex and targets it to the centrosome where ciliogenesis is initiated.
GO:0005929 cilium	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt subcellular location vocabulary mapping based on cilium localization reported in PMID:21844891. Reason: Cilium localization is supported by IDA evidence but represents a secondary ciliogenesis-related function. The V-ATPase participates in ciliogenesis via vesicular trafficking to the cilium base. Supporting Evidence: PMID:21844891 Like SNX10, V-ATPase regulates ciliogenesis in vitro and in vivo and does so synergistically with SNX10. We further discover that SNX10 and V-ATPase regulate the ciliary trafficking of Rab8a, which is a critical regulator of ciliary membrane extension.
GO:0016020 membrane	IEA GO_REF:0000044	MARK AS OVER ANNOTATED	Summary: Generic membrane localization from UniProt vocabulary mapping. The V1 D subunit associates with the cytoplasmic face of membranes as part of the V-ATPase complex. Reason: The generic membrane term is subsumed by the more specific lysosomal membrane, Golgi membrane, and endosome membrane annotations. The IDA annotation from PMID:18752060 (membrane) is more specific in context and provides better granularity.
GO:0030665 clathrin-coated vesicle membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt subcellular location vocabulary mapping based on ortholog data. V-ATPase functions on clathrin-coated vesicles for endocytic pathway acidification. Reason: The clathrin-coated vesicle membrane localization is consistent with V-ATPase's broad role in acidifying endocytic vesicles, but is not the primary functional context for this subunit.
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based annotation. The enables qualifier for the whole-complex activity is somewhat imprecise for a structural subunit, but the rotational ATPase activity is the core molecular function. Reason: The proton-transporting ATPase activity via rotational mechanism is the core molecular function of the complex in which ATP6V1D is an indispensable structural component. The IBA annotation with contributes_to is more precise, but this IEA is consistent.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a large-scale human interactome proteome map. Not informative for the specific function of ATP6V1D. Reason: Protein binding is uninformative for this V-ATPase subunit. A high-throughput interactome map does not establish a meaningful GO annotation for ATP6V1D core function.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a reference human binary protein interactome map. High-throughput; not informative. Reason: Protein binding from high-throughput interactome studies lacks specificity and is not useful for understanding ATP6V1D function.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a dual proteome-scale interactome network study. High-throughput; not informative. Reason: High-throughput interactome data should not be used to assert generic protein binding as a meaningful function for a structural V-ATPase subunit.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from the OpenCell endogenous tagging study. High-throughput; not informative for core function. Reason: Protein binding is uninformative for ATP6V1D; these high-throughput interaction data points do not reveal specific biological function.
GO:0015078 proton transmembrane transporter activity	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl ortholog-transfer annotation. Proton transmembrane transporter activity is the molecular function of the V-ATPase complex; subunit D contributes via the rotary mechanism. Reason: This is an appropriate annotation for a core V-ATPase structural subunit. The contributes_to qualifier correctly acknowledges that the molecular function belongs to the whole complex.
GO:0033176 proton-transporting V-type ATPase complex	IEA GO_REF:0000120	ACCEPT	Summary: Automated IEA annotation consistent with the IBA and IDA evidence for complex membership. Reason: Redundant with IBA but consistent with cryo-EM structural evidence.
GO:0097401 synaptic vesicle lumen acidification	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl ortholog-transfer annotation for synaptic vesicle lumen acidification. V-ATPase acidifies synaptic vesicles to enable neurotransmitter loading. However, there is no direct evidence that the ubiquitous D subunit specifically functions in neuronal synaptic vesicles as opposed to other organelles. Reason: Synaptic vesicle lumen acidification is a legitimate biological process in which V-ATPase participates; the D subunit is a ubiquitously expressed component that would be present in neuronal V-ATPase complexes. However, this is a non-core context relative to lysosomal/endosomal function.
GO:0098850 extrinsic component of synaptic vesicle membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl ortholog-transfer annotation placing the D subunit on synaptic vesicle membrane. The V1 peripheral sector is an extrinsic component of vesicle membranes. Reason: Supported by the V-ATPase's role in synaptic vesicle acidification, but this is non-core relative to the primary lysosomal/endosomal acidification function.
GO:0071230 cellular response to amino acid stimulus	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	ACCEPT	Summary: Direct evidence from Zoncu et al. (2011) showing the V-ATPase (specifically the V1 domain including subunit D) is required for mTORC1 activation in response to amino acids. The V1 D subunit directly contacts the Ragulator complex, and amino acids regulate this interaction. Reason: The V-ATPase's role in amino acid sensing for mTORC1 is a genuine secondary function with direct experimental evidence. Subunit D specifically interacts with Ragulator p18 and p14 in vitro. This is well-supported functional biology beyond simple proton pumping. Supporting Evidence: PMID:22053050 the v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome. In a cell-free system, ATP hydrolysis by the v-ATPase was necessary for amino acids to regulate the v-ATPase-Ragulator interaction and promote mTORC1 translocation. PMID:22053050 the V1 component D with p18 and, to a lesser degree, with p14 (Fig. 3D). No direct interactions were detected between the Rag GTPases and purified v-ATPase subunits
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: The V-ATPase contributes to GEF activator activity in the context of Ragulator-mediated Rag GTPase nucleotide exchange during amino acid signaling to mTORC1. The mechanistic link is that V-ATPase activity (ATP hydrolysis-driven rotation) is required to activate Ragulator as a GEF activator complex. Reason: This annotation reflects a genuine but secondary function of the V-ATPase complex in mTORC1 signaling. It is mechanistically supported but is not the primary proton-pump function of the complex. Supporting Evidence: PMID:22053050 amino acids activate the Rag guanosine triphosphatases (GTPases), which promote the translocation of mTORC1 to the lysosomal surface, the site of mTORC1 activation. We found that the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1.
GO:0005765 lysosomal membrane	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	ACCEPT	Summary: Direct experimental evidence from the Zoncu et al. (2011) study shows the V-ATPase is active at the lysosomal membrane for both proton pumping and amino acid-sensitive mTORC1 signaling. Reason: Lysosomal membrane is the primary site of V-ATPase function, and this IDA annotation from a key mechanistic study is well-supported. Supporting Evidence: PMID:22053050 the v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome.
GO:0046611 lysosomal proton-transporting V-type ATPase complex	IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me...	ACCEPT	Summary: Direct evidence from the Zoncu et al. (2011) study showing the V-ATPase complex on lysosomes; subunit D is part of this complex. Reason: Well-supported by both the amino acid sensing study (PMID:22053050) and the structural data (PMID:33065002). Supporting Evidence: PMID:22053050 the v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome.
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: The V-ATPase is required for positive regulation of mTORC1 signaling by amino acids. Subunit D directly contacts Ragulator, and ATP hydrolysis is required for mTORC1 activation. This is a genuine secondary function. Reason: Positive regulation of TORC1 signaling is supported and real but is a secondary function of the V-ATPase complex, not the primary proton-pumping role. Supporting Evidence: PMID:22053050 ATP hydrolysis and the associated rotation of the v-ATPase appear to be essential to relay an amino acid signal from the lysosomal lumen to the Rag GTPases, whereas the capacity of the v-ATPase to set up the lysosomal proton gradient is dispensable.
GO:0005886 plasma membrane	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Immunofluorescence-based annotation. V-ATPase can be targeted to the plasma membrane in specialized cell types for extracellular acidification. Reason: Plasma membrane localization of V-ATPase is real in specialized contexts (osteoclasts, kidney intercalated cells, tumor cells) but is not the primary site of function for this ubiquitously expressed subunit.
GO:0000139 Golgi membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review (Vasanthakumar and Rubinstein 2020). V-ATPase acidifies the Golgi apparatus, and the D subunit is present as part of the complex. Reason: Golgi membrane localization is a well-established aspect of V-ATPase biology; Golgi acidification is required for proper glycosylation and protein trafficking.
GO:0005765 lysosomal membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. Consistent with multiple other lysosomal membrane annotations. Reason: Core localization supported by multiple evidence types.
GO:0005886 plasma membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	KEEP AS NON CORE	Summary: NAS from V-ATPase review. Reason: Plasma membrane localization of V-ATPase is real in specialized contexts but is not the primary site for the ubiquitous D subunit.
GO:0007035 vacuolar acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. Consistent with core V-ATPase function. Reason: Vacuolar acidification is the core biological process of V-ATPase.
GO:0007042 lysosomal lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. Lysosomal lumen acidification is a specific, well-established aspect of V-ATPase function that is more precise than the broader vacuolar acidification term. Reason: Lysosomal lumen acidification is a core function of the V-ATPase.
GO:0007042 lysosomal lumen acidification	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: NAS from the structural study (Wang et al. 2020). Consistent with the established role of V-ATPase in lysosomal acidification. Reason: Supported by extensive V-ATPase biology.
GO:0010008 endosome membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. V-ATPase acidifies endosomes; the D subunit is present as part of the complex. Reason: Endosome membrane is an established location for V-ATPase function in the endocytic pathway.
GO:0016020 membrane	IDA PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	MARK AS OVER ANNOTATED	Summary: IDA from the human V-ATPase structural study (cryo-EM). The D subunit is part of the membrane-associated V-ATPase complex on the cytoplasmic face of membranes. Reason: The generic membrane annotation is subsumed by the more specific lysosomal membrane, Golgi membrane, and endosome membrane annotations.
GO:0033176 proton-transporting V-type ATPase complex	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: NAS from the structural study. Consistent with IDA from PMID:18752060 and IBA annotation. Reason: Well-supported complex membership.
GO:0048388 endosomal lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. Endosomal lumen acidification by V-ATPase is a core function. Reason: Core function of V-ATPase in the endocytic pathway.
GO:0051452 intracellular pH reduction	NAS PMID:32001091 Structure and Roles of V-type ATPases.	MARK AS OVER ANNOTATED	Summary: NAS from V-ATPase review. Intracellular pH reduction is a core outcome of V-ATPase activity. This term is somewhat redundant with the more specific acidification terms. Reason: The intracellular pH reduction term is a less specific way to describe the same function captured by the more precise lysosomal/endosomal/Golgi lumen acidification annotations. Redundant and non-specific.
GO:0061795 Golgi lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. V-ATPase acidifies the Golgi lumen, which is important for glycosylation and protein sorting. Reason: Core function of V-ATPase in Golgi biology.
GO:1902600 proton transmembrane transport	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: NAS from the structural study. Proton transmembrane transport is the core molecular process performed by V-ATPase. Reason: Core biological process of V-ATPase.
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	ISS GO_REF:0000024	ACCEPT	Summary: Ortholog-based annotation placing the D subunit in the V1 domain. Confirmed by human cryo-EM structural data. Reason: The D subunit is a defining structural component of the V1 domain, confirmed by cryo-EM. Supporting Evidence: PMID:33065002 Vesicular- or vacuolar-type adenosine triphosphatases (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.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6799350	KEEP AS NON CORE	Summary: Reactome TAS annotation placing ATP6V1D in specific granule membrane of neutrophils. V-ATPase is present in neutrophil granules. Reason: Neutrophil-specific granule function is a non-core context for this ubiquitous subunit.
GO:0035579 specific granule membrane	TAS Reactome:R-HSA-6799350	KEEP AS NON CORE	Summary: Reactome TAS annotation for V-ATPase in neutrophil specific granule membrane. Reason: Neutrophil-specific context; non-core for this ubiquitous subunit.
GO:0016241 regulation of macroautophagy	NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	MARK AS OVER ANNOTATED	Summary: NAS from a study on lipofuscin and macroautophagy (PMID:22982048). V-ATPase is required for lysosomal acidification, which is necessary for autophagosome-lysosome fusion and degradation. However, this is an indirect effect rather than a specific regulatory function. Reason: Regulation of macroautophagy is an indirect consequence of V-ATPase's role in lysosomal acidification. The annotation overstates the specificity; the core function is lysosomal proton pumping, not macroautophagy regulation per se.
GO:0033176 proton-transporting V-type ATPase complex	IDA PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	ACCEPT	Summary: Direct experimental evidence from Smith et al. (2008) demonstrating that human D subunit co-purifies with V-ATPase complex and directly interacts with central stalk components. Reason: The most specific experimental evidence for complex membership. Pulldown experiments demonstrated direct D-F and D-d subunit interactions. Supporting Evidence: PMID:18752060 each can pull down the central stalk's D and F subunits from human kidney membrane, and in vitro studies using D and F further showed that the interactions between these proteins and the d subunit is direct.
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	MARK AS OVER ANNOTATED	Summary: High-throughput proteomics detection of ATP6V1D in parotid gland exosomes. V-ATPase subunits can co-purify with exosomes due to membrane association. Reason: Exosome detection by proteomics likely reflects membrane co-purification rather than a specific function of subunit D in exosomes. This is a non-core, likely artifactual localization for a primarily lysosomal/endosomal subunit.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	Summary: High-throughput proteomics detection in urinary exosomes. Same reasoning as the parotid gland exosome annotation. Reason: Urinary exosome proteomics detection likely reflects lysosomal membrane co-purification; not a specific function.
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	ACCEPT	Summary: Lysosomal membrane proteomics study detected ATP6V1D, confirming its lysosomal membrane localization. Reason: This direct proteomics evidence for lysosomal membrane localization is consistent with the established biology of V-ATPase.
GO:0061512 protein localization to cilium	IMP PMID:21844891 A SNX10/V-ATPase pathway regulates ciliogenesis in vitro and...	KEEP AS NON CORE	Summary: The V-ATPase (including subunit D via SNX10 interaction) is required for proper localization of proteins to the cilium. V-ATPase knockout disrupts Rab8a ciliary trafficking. Reason: This is a genuine secondary function of the V-ATPase involving subunit D, but it is not the core lysosomal acidification function. Supporting Evidence: PMID:21844891 SNX10 and V-ATPase regulate the ciliary trafficking of Rab8a, which is a critical regulator of ciliary membrane extension.
GO:0005515 protein binding	IPI PMID:21844891 A SNX10/V-ATPase pathway regulates ciliogenesis in vitro and...	MARK AS OVER ANNOTATED	Summary: The interaction detected in PMID:21844891 is the specific SNX10-V-ATPase interaction; however, the annotation is recorded as generic protein binding rather than the informative SNX10 interaction. Reason: Protein binding is uninformative; the underlying interaction with SNX10 is more informative. The generic protein binding term should be replaced if a more specific term exists. As no specific SNX10-binding GO term exists, this is best flagged as over-annotated.
GO:0005813 centrosome	IDA PMID:21844891 A SNX10/V-ATPase pathway regulates ciliogenesis in vitro and...	KEEP AS NON CORE	Summary: Direct experimental evidence (IDA) showing ATP6V1D colocalizes with centrosome marker proteins, mediated by SNX10 interaction that targets V-ATPase to the centrosome. Reason: Centrosome colocalization is experimentally supported but is a secondary ciliogenesis-related function. Supporting Evidence: PMID:21844891 SNX10 interacts with V-ATPase complex and targets it to the centrosome where ciliogenesis is initiated.
GO:0005929 cilium	IDA PMID:21844891 A SNX10/V-ATPase pathway regulates ciliogenesis in vitro and...	KEEP AS NON CORE	Summary: Direct evidence that V-ATPase (including D subunit) colocalizes with cilium. Reason: Secondary ciliogenesis function.
GO:0060271 cilium assembly	IMP PMID:21844891 A SNX10/V-ATPase pathway regulates ciliogenesis in vitro and...	KEEP AS NON CORE	Summary: V-ATPase loss-of-function (through V-ATPase subunit knockdown including components targeting D subunit's complex) impairs cilium assembly in vitro and in vivo. Reason: Cilium assembly is a genuine secondary function of the V-ATPase complex, supported by IMP evidence, but is not the primary lysosomal acidification role. Supporting Evidence: PMID:21844891 V-ATPase regulates ciliogenesis in vitro and in vivo and does so synergistically with SNX10.
GO:0005829 cytosol	TAS Reactome:R-HSA-1222516	KEEP AS NON CORE	Summary: Reactome TAS annotation placing ATP6V1D in cytosol, consistent with the V1 domain being a peripheral complex on the cytoplasmic face of membranes. Reason: The V1 peripheral sector, including subunit D, is present in the cytosol as a soluble complex during regulated disassembly from V0.
GO:0005829 cytosol	TAS Reactome:R-HSA-5252133	KEEP AS NON CORE	Summary: Additional Reactome TAS annotation for cytosol localization. Reason: Same reasoning as above; the V1 domain can exist in cytosol.
GO:0005829 cytosol	TAS Reactome:R-HSA-74723	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent with V1 domain biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-917841	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent with V1 domain biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9639286	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol in RRAG-related pathway context. Reason: V-ATPase participates in mTORC1 signaling on lysosomal surface, with V1 components accessible from cytosol.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640167	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640168	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640175	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640195	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9645598	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9645608	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9646468	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005515 protein binding	IPI PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	MARK AS OVER ANNOTATED	Summary: The IPI protein binding annotation from PMID:18752060 reflects specific interactions of subunit D with the V0 d subunit and with subunit F, which are mechanistically important. However, the generic protein binding term is less informative than the established subunit interactions. Reason: The specific interactions (D-F central stalk; D-d1/d2 rotor junction) are more meaningful than a generic protein binding annotation. No specific binding term exists for the D-F or D-d interactions, but protein binding is uninformative here.
GO:0016020 membrane	IDA PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	MARK AS OVER ANNOTATED	Summary: IDA from Smith et al. (2008) showing D subunit in membrane preparations. The D subunit is a peripheral membrane protein on the cytoplasmic face. Reason: The generic membrane annotation is subsumed by the more specific lysosomal membrane and other organelle membrane annotations.

Core Functions

Central rotor component of the V1 sector of the vacuolar-type H+-ATPase (V-ATPase). Subunit D, together with subunit F, forms the central stalk that transmits ATP hydrolysis energy from the catalytic A3B3 hexamer to rotate the V0 proteolipid ring, enabling proton translocation across organelle membranes. Primary role is in acidification of lysosomes, endosomes, and the Golgi apparatus.

Directly Involved In:

lysosomal lumen acidification endosomal lumen acidification Golgi lumen acidification

Cellular Locations:

lysosomal membrane

Supporting Evidence:

PMID:33065002
Vesicular- or vacuolar-type adenosine triphosphatases (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
Energy from this reaction drives the rotation of a central stalk consisting of V1 subunits D and F and this is coupled to rotation of the V0 proteolipid ring made up of c, c′ and c″.

Secondary role in mTORC1 amino acid sensing. The D subunit directly contacts the Ragulator scaffold (p18/p14) on lysosomes, and V-ATPase ATP hydrolysis is required upstream of Rag GTPase activation for mTORC1 translocation to lysosomes in response to amino acids.

Directly Involved In:

positive regulation of TORC1 signaling cellular response to amino acid stimulus

Cellular Locations:

lysosomal membrane

Supporting Evidence:

PMID:22053050
the V1 component D with p18 and, to a lesser degree, with p14 (Fig. 3D). No direct interactions were detected between the Rag GTPases and purified v-ATPase subunits

Secondary role in ciliogenesis. Via interaction with SNX10, the V-ATPase (including subunit D) is targeted to the centrosome and cilium base, where it regulates ciliary trafficking of Rab8a and cilium assembly.

Directly Involved In:

cilium assembly

Cellular Locations:

centrosome

Supporting Evidence:

PMID:21844891
V-ATPase regulates ciliogenesis in vitro and in vivo and does so synergistically with SNX10.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

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

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

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

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

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

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:17897319

Integral and associated lysosomal membrane proteins.

ATP6V1D detected in lysosomal membrane proteomics study.

PMID:18752060

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

Human V-ATPase D subunit directly interacts with d1, d2, and F subunits, forming the central stalk of V1.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

ATP6V1D detected in urinary exosomes by mass spectrometry.

PMID:19199708

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

ATP6V1D detected in parotid gland exosome proteome.

PMID:21844891

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

V-ATPase (including D subunit) interacts with SNX10 and localizes to centrosome and cilium; required for ciliogenesis and ciliary Rab8a trafficking.

PMID:22053050

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

V-ATPase D subunit directly interacts with Ragulator (p18/p14) on lysosomes; ATP hydrolysis by V-ATPase required for amino acid-induced mTORC1 activation.

PMID:22982048

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

V-ATPase (via lysosomal acidification) broadly required for macroautophagy.

PMID:25416956

A proteome-scale map of the human interactome network.

ATP6V1D detected in high-throughput interactome study.

PMID:32001091

Structure and Roles of V-type ATPases.

Comprehensive review of V-ATPase structure, function, and disease relevance.

PMID:32296183

A reference map of the human binary protein interactome.

ATP6V1D detected in binary interactome map.

PMID:33065002

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

Cryo-EM structures of complete human V-ATPase at 2.9 A; D subunit identified as central rotor component with subunit F.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

ATP6V1D detected in proteome-scale interactome study.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

ATP6V1D localization mapped by endogenous tagging.

Reactome:R-HSA-1222516

Intraphagosomal pH is lowered to 5 by V-ATPase

Reactome:R-HSA-5252133

ATP6AP1 binds V-ATPase

Reactome:R-HSA-6799350

Exocytosis of specific granule membrane proteins

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

Suggested Experiments

Experiment: Cryo-EM structure determination of the V-ATPase-Ragulator complex to define the D subunit contact interface with p18 and p14, and to identify amino acid-dependent conformational changes.

Hypothesis: The D subunit directly contacts Ragulator at the lysosomal surface and this interface can be structurally defined.

Type: structural biology

Experiment: Engineer separation-of-function mutations in ATP6V1D that disrupt the Ragulator interaction without affecting V-ATPase proton pumping activity, then test mTORC1 activation in response to amino acids.

Hypothesis: The D-Ragulator contact can be uncoupled from proton pumping by targeted mutations.

Type: mutagenesis and functional assay

Experiment: Time-lapse imaging of fluorescently tagged V-ATPase-SNX10 complex during ciliation initiation; test whether V-ATPase proton-pumping activity or only its structural association with SNX10 is required for ciliogenesis.

Hypothesis: V-ATPase targeting to the centrosome by SNX10 is required for ciliogenesis and occurs during a specific window of ciliation initiation.

Type: live cell imaging and genetic rescue

Deep Research

Falcon

(ATP6V1D-deep-research-falcon.md)

Comprehensive Research Report: ATP6V1D (V-type Proton ATPase Subunit D) Falcon

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Comprehensive Research Report: ATP6V1D (V-type Proton ATPase Subunit D)

Gene Identity and Verification

ATP6V1D (UniProt Q9Y5K8) encodes the D subunit of the vacuolar-type H+-ATPase (V-ATPase) in Homo sapiens, belonging to the V-ATPase D subunit family (wang2020structuresofa pages 1-3). This protein is a core component of the cytosolic V1 domain of V-ATPase, a multi-subunit rotary proton pump essential for cellular pH homeostasis and numerous physiological processes (eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 1-2).

Structural Organization and Composition

The V-ATPase is a large multi-protein complex (~830 kDa) composed of two functional domains: the cytosolic V1 domain responsible for ATP hydrolysis and the membrane-embedded V0 domain that translocates protons (wang2020structuresofa pages 1-3, abbas2020structureofvatpase pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5). The human V1 domain comprises three copies each of subunits A, B, E, and G, plus single copies of subunits C, D, F, and H (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5).

ATP6V1D, together with subunit F, forms the central stalk (DF stalk) of the V-ATPase complex (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5). This central stalk connects the catalytic A3B3 hexamer head in the V1 domain to the membrane-embedded c-ring of the V0 domain (wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7). Structural studies using cryo-electron microscopy at near-atomic resolution have revealed that the D subunit adopts a cone-like structure, with its concave surface accepting the lower part of the DF central stalk in a shape-complementary manner (wang2020structuresofa pages 3-5). The DF stalk inserts into the middle hole of the A3B3 hexamer, thereby forming the rotor apparatus of this rotary motor enzyme (wang2020structuresofa pages 3-5).

Primary Function and Catalytic Mechanism

ATP6V1D plays a critical mechanical coupling role in V-ATPase function rather than serving as a catalytic site itself. While ATP hydrolysis occurs in the A/B catalytic hexamer of the V1 domain, ATP6V1D is essential for transmitting the torque generated by ATP hydrolysis to drive proton translocation (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5, chen2024vatpaseincancer pages 3-5).

The catalytic mechanism operates through a rotary cycle: ATP binding and hydrolysis in the A3B3 head trigger conformational changes that lead to tilting and twisting of the A3B3 hexamer relative to the central axis (wang2020structuresofa pages 3-5). This conformational precession drives rotation of the central DF stalk, which in turn rotates the c-ring of the V0 domain against the stationary subunit a (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5). As the c-ring rotates, conserved glutamate residues on the c, c', and c'' subunits undergo cycles of protonation and deprotonation at distinct half-channels in subunit a, resulting in net proton translocation across the membrane (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7).

The ATP:proton stoichiometry for the mammalian brain V-ATPase has been defined as 3:10, meaning three ATP molecules are hydrolyzed for every 10 protons translocated (abbas2020structureofvatpase pages 1-2). This coupling is absolutely dependent on the intact DF stalk containing ATP6V1D, as the subunit forms extensive interactions with both the central stalk F subunit and the c-ring elements (wang2020structuresofa pages 3-5). Disruption of the DF stalk would prevent coupling of ATP hydrolysis to proton transport, rendering the enzyme non-functional (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5).

Recent studies have revealed that V-ATPases do not pump continuously but instead stochastically switch between three ultralong-lived modes: proton-pumping, inactive, and proton-leaky (kosmidis2022regulationofthe pages 1-3). ATP regulates V-ATPase activity primarily through modulating the switching probability of the proton-pumping mode rather than directly controlling the intrinsic pumping rate (kosmidis2022regulationofthe pages 1-3). This mode-switching behavior has important implications for organelle acidification dynamics.

Substrate Specificity

At the holoenzyme level, the energy substrate is ATP, and the transported species is H+ (protons) (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 1-2). ATP6V1D itself does not directly bind ATP; instead, it participates in utilizing the mechanical energy derived from ATP hydrolysis by the A3B3 head to drive proton movement (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5, chen2024vatpaseincancer pages 3-5). The V-ATPase pumps protons into organelle lumens, creating an acidic pH (typically pH 4.5-5.5 in lysosomes and late endosomes) or, in specialized cells, transports protons to the extracellular space (song2020theemergingroles pages 1-2, sava2024reversibleassemblyand pages 1-2).

Subcellular Localization

ATP6V1D is present in V-ATPase complexes distributed across multiple membrane compartments throughout the cell. The primary sites of localization include:

Lysosomes and Late Endosomes: These represent the major sites of V-ATPase activity, where the enzyme maintains the highly acidic pH (pH ~4.5-5.0) required for optimal lysosomal hydrolase activity (song2020theemergingroles pages 1-2, sava2024reversibleassemblyand pages 1-2). The acidification is essential for protein degradation, lipid metabolism, and cellular catabolism (song2020theemergingroles pages 1-2, ratto2022directcontrolof pages 1-2).

Early Endosomes and Endolysosomes: V-ATPase acidifies early endosomes (pH ~6.0-6.5) and hybrid endolysosomes formed during endocytic trafficking (sava2024reversibleassemblyand pages 1-2). This acidification is critical for receptor-ligand dissociation, cargo sorting, and vesicle maturation along the endocytic pathway (song2020theemergingroles pages 1-2).

Golgi Apparatus: V-ATPase localizes to the trans-Golgi network where it maintains an acidic pH (pH ~6.0-6.5) necessary for post-translational modifications, including glycosylation and protein sorting (song2020theemergingroles pages 1-2, chu2021thevatpasea3 pages 1-2). Different isoforms of the V0 a subunit target V-ATPase to specific Golgi sub-compartments (wang2020structuresofa pages 1-3).

Secretory and Synaptic Vesicles: In neurons, V-ATPase containing ATP6V1D is essential for acidifying synaptic vesicles (abbas2020structureofvatpase pages 1-2, kosmidis2022regulationofthe pages 1-3). The proton gradient established by V-ATPase energizes the secondary active transport of neurotransmitters into synaptic vesicles via specific neurotransmitter transporters (abbas2020structureofvatpase pages 1-2, kosmidis2022regulationofthe pages 1-3). Approximately one V-ATPase molecule per synaptic vesicle is sufficient to establish the electrochemical gradient needed for neurotransmitter loading (kosmidis2022regulationofthe pages 1-3).

Autophagosomes and Autolysosomes: V-ATPase acidifies autolysosomes formed during macroautophagy, enabling the degradation of cytoplasmic contents delivered via the autophagy pathway (song2020theemergingroles pages 1-2, sava2024reversibleassemblyand pages 1-2).

Plasma Membrane (Specialized Cells): In certain specialized cell types, V-ATPase is recruited to the plasma membrane to acidify the extracellular environment. This occurs in osteoclasts (for bone resorption), kidney intercalated cells (for urinary acidification), and some cancer cells (for creating an acidic tumor microenvironment) (eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 1-2, chu2021thevatpasea3 pages 1-2).

Dynamic Localization: The V1 domain containing ATP6V1D exhibits dynamic localization regulated by reversible assembly and disassembly. When V-ATPase is inactive or disassembled, the V1 subcomplex resides in the cytosol (sava2024reversibleassemblyand pages 1-2, ratto2022directcontrolof pages 1-2). Upon activation signals, V1 domains are recruited to membrane-localized V0 complexes to form active holoenzymes (sava2024reversibleassemblyand pages 1-2, ratto2022directcontrolof pages 1-2). This reversible assembly is regulated by nutrient availability, mTORC1 activity, and cellular energy status (sava2024reversibleassemblyand pages 1-2, ratto2022directcontrolof pages 1-2).

Biochemical and Signaling Pathways

ATP6V1D-containing V-ATPase participates in multiple signaling and biochemical pathways beyond its canonical proton-pumping function:

mTORC1 Nutrient Sensing Pathway

V-ATPase serves as a critical scaffold for mechanistic target of rapamycin complex 1 (mTORC1) assembly at lysosomal membranes (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 3-5, ratto2022directcontrolof pages 1-2). In amino acid-replete conditions, amino acids activate mTORC1 at the lysosomal surface through the Ragulator complex, which interacts directly with V-ATPase subunits (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 3-5). mTORC1, in turn, regulates V-ATPase assembly state: when mTORC1 is active, V1 domains (including ATP6V1D) are stabilized in the cytosol by association with the chaperonin TRiC, resulting in most lysosomes displaying low catabolic activity (ratto2022directcontrolof pages 1-2). When mTORC1 activity declines (e.g., during amino acid starvation), V1 domains move to membrane-integral V0 domains at lysosomes to assemble active proton pumps, triggering lysosomal acidification and increased proteolysis (ratto2022directcontrolof pages 1-2). This mechanism allows cells to rapidly mobilize the latent catabolic capacity of lysosomes in response to nutrient availability (ratto2022directcontrolof pages 1-2).

AMPK Activation and Energy Sensing

V-ATPase participates in AMP-activated protein kinase (AMPK) activation through a lysosomal glucose-sensing pathway (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 3-5). The interaction between V-ATPase and the AXIN/LKB1-AMPK complex is enhanced under conditions of nutrient scarcity or energy stress, leading to AMPK activation and mTORC1 inhibition (chen2024vatpaseincancer pages 3-5). This metabolic switch prompts cells to transition from anabolic to catabolic metabolism (chen2024vatpaseincancer pages 3-5).

Autophagy and Lysosomal Catabolism

V-ATPase-mediated lysosomal acidification is absolutely essential for autophagy (song2020theemergingroles pages 1-2, sava2024reversibleassemblyand pages 1-2). The acidic pH activates lysosomal hydrolases required for degrading autophagic cargo delivered via autophagosome-lysosome fusion (song2020theemergingroles pages 1-2). Furthermore, V-ATPase activity influences autophagosome-lysosome fusion events and the subsequent reformation of lysosomes from hybrid autolysosomes (sava2024reversibleassemblyand pages 1-2). Recent work demonstrates that V-ATPase assembly and disassembly plays a key role in regulating the lysosome regeneration cycle in continuously fed cells, with net recruitment of V1 subunits during endolysosome formation and loss during lysosome reformation (sava2024reversibleassemblyand pages 1-2).

Endocytic Pathway Regulation

V-ATPase-driven acidification of endosomes is crucial for multiple steps in the endocytic pathway (song2020theemergingroles pages 1-2). The progressive acidification from early endosomes (pH ~6.0-6.5) to late endosomes/lysosomes (pH ~4.5-5.0) facilitates receptor-ligand dissociation, cargo sorting, vesicle maturation, and ultimately delivery to lysosomes for degradation (song2020theemergingroles pages 1-2, sava2024reversibleassemblyand pages 1-2). The acidic pH also enables the function of pH-dependent enzymes involved in membrane trafficking and protein processing (song2020theemergingroles pages 1-2).

Wnt and Notch Signaling

V-ATPase participates in Wnt signaling through its interaction with ATP6AP2 (the prorenin receptor), a V0 domain subunit that in other contexts is involved in the renin-angiotensin system regulating blood pressure (abbas2020structureofvatpase pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5). V-ATPase activity is also required for proper Notch signaling, likely through pH-dependent proteolytic processing events (eaton2021theh+atpase(vatpase) pages 1-5).

Neurotransmitter Loading in Synaptic Vesicles

In neurons, the electrochemical proton gradient established by V-ATPase containing ATP6V1D is the driving force for neurotransmitter uptake into synaptic vesicles (abbas2020structureofvatpase pages 1-2, kosmidis2022regulationofthe pages 1-3). Neurotransmitter transporters use the proton gradient to concentrate neurotransmitters inside synaptic vesicles against their concentration gradients, a process essential for neurotransmission (abbas2020structureofvatpase pages 1-2, kosmidis2022regulationofthe pages 1-3). Studies of single V-ATPase molecules in single synaptic vesicles have revealed that the enzyme switches between proton-pumping, inactive, and proton-leaky modes, which may introduce stochasticity in neurotransmitter loading (kosmidis2022regulationofthe pages 1-3).

Recent Developments (2023-2024)

Recent high-resolution structural studies have provided unprecedented insights into V-ATPase assembly and regulation. Cryo-EM structures of human V-ATPase at 2.9-3.1 Å resolution have defined all protein subunits with associated N-linked glycans and identified glycolipids and phospholipids as integral components (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5). These studies revealed that ATP6AP1 serves as a structural hub for V0 complex assembly by connecting to multiple V0 subunits and phospholipids (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5).

Work on V-ATPase assembly factors has elucidated how the V0 complex is assembled in the endoplasmic reticulum before being transported to the Golgi where V1 binds (wang2023structuralbasisof pages 1-2). The assembly factors Vma12p, Vma21p, and Vma22p (mammalian homologs TMEM199, VMA21, and CCDC115) function in V-ATPase assembly and quality control, ensuring that only properly assembled V0 leaves the ER and preventing premature proton pumping (wang2023structuralbasisof pages 1-2).

Studies on V-ATPase regulation have demonstrated that reversible V1-V0 assembly/disassembly is a key mechanism for controlling enzyme activity in response to cellular conditions (sava2024reversibleassemblyand pages 1-2, ratto2022directcontrolof pages 1-2). In continuously fed mammalian cells, V-ATPase assembly and disassembly occurs during the lysosome regeneration cycle, with a dynamic equilibrium and rapid exchange between cytosolic and membrane-bound pools of V1 subunits (sava2024reversibleassemblyand pages 1-2). This regulation differs from that in cells subject to amino acid depletion/refeeding and does not require changes in mTORC1 signaling in the continuously fed state (sava2024reversibleassemblyand pages 1-2).

Research on mode-switching has revealed that mammalian brain V-ATPase exhibits ultraslow stochastic switching between proton-pumping, inactive, and proton-leaky modes (kosmidis2022regulationofthe pages 1-3). This mode-switching is regulated by ATP concentration and electrochemical proton gradients, with important implications for vesicle acidification dynamics and neurotransmitter loading (kosmidis2022regulationofthe pages 1-3).

Clinical and Pathological Relevance

Dysfunction of V-ATPase is implicated in numerous diseases. Complete loss of V-ATPase activity is embryonic lethal in higher organisms, highlighting its essential cellular functions (eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 1-2). Partial loss of V-ATPase function is associated with neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), renal tubular acidosis, osteopetrosis, and cancer (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 1-2, chu2021thevatpasea3 pages 1-2).

In cancer, increased V-ATPase expression and relocalization to the plasma membrane contributes to tumor cell proliferation and metastasis by maintaining an alkaline intracellular pH and creating an acidic extracellular environment (chen2024vatpaseincancer pages 1-3, chen2024vatpaseincancer pages 3-5, song2020theemergingroles pages 1-2). In neurodegenerative diseases, impaired V-ATPase function leads to defective lysosomal acidification, accumulation of protein aggregates, and neuronal cell death (song2020theemergingroles pages 1-2). In osteopetrosis, mutations in the a3 isoform of V-ATPase (which pairs with the same ATP6V1D in the V1 domain) impair osteoclast function and bone resorption (chu2021thevatpasea3 pages 1-2).

Summary

Feature	ATP6V1D summary
Protein name	V-type proton ATPase subunit D; a core subunit of the vacuolar-type H+-ATPase (V-ATPase) V1 sector in humans (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5)
Gene symbol	ATP6V1D (human V1-domain D subunit gene matching UniProt Q9Y5K8)
UniProt ID	Q9Y5K8
Organism	Homo sapiens
Protein family / domain context	Belongs to the V-ATPase D subunit family; structurally part of the DF central stalk in the soluble V1 domain, together with subunit F (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5)
Protein complex	Subunit of the multisubunit V-ATPase holoenzyme, composed of a cytosolic V1 ATP-hydrolysis domain and membrane-embedded V0 proton-translocation domain. In mammalian/human V1, the complex contains A_3B_3E_3G_3 plus single-copy C, D, F, and H; D is one of the single-copy rotor-associated subunits (wang2020structuresofa pages 1-3, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 3-5)
Structural position	ATP6V1D forms the main shaft of the central rotor stalk and is physically connected to subunit F in V1 and to subunit d/c-ring elements of V0, thereby linking the catalytic head to the proton-translocating rotor apparatus (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7)
Primary function	Mechanical coupling subunit rather than the catalytic ATP-binding site itself: ATP6V1D transmits torque generated by ATP hydrolysis in the A_3B_3 catalytic head to the V0 rotor, enabling proton pumping across organellar or plasma membranes (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5, kosmidis2022regulationofthe pages 1-3)
Immediate biochemical role	Converts conformational changes generated in the catalytic V1 head into rotary motion of the central stalk/rotor. This is essential for coupling ATP hydrolysis to proton translocation and for preventing uncoupled energy loss (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7)
Catalytic activity	ATP6V1D itself is not the ATP hydrolytic active site; ATP hydrolysis occurs in the A/B catalytic hexamer of V1. ATP6V1D is required for coupling that hydrolysis to the rotary mechanism and thus to proton transport (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5, chen2024vatpaseincancer pages 3-5)
Substrate / transported species	At the holoenzyme level, the energy substrate is ATP and the transported species is H+ (protons). ATP6V1D participates in use of ATP-derived mechanical energy to drive H+ movement into organelle lumens or, in specialized cells, to the extracellular space (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 1-2)
Catalytic / transport mechanism	ATP hydrolysis in the A_3B_3 head drives conformational cycling and precession/rotation of the DF stalk; this rotates the c-ring of V0 against subunit a, allowing protonation/deprotonation cycles on rotor proteolipids and net H+ translocation. Thus ATP6V1D is a core rotor element in the chemo-mechanical coupling pathway (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5, chen2024vatpaseincancer pages 3-5, wang2020structuresofa pages 5-7)
Coupling role of the DF stalk	The DF stalk is explicitly described as connecting the A_3B_3 head in V1 to the V0 complex for torque transmission; ATP6V1D is the D component of this DF stalk and therefore central to rotor function (wang2020structuresofa pages 3-5)
Functional consequence of activity	Drives acidification required for lysosomal hydrolase activity, endocytic trafficking, Golgi/secretory pathway function, synaptic vesicle loading, autophagic cargo degradation, and specialized extracellular acidification (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 1-2)
Subcellular localization of ATP6V1D-containing complexes	Cytosolic-facing V1 subcomplex on lysosomes, late endosomes, early endosomes, trans-Golgi network/Golgi, endolysosomes, autolysosomes, secretory vesicles, and synaptic vesicles; in specialized cells, assembled V-ATPase is also found at the plasma membrane (for example in osteoclasts and kidney intercalated cells) (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 1-2, sava2024reversibleassemblyand pages 1-2)
Dynamic localization / regulation	V1 subunits, including ATP6V1D, can be cytosolic when disassembled and are recruited to membrane V0 sectors during assembly of active proton pumps; mTORC1 status and organelle state regulate this assembly/disassembly behavior in mammalian cells (sava2024reversibleassemblyand pages 1-2, ratto2022directcontrolof pages 1-2)
Key signaling / pathway associations	mTORC1 nutrient sensing and lysosomal signaling; AMPK-related lysosomal nutrient/energy sensing; autophagy and lysosome catabolism; endocytic maturation and receptor/cargo sorting; Wnt and Notch-associated V-ATPase signaling functions; neurotransmitter loading in synaptic vesicles via proton-gradient-dependent uptake (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 3-5, song2020theemergingroles pages 1-2, ratto2022directcontrolof pages 1-2)
Recent mechanistic insights relevant to ATP6V1D	Recent work emphasizes that V-ATPase function is controlled by reversible V1-V0 assembly, nutrient-sensitive recruitment of V1 to lysosomes, and stochastic mode switching of proton-pumping activity; these findings are directly relevant to ATP6V1D because D is an essential V1 rotor/coupling subunit (kosmidis2022regulationofthe pages 1-3, sava2024reversibleassemblyand pages 1-2, ratto2022directcontrolof pages 1-2)
Real-world biological relevance	Dysfunction of V-ATPase impairs organelle acidification and is implicated broadly in neurodegeneration, cancer, renal acid-base disorders, osteoclast-mediated bone resorption, and defective lysosomal catabolism; ATP6V1D contributes to these processes through its indispensable role in holoenzyme coupling rather than by isoform-specific targeting (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 1-2)

Table: This table summarizes the verified identity, structure, function, localization, and pathway context of human ATP6V1D. It is especially useful for showing that ATP6V1D is a DF central-stalk rotor subunit that couples ATP hydrolysis in V1 to proton transport by V0.

ATP6V1D encodes a structurally and functionally essential component of the V-ATPase proton pump. As part of the central rotor stalk (DF stalk), ATP6V1D couples ATP hydrolysis in the cytosolic V1 domain to proton translocation through the membrane-embedded V0 domain (wang2023structuralbasisof pages 1-2, wang2020structuresofa pages 3-5). This coupling function is critical for establishing the pH gradients required for lysosomal degradation, endocytic trafficking, Golgi processing, autophagy, and in specialized cells, extracellular acidification (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 1-2). Beyond its canonical proton-pumping role, ATP6V1D-containing V-ATPase serves as a signaling hub for nutrient sensing through mTORC1 and AMPK pathways, highlighting its central importance in cellular metabolism and homeostasis (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 3-5, ratto2022directcontrolof pages 1-2). Recent structural and functional studies continue to reveal sophisticated regulatory mechanisms controlling V-ATPase activity, including reversible assembly/disassembly and mode-switching, underscoring the complexity of this essential molecular machine (kosmidis2022regulationofthe pages 1-3, sava2024reversibleassemblyand pages 1-2, ratto2022directcontrolof pages 1-2).

References

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(eaton2021theh+atpase(vatpase) pages 1-5): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h⁺-atpase (v-atpase): from proton pump to signaling complex in health and disease. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.
(song2020theemergingroles pages 1-2): Qiaoyun Song, Bo Meng, Haidong Xu, and Zixu Mao. The emerging roles of vacuolar-type atpase-dependent lysosomal acidification in neurodegenerative diseases. Translational Neurodegeneration, May 2020. URL: https://doi.org/10.1186/s40035-020-00196-0, doi:10.1186/s40035-020-00196-0. This article has 255 citations and is from a domain leading peer-reviewed journal.
(abbas2020structureofvatpase pages 1-2): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(wang2020structuresofa pages 3-5): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(wang2023structuralbasisof pages 1-2): Hanlin Wang, Stephanie A. Bueler, and John L. Rubinstein. Structural basis of v-atpase v _o region assembly by vma12p, 21p, and 22p. Proceedings of the National Academy of Sciences, Feb 2023. URL: https://doi.org/10.1073/pnas.2217181120, doi:10.1073/pnas.2217181120. This article has 18 citations and is from a highest quality peer-reviewed journal.
(wang2020structuresofa pages 5-7): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(chen2024vatpaseincancer pages 3-5): Tingting Chen, Xiaotan Lin, Shuo Lu, and Bo Li. V-atpase in cancer: mechanistic insights and therapeutic potentials. Cell Communication and Signaling : CCS, Dec 2024. URL: https://doi.org/10.1186/s12964-024-01998-9, doi:10.1186/s12964-024-01998-9. This article has 25 citations.
(kosmidis2022regulationofthe pages 1-3): Eleftherios Kosmidis, Christopher G. Shuttle, Julia Preobraschenski, Marcelo Ganzella, Peter J. Johnson, Salome Veshaguri, Jesper Holmkvist, Mads P. Møller, Orestis Marantos, Frank Marcoline, Michael Grabe, Jesper L. Pedersen, Reinhard Jahn, and Dimitrios Stamou. Regulation of the mammalian-brain v-atpase through ultraslow mode-switching. Nature, 611(7937):827-834, Nov 2022. URL: https://doi.org/10.1038/s41586-022-05472-9, doi:10.1038/s41586-022-05472-9. This article has 39 citations and is from a highest quality peer-reviewed journal.
(sava2024reversibleassemblyand pages 1-2): Ioana Sava, Luther J. Davis, Sally R. Gray, Nicholas A. Bright, and J. Paul Luzio. Reversible assembly and disassembly of v-atpase during the lysosome regeneration cycle. Molecular Biology of the Cell, May 2024. URL: https://doi.org/10.1091/mbc.e23-08-0322, doi:10.1091/mbc.e23-08-0322. This article has 24 citations and is from a domain leading peer-reviewed journal.
(ratto2022directcontrolof pages 1-2): Edoardo Ratto, S. Roy Chowdhury, Nora S. Siefert, Martin Schneider, Marten Wittmann, Dominic Helm, and Wilhelm Palm. Direct control of lysosomal catabolic activity by mtorc1 through regulation of v-atpase assembly. Nature Communications, Aug 2022. URL: https://doi.org/10.1038/s41467-022-32515-6, doi:10.1038/s41467-022-32515-6. This article has 179 citations and is from a highest quality peer-reviewed journal.
(chu2021thevatpasea3 pages 1-2): Anh Chu, Ralph A. Zirngibl, and Morris F. Manolson. The v-atpase a3 subunit: structure, function and therapeutic potential of an essential biomolecule in osteoclastic bone resorption. International Journal of Molecular Sciences, 22:6934, Jun 2021. URL: https://doi.org/10.3390/ijms22136934, doi:10.3390/ijms22136934. This article has 37 citations.
(chen2024vatpaseincancer pages 1-3): Tingting Chen, Xiaotan Lin, Shuo Lu, and Bo Li. V-atpase in cancer: mechanistic insights and therapeutic potentials. Cell Communication and Signaling : CCS, Dec 2024. URL: https://doi.org/10.1186/s12964-024-01998-9, doi:10.1186/s12964-024-01998-9. This article has 25 citations.

📚 Additional Documentation

Notes

(ATP6V1D-notes.md)

ATP6V1D Research Notes

Gene Identity

UniProt: Q9Y5K8 (VATD_HUMAN)
Gene symbol: ATP6V1D (also known as ATP6M, VATD)
Protein: V-type proton ATPase subunit D; 247 amino acids, ~28 kDa

Core V-ATPase Biology

ATP6V1D encodes the D subunit of the V1 peripheral sector of the vacuolar-type H+-ATPase (V-ATPase). This is a ubiquitously expressed, evolutionarily conserved subunit that forms part of the central rotor of the V1 domain.

PMID:18752060

The cryo-EM structure of the complete human V-ATPase (Wang et al. 2020) places subunit D as one of two central rotor subunits (D and F) that transmit ATP hydrolysis energy from the catalytic head to the V0 ring.

PMID:33065002

Smith et al. (2008) directly demonstrated that the human D subunit physically interacts with the V0 d subunit (d1 and d2) and with subunit F, establishing that subunit D forms part of the central stalk in man:

PMID:18752060

Role in mTORC1 Amino Acid Sensing

Zoncu et al. (2011) demonstrated that the V-ATPase is required for mTORC1 activation by amino acids through an inside-out mechanism. The V1 subunit D directly contacts the Ragulator complex:

PMID:22053050

The V-ATPase acts upstream of the Rag GTPases and its ATP hydrolysis (not just the proton gradient) is required for amino acid signaling:

PMID:22053050

Subcellular Localization

Primary: lysosomal membrane (as part of V-ATPase complex on lysosomes)
Also documented on: Golgi, endosomes, plasma membrane (in some cell types), clathrin-coated vesicles
Notably, ATP6V1D also localizes to centrosome and cilia base (via SNX10 interaction)

PMID:21844891
PMID:21844891

Ciliogenesis Role

ATP6V1D (with the whole V-ATPase complex) was found required for ciliogenesis in vitro. Its interaction with sorting nexin SNX10 targets V-ATPase to the centrosome.

PMID:21844891

This is a secondary function relative to the primary proton-pump/acidification role. The ciliogenesis role appears to operate through V-ATPase's vesicular trafficking/acidification function rather than being independent.

V-ATPase Structure (Human)

PMID:33065002

Regulation of Macroautophagy

V-ATPase is broadly required for lysosomal function and autophagy. The annotation to "regulation of macroautophagy" (PMID:22982048) is an indirect inference; direct evidence for a specific regulatory function of subunit D in macroautophagy control, beyond its role in lysosomal acidification, is lacking.

[PMID:22982048 - abstract only; NAS annotation from ParkinsonsUK-UCL - indirect/downstream effect of lysosomal acidification function]

Curation Notes

The annotations to guanyl nucleotide exchange factor activator activity (GO:0160124) and positive regulation of TORC1 signaling (GO:1904263) from PMID:22053050 reflect a genuine secondary function: the V-ATPase complex (specifically V1-Ragulator interaction involving subunit D) acts upstream of Rag GTPase activation in the mTORC1 amino acid sensing pathway.
The cytosol annotations (multiple Reactome TAS) are consistent with the fact that the V1 domain is a peripheral complex on the cytoplasmic face of membranes.
Extracellular exosome (HDA) annotations from proteomics studies are technically valid observations but represent non-functional localization data for a structural component that may co-purify with exosome membrane fragments.
Cilium and centrosome annotations (IDA from PMID:21844891) are supported but represent a secondary function.

Falcon deep research synthesis (2026-06-21)

Falcon deep research has now completed (file:human/ATP6V1D/ATP6V1D-deep-research-falcon.md,
21 citations). It corroborates the central-rotor core above and adds general
V-ATPase regulatory detail; no change to annotation calls.

Core confirmed. D is one of the two central-rotor (central-stalk)
subunits (with F); it transmits torque from A3B3 ATP hydrolysis to the V0
proteolipid ring, coupling chemistry to proton translocation. Ubiquitous,
essential, not catalytic. No change to the rotor/proton-transport-coupling calls.
Reversible-assembly regulation (Sava 2024; Ratto 2022). In continuously fed
mammalian cells, V1–V0 assembly/disassembly occurs during the lysosome
regeneration cycle with rapid cytosolic↔membrane exchange of V1 subunits,
distinct from amino-acid-depletion control and not requiring mTORC1 changes
in the fed state. Relevant regulatory context for the PN regulation branch.
Mode-switching (Kosmidis 2022). Single mammalian-brain V-ATPase stochastically
switches between proton-pumping, inactive, and proton-leaky modes, tuned by ATP
and the electrochemical proton gradient — affecting vesicle-acidification and
neurotransmitter-loading dynamics. Mechanistic context, not a D-specific MF.
Disease. No ATP6V1D-specific Mendelian disease reported; the section is
generic V-ATPase (neurodegeneration, dRTA, osteopetrosis via a3, cancer).
Non-core context.

Net: no change to calls — D is the ubiquitous central-rotor V1 subunit coupling
ATP hydrolysis to proton translocation.

Pn Notes

(ATP6V1D-pn-notes.md)

ATP6V1D PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9Y5K8
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V1D/ATP6V1D-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V1D/ATP6V1D-ai-review.html
Gene notes: present - genes/human/ATP6V1D/ATP6V1D-notes.md
GOA TSV: present - genes/human/ATP6V1D/ATP6V1D-goa.tsv
UniProt record: present - genes/human/ATP6V1D/ATP6V1D-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V1D.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V1D.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

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

AIGR Review Snapshot

Description: ATP6V1D encodes the D subunit (28 kDa) of the V1 peripheral sector of the vacuolar-type H+-ATPase (V-ATPase). Subunit D forms the central rotor of V1 together with subunit F; ATP hydrolysis by the catalytic A3B3 hexamer drives rotation of the D-F stalk, which is mechanically coupled to the V0 proteolipid c-ring to translocate protons across organelle membranes. The human V-ATPase complex is responsible for acidifying lysosomes, endosomes, the Golgi apparatus, and other intracellular compartments, and in specialized cell types for extracellular acidification at the plasma membrane. Beyond proton pumping, the V1 D subunit directly contacts the Ragulator scaffold on lysosomes, and V-ATPase activity is required for amino acid-sensitive mTORC1 activation via an inside-out signaling mechanism. ATP6V1D additionally interacts with SNX10 and localizes to the centrosome and cilium base, where the V-ATPase is required for ciliogenesis. The protein is ubiquitously expressed in human tissues.
Existing/core annotation action counts: ACCEPT: 23; KEEP_AS_NON_CORE: 27; MARK_AS_OVER_ANNOTATED: 13

PN Consistency Summary

Consistency: Consistent and information-rich. Notes ↔ review agree: D = central-rotor subunit (with F), directly contacts Ragulator p18/p14 (PMID:22053050 RESULTS), plus secondary ciliogenesis role via SNX10 (PMID:21844891). PN's mTORC1/nutrient-sensing row is directly substantiated here (GO:0071230 ACCEPT; GO:1904263, GO:0160124 KEEP_AS_NON_CORE). No contradictions.
PN story / NEW pressure: No unmet pressure on PN's stated story. The review goes BEYOND PN with two non-PN roles (ciliogenesis GO:0060271/GO:0061512; centrosome GO:0005813) — these are not PN claims and need no PN action. GO:0007042 already in GOA (dossier: already_in_goa_exact; 2 hits) ACCEPT. GO:0046612 (verified) absent from GOA — defensible more-specific ADD.
Evidence alignment: Divergent sources, convergent conclusion. PN cites review titles; review anchors on D-specific primaries: PMID:18752060 (d-subunit/central stalk, IDA), 22053050 (Zoncu — direct D-Ragulator), 21844891 (SNX10/cilia), 33065002. PN's mTORC1-review evidence is the weaker counterpart of the review's Zoncu primary (which here even resolves the D-p18 contact).
Verdict: Consistent / ADD GO:0046612 (verified) as more-specific CC; review exceeds PN scope (cilia) without conflict. Recommended edits: [MAP] align subtype complex target GO:0033176 → GO:0046611 (lysosomal V-ATPase complex, already ACCEPTed for D).

Full Consistency Review

UniProt: Q9Y5K8 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE (large, mature; ~65 annotations, full core_functions)
PN placement: Autophagy-Lysosome Pathway|...|V1 lysosomal v-ATPase proton pump component (two rows, identical pattern) ; PN-node mapping: subtype=mapped/ok GO:0046612 + GO:0033176; type=mapped/ok GO:0007042; ancestors no_mapping/context_only.
Consistency: Consistent and information-rich. Notes ↔ review agree: D = central-rotor subunit (with F), directly contacts Ragulator p18/p14 (PMID:22053050 RESULTS), plus secondary ciliogenesis role via SNX10 (PMID:21844891). PN's mTORC1/nutrient-sensing row is directly substantiated here (GO:0071230 ACCEPT; GO:1904263, GO:0160124 KEEP_AS_NON_CORE). No contradictions.
PN story / NEW pressure: No unmet pressure on PN's stated story. The review goes BEYOND PN with two non-PN roles (ciliogenesis GO:0060271/GO:0061512; centrosome GO:0005813) — these are not PN claims and need no PN action. GO:0007042 already in GOA (dossier: already_in_goa_exact; 2 hits) ACCEPT. GO:0046612 (verified) absent from GOA — defensible more-specific ADD.
Mapping strategy: D does not change node mapping but, like A, demonstrates the review already carries the more-specific GO:0046611 "lysosomal V-ATPase complex" (IDA, ACCEPT) and GO:0016471 vacuolar complex — so the subtype-complex projection GO:0033176 is broader than what the review supports.
Evidence alignment: Divergent sources, convergent conclusion. PN cites review titles; review anchors on D-specific primaries: PMID:18752060 (d-subunit/central stalk, IDA), 22053050 (Zoncu — direct D-Ragulator), 21844891 (SNX10/cilia), 33065002. PN's mTORC1-review evidence is the weaker counterpart of the review's Zoncu primary (which here even resolves the D-p18 contact).
Verdict: Consistent / ADD GO:0046612 (verified) as more-specific CC; review exceeds PN scope (cilia) without conflict. Recommended edits: [MAP] align subtype complex target GO:0033176 → GO:0046611 (lysosomal V-ATPase complex, already ACCEPTed for D).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/ATP6V1D/ATP6V1D-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V1 lysosomal v-ATPase proton pump component

UniProt: Q9Y5K8
In branches: ALP
Notes: Subunit of the V1 (cytosolic) 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|V1 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0046612 lysosomal proton-transporting V-type ATPase, V1 domain]
  rationale: This PN leaf is restricted to V1-sector lysosomal V-ATPase components. The GO lysosomal V1-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 | V1 lysosomal v-ATPase proton pump component

UniProt: Q9Y5K8
In branches: ALP
Notes: Subunit of the V1 (cytosolic) 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|V1 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0033176 proton-transporting V-type ATPase complex]
  rationale: This PN subtype denotes the V1-sector component of the lysosomal V-ATPase. In the current GO cache, the broader V-type ATPase complex is the safest validated target for this component role.
- [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:0046612 lysosomal proton-transporting V-type ATPase, V1 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|V1 lysosomal v-ATPase proton pump component
GO:0007042 lysosomal lumen acidification | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
GO:0033176 proton-transporting V-type ATPase complex | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V1 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: Q9Y5K8
gene_symbol: ATP6V1D
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ATP6V1D encodes the D subunit (28 kDa) of the V1 peripheral sector of the
  vacuolar-type H+-ATPase (V-ATPase). Subunit D forms the central rotor of V1 together
  with subunit F; ATP hydrolysis by the catalytic A3B3 hexamer drives rotation of the
  D-F stalk, which is mechanically coupled to the V0 proteolipid c-ring to translocate
  protons across organelle membranes. The human V-ATPase complex is responsible for
  acidifying lysosomes, endosomes, the Golgi apparatus, and other intracellular compartments,
  and in specialized cell types for extracellular acidification at the plasma membrane.
  Beyond proton pumping, the V1 D subunit directly contacts the Ragulator scaffold on
  lysosomes, and V-ATPase activity is required for amino acid-sensitive mTORC1 activation
  via an inside-out signaling mechanism. ATP6V1D additionally interacts with SNX10
  and localizes to the centrosome and cilium base, where the V-ATPase is required for
  ciliogenesis. The protein is ubiquitously expressed in human tissues.
existing_annotations:
- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic inference that ATP6V1D is part of the V-type ATPase complex.
      Confirmed by cryo-EM structure and biochemical data.
    action: ACCEPT
    reason: The D subunit is a core structural and functional component of the V1 sector
      of the V-type ATPase complex. Multiple lines of evidence including cryo-EM (PMID:33065002)
      and biochemical pulldowns (PMID:18752060) confirm complex membership.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases)
        are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis
        and a membrane-embedded Vo complex for proton transfer.
      reference_section_type: ABSTRACT
    - reference_id: file:human/ATP6V1D/ATP6V1D-uniprot.txt
      supporting_text: Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase),
        a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP
        and a membrane integral complex (V0) that translocates protons
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference that ATP6V1D participates in vacuolar acidification.
      Well-supported by the established role of V-ATPase in acidifying intracellular
      compartments.
    action: ACCEPT
    reason: The V-ATPase is the primary driver of organellar acidification in eukaryotes,
      and subunit D is a core structural component essential for complex function. Vacuolar
      acidification is the core biological process.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: Vesicular- or vacuolar-type adenosine triphosphatases (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. They play important roles
        in acidification of intracellular vesicles, organelles, and the extracellular
        milieu in eukaryotes.
      reference_section_type: ABSTRACT
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are membrane-embedded protein complexes that function
        as ATP hydrolysis-driven proton pumps. V-ATPases are the primary source of organellar
        acidification in all eukaryotes, making them essential for many fundamental cellular
        processes.
      reference_section_type: ABSTRACT

- 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: Phylogenetic inference that subunit D contributes to proton-transporting
      ATPase activity via rotational mechanism. Supported by the established central
      rotor function of subunit D in the rotary mechanism.
    action: ACCEPT
    reason: Subunit D is a core structural component of the V1 central rotor that directly
      participates in the rotary mechanism. The contributes_to qualifier is appropriate
      since this is a complex-level activity.
    supported_by:
    - reference_id: PMID:18752060
      supporting_text: Energy from this reaction drives the rotation of a central stalk
        consisting of V1 subunits D and F and this is coupled to rotation of the V0 proteolipid
        ring made up of c, c′ and c″.
      reference_section_type: INTRODUCTION
    - reference_id: PMID:33065002
      supporting_text: Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases)
        are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis
        and a membrane-embedded Vo complex for proton transfer.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt subcellular location vocabulary mapping. Well-supported by multiple
      independent HDA and IDA lysosomal membrane annotations.
    action: ACCEPT
    reason: Lysosomal membrane is the primary functional location of the V-ATPase complex.
      Supported by HDA proteomics (PMID:17897319) and IDA data (PMID:22053050).

- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt subcellular location vocabulary mapping based on the centrosome
      localization reported in PMID:21844891.
    action: KEEP_AS_NON_CORE
    reason: Centrosome localization of ATP6V1D (via SNX10 interaction) is supported by
      IDA evidence (PMID:21844891) but represents a secondary ciliogenesis-related function
      rather than the core lysosomal proton-pumping role.
    supported_by:
    - reference_id: PMID:21844891
      supporting_text: SNX10 interacts with V-ATPase complex and targets it to the centrosome
        where ciliogenesis is initiated.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005929
    label: cilium
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt subcellular location vocabulary mapping based on cilium localization
      reported in PMID:21844891.
    action: KEEP_AS_NON_CORE
    reason: Cilium localization is supported by IDA evidence but represents a secondary
      ciliogenesis-related function. The V-ATPase participates in ciliogenesis via
      vesicular trafficking to the cilium base.
    supported_by:
    - reference_id: PMID:21844891
      supporting_text: Like SNX10, V-ATPase regulates ciliogenesis in vitro and in vivo
        and does so synergistically with SNX10. We further discover that SNX10 and V-ATPase
        regulate the ciliary trafficking of Rab8a, which is a critical regulator of ciliary
        membrane extension.
      reference_section_type: ABSTRACT

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Generic membrane localization from UniProt vocabulary mapping. The V1 D
      subunit associates with the cytoplasmic face of membranes as part of the V-ATPase
      complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic membrane term is subsumed by the more specific lysosomal membrane,
      Golgi membrane, and endosome membrane annotations. The IDA annotation from PMID:18752060
      (membrane) is more specific in context and provides better granularity.

- term:
    id: GO:0030665
    label: clathrin-coated vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt subcellular location vocabulary mapping based on ortholog data.
      V-ATPase functions on clathrin-coated vesicles for endocytic pathway acidification.
    action: KEEP_AS_NON_CORE
    reason: The clathrin-coated vesicle membrane localization is consistent with V-ATPase's
      broad role in acidifying endocytic vesicles, but is not the primary functional
      context for this subunit.

- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based annotation. The enables qualifier for the whole-complex
      activity is somewhat imprecise for a structural subunit, but the rotational ATPase
      activity is the core molecular function.
    action: ACCEPT
    reason: The proton-transporting ATPase activity via rotational mechanism is the core
      molecular function of the complex in which ATP6V1D is an indispensable structural
      component. The IBA annotation with contributes_to is more precise, but this IEA
      is consistent.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Generic protein binding from a large-scale human interactome proteome map.
      Not informative for the specific function of ATP6V1D.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is uninformative for this V-ATPase subunit. A high-throughput
      interactome map does not establish a meaningful GO annotation for ATP6V1D core function.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein binding from a reference human binary protein interactome
      map. High-throughput; not informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding from high-throughput interactome studies lacks specificity
      and is not useful for understanding ATP6V1D function.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Generic protein binding from a dual proteome-scale interactome network
      study. High-throughput; not informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome data should not be used to assert generic protein
      binding as a meaningful function for a structural V-ATPase subunit.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: Generic protein binding from the OpenCell endogenous tagging study. High-throughput;
      not informative for core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is uninformative for ATP6V1D; these high-throughput interaction
      data points do not reveal specific biological function.

- term:
    id: GO:0015078
    label: proton transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: contributes_to
  review:
    summary: Ensembl ortholog-transfer annotation. Proton transmembrane transporter
      activity is the molecular function of the V-ATPase complex; subunit D contributes
      via the rotary mechanism.
    action: ACCEPT
    reason: This is an appropriate annotation for a core V-ATPase structural subunit.
      The contributes_to qualifier correctly acknowledges that the molecular function
      belongs to the whole complex.

- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: Automated IEA annotation consistent with the IBA and IDA evidence for
      complex membership.
    action: ACCEPT
    reason: Redundant with IBA but consistent with cryo-EM structural evidence.

- term:
    id: GO:0097401
    label: synaptic vesicle lumen acidification
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl ortholog-transfer annotation for synaptic vesicle lumen acidification.
      V-ATPase acidifies synaptic vesicles to enable neurotransmitter loading. However,
      there is no direct evidence that the ubiquitous D subunit specifically functions
      in neuronal synaptic vesicles as opposed to other organelles.
    action: KEEP_AS_NON_CORE
    reason: Synaptic vesicle lumen acidification is a legitimate biological process in
      which V-ATPase participates; the D subunit is a ubiquitously expressed component
      that would be present in neuronal V-ATPase complexes. However, this is a non-core
      context relative to lysosomal/endosomal function.

- term:
    id: GO:0098850
    label: extrinsic component of synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Ensembl ortholog-transfer annotation placing the D subunit on synaptic
      vesicle membrane. The V1 peripheral sector is an extrinsic component of vesicle
      membranes.
    action: KEEP_AS_NON_CORE
    reason: Supported by the V-ATPase's role in synaptic vesicle acidification, but
      this is non-core relative to the primary lysosomal/endosomal acidification function.

- term:
    id: GO:0071230
    label: cellular response to amino acid stimulus
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: involved_in
  review:
    summary: Direct evidence from Zoncu et al. (2011) showing the V-ATPase (specifically
      the V1 domain including subunit D) is required for mTORC1 activation in response
      to amino acids. The V1 D subunit directly contacts the Ragulator complex, and
      amino acids regulate this interaction.
    action: ACCEPT
    reason: The V-ATPase's role in amino acid sensing for mTORC1 is a genuine secondary
      function with direct experimental evidence. Subunit D specifically interacts with
      Ragulator p18 and p14 in vitro. This is well-supported functional biology beyond
      simple proton pumping.
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: the v-ATPase engages in extensive amino acid-sensitive interactions
        with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the
        lysosome. In a cell-free system, ATP hydrolysis by the v-ATPase was necessary
        for amino acids to regulate the v-ATPase-Ragulator interaction and promote mTORC1
        translocation.
      reference_section_type: ABSTRACT
    - reference_id: PMID:22053050
      supporting_text: the V1 component D with p18 and, to a lesser degree, with p14
        (Fig. 3D). No direct interactions were detected between the Rag GTPases and
        purified v-ATPase subunits
      reference_section_type: RESULTS

- term:
    id: GO:0160124
    label: guanyl nucleotide exchange factor activator activity
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: contributes_to
  review:
    summary: The V-ATPase contributes to GEF activator activity in the context of Ragulator-mediated
      Rag GTPase nucleotide exchange during amino acid signaling to mTORC1. The mechanistic
      link is that V-ATPase activity (ATP hydrolysis-driven rotation) is required to
      activate Ragulator as a GEF activator complex.
    action: KEEP_AS_NON_CORE
    reason: This annotation reflects a genuine but secondary function of the V-ATPase
      complex in mTORC1 signaling. It is mechanistically supported but is not the primary
      proton-pump function of the complex.
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: amino acids activate the Rag guanosine triphosphatases (GTPases),
        which promote the translocation of mTORC1 to the lysosomal surface, the site
        of mTORC1 activation. We found that the vacuolar H(+)-adenosine triphosphatase
        ATPase (v-ATPase) is necessary for amino acids to activate mTORC1.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: is_active_in
  review:
    summary: Direct experimental evidence from the Zoncu et al. (2011) study shows the
      V-ATPase is active at the lysosomal membrane for both proton pumping and amino
      acid-sensitive mTORC1 signaling.
    action: ACCEPT
    reason: Lysosomal membrane is the primary site of V-ATPase function, and this IDA
      annotation from a key mechanistic study is well-supported.
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: the v-ATPase engages in extensive amino acid-sensitive interactions
        with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the
        lysosome.
      reference_section_type: ABSTRACT

- 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: Direct evidence from the Zoncu et al. (2011) study showing the V-ATPase
      complex on lysosomes; subunit D is part of this complex.
    action: ACCEPT
    reason: Well-supported by both the amino acid sensing study (PMID:22053050) and
      the structural data (PMID:33065002).
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: the v-ATPase engages in extensive amino acid-sensitive interactions
        with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the
        lysosome.
      reference_section_type: ABSTRACT

- term:
    id: GO:1904263
    label: positive regulation of TORC1 signaling
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: involved_in
  review:
    summary: The V-ATPase is required for positive regulation of mTORC1 signaling by
      amino acids. Subunit D directly contacts Ragulator, and ATP hydrolysis is required
      for mTORC1 activation. This is a genuine secondary function.
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of TORC1 signaling is supported and real but is a secondary
      function of the V-ATPase complex, not the primary proton-pumping role.
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: ATP hydrolysis and the associated rotation of the v-ATPase appear
        to be essential to relay an amino acid signal from the lysosomal lumen to the
        Rag GTPases, whereas the capacity of the v-ATPase to set up the lysosomal proton
        gradient is dispensable.
      reference_section_type: RESULTS

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence-based annotation. V-ATPase can be targeted to the plasma
      membrane in specialized cell types for extracellular acidification.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane localization of V-ATPase is real in specialized contexts
      (osteoclasts, kidney intercalated cells, tumor cells) but is not the primary site
      of function for this ubiquitously expressed subunit.

- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: NAS from V-ATPase review (Vasanthakumar and Rubinstein 2020). V-ATPase
      acidifies the Golgi apparatus, and the D subunit is present as part of the complex.
    action: ACCEPT
    reason: Golgi membrane localization is a well-established aspect of V-ATPase biology;
      Golgi acidification is required for proper glycosylation and protein trafficking.

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: NAS from V-ATPase review. Consistent with multiple other lysosomal membrane
      annotations.
    action: ACCEPT
    reason: Core localization supported by multiple evidence types.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: NAS from V-ATPase review.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane localization of V-ATPase is real in specialized contexts
      but is not the primary site for the ubiquitous D subunit.

- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review. Consistent with core V-ATPase function.
    action: ACCEPT
    reason: Vacuolar acidification is the core biological process of V-ATPase.

- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review. Lysosomal lumen acidification is a specific,
      well-established aspect of V-ATPase function that is more precise than the broader
      vacuolar acidification term.
    action: ACCEPT
    reason: Lysosomal lumen acidification is a core function of the V-ATPase.

- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: NAS from the structural study (Wang et al. 2020). Consistent with the established
      role of V-ATPase in lysosomal acidification.
    action: ACCEPT
    reason: Supported by extensive V-ATPase biology.

- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: NAS from V-ATPase review. V-ATPase acidifies endosomes; the D subunit
      is present as part of the complex.
    action: ACCEPT
    reason: Endosome membrane is an established location for V-ATPase function in the
      endocytic pathway.

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:33065002
  qualifier: located_in
  review:
    summary: IDA from the human V-ATPase structural study (cryo-EM). The D subunit
      is part of the membrane-associated V-ATPase complex on the cytoplasmic face of
      membranes.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic membrane annotation is subsumed by the more specific lysosomal
      membrane, Golgi membrane, and endosome membrane annotations.

- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: part_of
  review:
    summary: NAS from the structural study. Consistent with IDA from PMID:18752060
      and IBA annotation.
    action: ACCEPT
    reason: Well-supported complex membership.

- term:
    id: GO:0048388
    label: endosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review. Endosomal lumen acidification by V-ATPase is
      a core function.
    action: ACCEPT
    reason: Core function of V-ATPase in the endocytic pathway.

- term:
    id: GO:0051452
    label: intracellular pH reduction
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review. Intracellular pH reduction is a core outcome
      of V-ATPase activity. This term is somewhat redundant with the more specific acidification
      terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: The intracellular pH reduction term is a less specific way to describe the
      same function captured by the more precise lysosomal/endosomal/Golgi lumen acidification
      annotations. Redundant and non-specific.

- term:
    id: GO:0061795
    label: Golgi lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review. V-ATPase acidifies the Golgi lumen, which is
      important for glycosylation and protein sorting.
    action: ACCEPT
    reason: Core function of V-ATPase in Golgi biology.

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: NAS from the structural study. Proton transmembrane transport is the core
      molecular process performed by V-ATPase.
    action: ACCEPT
    reason: Core biological process of V-ATPase.

- term:
    id: GO:0000221
    label: vacuolar proton-transporting V-type ATPase, V1 domain
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: Ortholog-based annotation placing the D subunit in the V1 domain. Confirmed
      by human cryo-EM structural data.
    action: ACCEPT
    reason: The D subunit is a defining structural component of the V1 domain, confirmed
      by cryo-EM.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases)
        are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis
        and a membrane-embedded Vo complex for proton transfer.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799350
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing ATP6V1D in specific granule membrane of
      neutrophils. V-ATPase is present in neutrophil granules.
    action: KEEP_AS_NON_CORE
    reason: Neutrophil-specific granule function is a non-core context for this ubiquitous
      subunit.

- term:
    id: GO:0035579
    label: specific granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799350
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for V-ATPase in neutrophil specific granule membrane.
    action: KEEP_AS_NON_CORE
    reason: Neutrophil-specific context; non-core for this ubiquitous subunit.

- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: NAS
  original_reference_id: PMID:22982048
  qualifier: involved_in
  review:
    summary: NAS from a study on lipofuscin and macroautophagy (PMID:22982048). V-ATPase
      is required for lysosomal acidification, which is necessary for autophagosome-lysosome
      fusion and degradation. However, this is an indirect effect rather than a specific
      regulatory function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of macroautophagy is an indirect consequence of V-ATPase's role
      in lysosomal acidification. The annotation overstates the specificity; the core
      function is lysosomal proton pumping, not macroautophagy regulation per se.

- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: IDA
  original_reference_id: PMID:18752060
  qualifier: part_of
  review:
    summary: Direct experimental evidence from Smith et al. (2008) demonstrating that
      human D subunit co-purifies with V-ATPase complex and directly interacts with
      central stalk components.
    action: ACCEPT
    reason: The most specific experimental evidence for complex membership. Pulldown
      experiments demonstrated direct D-F and D-d subunit interactions.
    supported_by:
    - reference_id: PMID:18752060
      supporting_text: each can pull down the central stalk's D and F subunits from
        human kidney membrane, and in vitro studies using D and F further showed that
        the interactions between these proteins and the d subunit is direct.
      reference_section_type: ABSTRACT

- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  qualifier: located_in
  review:
    summary: High-throughput proteomics detection of ATP6V1D in parotid gland exosomes.
      V-ATPase subunits can co-purify with exosomes due to membrane association.
    action: MARK_AS_OVER_ANNOTATED
    reason: Exosome detection by proteomics likely reflects membrane co-purification
      rather than a specific function of subunit D in exosomes. This is a non-core,
      likely artifactual localization for a primarily lysosomal/endosomal subunit.

- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput proteomics detection in urinary exosomes. Same reasoning
      as the parotid gland exosome annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Urinary exosome proteomics detection likely reflects lysosomal membrane
      co-purification; not a specific function.

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: HDA
  original_reference_id: PMID:17897319
  qualifier: located_in
  review:
    summary: Lysosomal membrane proteomics study detected ATP6V1D, confirming its
      lysosomal membrane localization.
    action: ACCEPT
    reason: This direct proteomics evidence for lysosomal membrane localization is
      consistent with the established biology of V-ATPase.

- term:
    id: GO:0061512
    label: protein localization to cilium
  evidence_type: IMP
  original_reference_id: PMID:21844891
  qualifier: involved_in
  review:
    summary: The V-ATPase (including subunit D via SNX10 interaction) is required for
      proper localization of proteins to the cilium. V-ATPase knockout disrupts Rab8a
      ciliary trafficking.
    action: KEEP_AS_NON_CORE
    reason: This is a genuine secondary function of the V-ATPase involving subunit D,
      but it is not the core lysosomal acidification function.
    supported_by:
    - reference_id: PMID:21844891
      supporting_text: SNX10 and V-ATPase regulate the ciliary trafficking of Rab8a,
        which is a critical regulator of ciliary membrane extension.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21844891
  qualifier: enables
  review:
    summary: The interaction detected in PMID:21844891 is the specific SNX10-V-ATPase
      interaction; however, the annotation is recorded as generic protein binding rather
      than the informative SNX10 interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is uninformative; the underlying interaction with SNX10 is
      more informative. The generic protein binding term should be replaced if a more
      specific term exists. As no specific SNX10-binding GO term exists, this is best
      flagged as over-annotated.

- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:21844891
  qualifier: colocalizes_with
  review:
    summary: Direct experimental evidence (IDA) showing ATP6V1D colocalizes with centrosome
      marker proteins, mediated by SNX10 interaction that targets V-ATPase to the centrosome.
    action: KEEP_AS_NON_CORE
    reason: Centrosome colocalization is experimentally supported but is a secondary
      ciliogenesis-related function.
    supported_by:
    - reference_id: PMID:21844891
      supporting_text: SNX10 interacts with V-ATPase complex and targets it to the centrosome
        where ciliogenesis is initiated.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005929
    label: cilium
  evidence_type: IDA
  original_reference_id: PMID:21844891
  qualifier: colocalizes_with
  review:
    summary: Direct evidence that V-ATPase (including D subunit) colocalizes with cilium.
    action: KEEP_AS_NON_CORE
    reason: Secondary ciliogenesis function.

- term:
    id: GO:0060271
    label: cilium assembly
  evidence_type: IMP
  original_reference_id: PMID:21844891
  qualifier: involved_in
  review:
    summary: V-ATPase loss-of-function (through V-ATPase subunit knockdown including
      components targeting D subunit's complex) impairs cilium assembly in vitro and
      in vivo.
    action: KEEP_AS_NON_CORE
    reason: Cilium assembly is a genuine secondary function of the V-ATPase complex,
      supported by IMP evidence, but is not the primary lysosomal acidification role.
    supported_by:
    - reference_id: PMID:21844891
      supporting_text: V-ATPase regulates ciliogenesis in vitro and in vivo and does
        so synergistically with SNX10.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1222516
  qualifier: located_in
  review:
    summary: Reactome TAS annotation placing ATP6V1D in cytosol, consistent with the
      V1 domain being a peripheral complex on the cytoplasmic face of membranes.
    action: KEEP_AS_NON_CORE
    reason: The V1 peripheral sector, including subunit D, is present in the cytosol
      as a soluble complex during regulated disassembly from V0.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252133
  qualifier: located_in
  review:
    summary: Additional Reactome TAS annotation for cytosol localization.
    action: KEEP_AS_NON_CORE
    reason: Same reasoning as above; the V1 domain can exist in cytosol.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74723
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent with V1 domain biology.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917841
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent with V1 domain biology.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9639286
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol in RRAG-related pathway context.
    action: KEEP_AS_NON_CORE
    reason: V-ATPase participates in mTORC1 signaling on lysosomal surface, with V1
      components accessible from cytosol.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640167
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640168
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640175
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640195
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645598
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645608
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9646468
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18752060
  qualifier: enables
  review:
    summary: The IPI protein binding annotation from PMID:18752060 reflects specific
      interactions of subunit D with the V0 d subunit and with subunit F, which are
      mechanistically important. However, the generic protein binding term is less informative
      than the established subunit interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific interactions (D-F central stalk; D-d1/d2 rotor junction) are
      more meaningful than a generic protein binding annotation. No specific binding term
      exists for the D-F or D-d interactions, but protein binding is uninformative here.

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:18752060
  qualifier: located_in
  review:
    summary: IDA from Smith et al. (2008) showing D subunit in membrane preparations.
      The D subunit is a peripheral membrane protein on the cytoplasmic face.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic membrane annotation is subsumed by the more specific lysosomal
      membrane and other organelle membrane annotations.

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:17897319
  title: Integral and associated lysosomal membrane proteins.
  findings:
  - statement: ATP6V1D detected in lysosomal membrane proteomics study.
- id: PMID:18752060
  title: The d subunit plays a central role in human vacuolar H(+)-ATPases.
  findings:
  - statement: Human V-ATPase D subunit directly interacts with d1, d2, and F subunits,
      forming the central stalk of V1.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings:
  - statement: ATP6V1D detected in urinary exosomes by mass spectrometry.
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein
    identification technology (MudPIT).
  findings:
  - statement: ATP6V1D detected in parotid gland exosome proteome.
- id: PMID:21844891
  title: A SNX10/V-ATPase pathway regulates ciliogenesis in vitro and in vivo.
  findings:
  - statement: V-ATPase (including D subunit) interacts with SNX10 and localizes to
      centrosome and cilium; required for ciliogenesis and ciliary Rab8a trafficking.
- id: PMID:22053050
  title: mTORC1 senses lysosomal amino acids through an inside-out mechanism that
    requires the vacuolar H(+)-ATPase.
  findings:
  - statement: V-ATPase D subunit directly interacts with Ragulator (p18/p14) on
      lysosomes; ATP hydrolysis by V-ATPase required for amino acid-induced mTORC1
      activation.
- id: PMID:22982048
  title: Lipofuscin is formed independently of macroautophagy and lysosomal activity
    in stress-induced prematurely senescent human fibroblasts.
  findings:
  - statement: V-ATPase (via lysosomal acidification) broadly required for macroautophagy.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings:
  - statement: ATP6V1D detected in high-throughput interactome study.
- id: PMID:32001091
  title: Structure and Roles of V-type ATPases.
  findings:
  - statement: Comprehensive review of V-ATPase structure, function, and disease relevance.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: ATP6V1D detected in binary interactome map.
- id: PMID:33065002
  title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.
  findings:
  - statement: Cryo-EM structures of complete human V-ATPase at 2.9 A; D subunit identified
      as central rotor component with subunit F.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings:
  - statement: ATP6V1D detected in proteome-scale interactome study.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings:
  - statement: ATP6V1D localization mapped by endogenous tagging.
- id: Reactome:R-HSA-1222516
  title: Intraphagosomal pH is lowered to 5 by V-ATPase
  findings: []
- id: Reactome:R-HSA-5252133
  title: ATP6AP1 binds V-ATPase
  findings: []
- id: Reactome:R-HSA-6799350
  title: Exocytosis of specific granule membrane proteins
  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: []

core_functions:
- description: Central rotor component of the V1 sector of the vacuolar-type H+-ATPase
    (V-ATPase). Subunit D, together with subunit F, forms the central stalk that transmits
    ATP hydrolysis energy from the catalytic A3B3 hexamer to rotate the V0 proteolipid
    ring, enabling proton translocation across organelle membranes. Primary role is in
    acidification of lysosomes, endosomes, and the Golgi apparatus.
  contributes_to_molecular_function:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  directly_involved_in:
  - id: GO:0007042
    label: lysosomal lumen acidification
  - id: GO:0048388
    label: endosomal lumen acidification
  - id: GO:0061795
    label: Golgi lumen acidification
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  supported_by:
  - reference_id: PMID:33065002
    supporting_text: Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases)
      are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis
      and a membrane-embedded Vo complex for proton transfer.
    reference_section_type: ABSTRACT
  - reference_id: PMID:18752060
    supporting_text: Energy from this reaction drives the rotation of a central stalk
      consisting of V1 subunits D and F and this is coupled to rotation of the V0 proteolipid
      ring made up of c, c′ and c″.
    reference_section_type: INTRODUCTION
- description: Secondary role in mTORC1 amino acid sensing. The D subunit directly contacts
    the Ragulator scaffold (p18/p14) on lysosomes, and V-ATPase ATP hydrolysis is required
    upstream of Rag GTPase activation for mTORC1 translocation to lysosomes in response
    to amino acids.
  directly_involved_in:
  - id: GO:1904263
    label: positive regulation of TORC1 signaling
  - id: GO:0071230
    label: cellular response to amino acid stimulus
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  supported_by:
  - reference_id: PMID:22053050
    supporting_text: the V1 component D with p18 and, to a lesser degree, with p14
      (Fig. 3D). No direct interactions were detected between the Rag GTPases and
      purified v-ATPase subunits
    reference_section_type: RESULTS
- description: Secondary role in ciliogenesis. Via interaction with SNX10, the V-ATPase
    (including subunit D) is targeted to the centrosome and cilium base, where it regulates
    ciliary trafficking of Rab8a and cilium assembly.
  directly_involved_in:
  - id: GO:0060271
    label: cilium assembly
  locations:
  - id: GO:0005813
    label: centrosome
  supported_by:
  - reference_id: PMID:21844891
    supporting_text: V-ATPase regulates ciliogenesis in vitro and in vivo and does
      so synergistically with SNX10.
    reference_section_type: ABSTRACT

suggested_questions:
- question: Is the role of subunit D in the Ragulator interaction specific to this
    subunit, or shared by other V1 subunits? What is the structural basis of D-Ragulator
    binding?
  experts: []
- question: Do disease-causing mutations in V-ATPase subunits affect the D-F central
    stalk interactions, and if so, does this impair ciliogenesis in addition to acidification?
  experts: []
- question: What is the mechanism by which SNX10-V-ATPase targeting to the centrosome
    promotes ciliogenesis? Is this dependent on V-ATPase proton-pumping activity or
    structural interactions?
  experts: []

suggested_experiments:
- hypothesis: The D subunit directly contacts Ragulator at the lysosomal surface
    and this interface can be structurally defined.
  description: Cryo-EM structure determination of the V-ATPase-Ragulator complex
    to define the D subunit contact interface with p18 and p14, and to identify
    amino acid-dependent conformational changes.
  experiment_type: structural biology
- hypothesis: The D-Ragulator contact can be uncoupled from proton pumping by targeted
    mutations.
  description: Engineer separation-of-function mutations in ATP6V1D that disrupt
    the Ragulator interaction without affecting V-ATPase proton pumping activity,
    then test mTORC1 activation in response to amino acids.
  experiment_type: mutagenesis and functional assay
- hypothesis: V-ATPase targeting to the centrosome by SNX10 is required for ciliogenesis
    and occurs during a specific window of ciliation initiation.
  description: Time-lapse imaging of fluorescently tagged V-ATPase-SNX10 complex
    during ciliation initiation; test whether V-ATPase proton-pumping activity or
    only its structural association with SNX10 is required for ciliogenesis.
  experiment_type: live cell imaging and genetic rescue

ATP6V1D

Gene Description

Existing Annotations Review

Core Functions

Secondary role in mTORC1 amino acid sensing. The D subunit directly contacts the Ragulator scaffold (p18/p14) on lysosomes, and V-ATPase ATP hydrolysis is required upstream of Rag GTPase activation for mTORC1 translocation to lysosomes in response to amino acids.

Secondary role in ciliogenesis. Via interaction with SNX10, the V-ATPase (including subunit D) is targeted to the centrosome and cilium base, where it regulates ciliary trafficking of Rab8a and cilium assembly.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: ATP6V1D (V-type Proton ATPase Subunit D)

Gene Identity and Verification

Structural Organization and Composition

Primary Function and Catalytic Mechanism

Substrate Specificity

Subcellular Localization

Biochemical and Signaling Pathways

mTORC1 Nutrient Sensing Pathway

AMPK Activation and Energy Sensing

Autophagy and Lysosomal Catabolism

Endocytic Pathway Regulation

Wnt and Notch Signaling

Neurotransmitter Loading in Synaptic Vesicles

Recent Developments (2023-2024)

Clinical and Pathological Relevance

Summary

📚 Additional Documentation

Notes

ATP6V1D Research Notes

Gene Identity

Core V-ATPase Biology

Role in mTORC1 Amino Acid Sensing

Subcellular Localization

Ciliogenesis Role

V-ATPase Structure (Human)

Regulation of Macroautophagy

Curation Notes

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6V1D PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V1 lysosomal v-ATPase proton pump component

PN row 2: Autophagy-Lysosome Pathway | Lysosomal catabolism | Regulation of lysosomal environment | Lysosomal acidification | V1 lysosomal v-ATPase proton pump component

Projected GO annotations (3)

Note

📄 View Raw YAML