ATP6V0D2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IBA GO_REF:0000033	ACCEPT	Summary: ATP6V0D2 is definitively a component of the V-ATPase complex. The d2 subunit is part of the membrane-integral V0 domain of the vacuolar H+-ATPase. This has been confirmed through multiple lines of evidence including immunoprecipitation studies showing that d2 directly interacts with V1 subunits D and F [PMID:18752060 "d1-GST and d2-GST, but not GST alone, are each able to pull down the H+-ATPase D and F subunits from solubilized human kidney membrane preparations"]. Reason: This is a core annotation supported by extensive experimental evidence. The d2 subunit is an integral component of the V-ATPase complex, confirmed by pull-down experiments in human kidney membrane showing direct interaction with V1 subunits. Supporting Evidence: PMID:18752060 d1-GST and d2-GST, but not GST alone, are each able to pull down the H+-ATPase D and F subunits from solubilized human kidney membrane preparations
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IBA GO_REF:0000033	ACCEPT	Summary: ATP6V0D2 is part of the V-ATPase which functions via a rotational mechanism. The d subunit forms part of the pump's central stalk and is important in the rotary mechanism, as demonstrated by its direct interaction with the central stalk D and F subunits [PMID:18752060]. However, the d2 subunit itself does not have ATPase catalytic activity - it is a structural component that couples ATP hydrolysis (occurring in V1) to proton translocation (in V0). Reason: While the d2 subunit is not itself the catalytic subunit, it is an integral component of the V-ATPase that contributes to the rotational mechanism by linking the V1 central stalk to the V0 proteolipid ring. The IBA annotation correctly captures the function of the assembled complex. Supporting Evidence: PMID:18752060 the d subunit in man forms part of the pump's central stalk and is thus likely to be important in its rotary mechanism
GO:0005769 early endosome	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: V-ATPases are known to be present in early endosomes where they function in endosomal acidification. However, ATP6V0D2 shows tissue-restricted expression predominantly in kidney and osteoclasts [PMID:15800125 "in human, kidney and bone are two of the main sites of d2 mRNA expression"], and the primary literature on ATP6V0D2 emphasizes its localization to lysosomes, plasma membrane of specialized cells (intercalated cells, osteoclasts), and phagocytic vesicles rather than early endosomes specifically. Reason: While V-ATPases containing d2 may be present in early endosomes in certain cell types, this is not a primary or well-characterized localization for ATP6V0D2 specifically. The dominant literature focuses on lysosomal and plasma membrane localization in kidney and osteoclasts. Supporting Evidence: PMID:15800125 in human, kidney and bone are two of the main sites of d2 mRNA expression
GO:0007034 vacuolar transport	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: ATP6V0D2 participates in vacuolar/lysosomal function through its role in the V-ATPase, but "vacuolar transport" is a broad process term for this subunit. The clearest established process is compartment acidification. A more recent ccRCC study also supports a context-specific role in autophagosome-lysosome fusion through RAB7/HOPS machinery [PMID:39477683]. Reason: Retain this broad IBA term as non-core. It is consistent with V-ATPase-dependent acidification and with newer late-autophagy evidence, but the core ATP6V0D2 functions are better represented by V-ATPase complex membership, V0-domain contribution to rotary proton pumping, and vacuolar/lysosomal acidification. Supporting Evidence: PMID:39477683 Mechanistically, ATP6V0D2 directly bound to RAB7 and VPS41 and promoted the RAB7-HOPS interaction, facilitating SNARE complex assembly and autophagosome-lysosome fusion.
GO:0007035 vacuolar acidification	IBA GO_REF:0000033	ACCEPT	Summary: ATP6V0D2 is a core component of the V-ATPase responsible for acidification of vacuolar compartments and, in specialized cells, the extracellular environment. In human kidney intercalated cells, d2 co-localizes with the a4 subunit at the plasma membrane for urinary acidification [PMID:15800125]. Recent ccRCC work also reports that ATP6V0D2 promotes lysosomal acidification and activity during late autophagy [PMID:39477683]. The evidence also supports the more specific GO:0007042 lysosomal lumen acidification term for this gene. Reason: This is a core function of ATP6V0D2 as part of the V-ATPase proton pump. Both the phylogenetic inference (IBA) and direct experimental evidence support this annotation. Supporting Evidence: PMID:15800125 high-intensity d2 staining was observed only in intercalated cells of the collecting duct in fresh-frozen human kidney, where it co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern PMID:39477683 ATP6V0D2 promoted autolysosome degradation by increasing the acidification and activity of lysosomes during the later stages of macroautophagy/autophagy.
GO:0033181 plasma membrane proton-transporting V-type ATPase complex	IBA GO_REF:0000033	ACCEPT	Summary: ATP6V0D2 is specifically expressed in cells where V-ATPases localize to the plasma membrane, including kidney intercalated cells and osteoclasts. Immunohistochemistry in human kidney shows d2 at the apical plasma membrane of intercalated cells [PMID:15800125 "d2 staining was observed only in intercalated cells of the collecting duct... where it co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern"]. Reason: This is a well-supported core localization for ATP6V0D2. Unlike the ubiquitous d1 isoform, d2 is predominantly expressed in cells with plasma membrane V-ATPases for specialized proton secretion functions. Supporting Evidence: PMID:15800125 high-intensity d2 staining was observed only in intercalated cells of the collecting duct in fresh-frozen human kidney, where it co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern
GO:0006811 monoatomic ion transport	IEA GO_REF:0000043	ACCEPT	Summary: This is a very broad term inferred from UniProt keywords. ATP6V0D2 is part of the V-ATPase which specifically transports protons (H+). The term "monoatomic ion transport" is technically correct but very general. Reason: This IEA annotation is correct but non-specific. It is a parent term of the more specific proton transport annotations. Acceptable as a general annotation that does not conflict with more specific evidence.
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IEA GO_REF:0000117	ACCEPT	Summary: Duplicate of the IBA annotation for the same GO term. This is an automated annotation from ARBA machine learning that correctly identifies ATP6V0D2 as a V-ATPase component. Reason: Correct annotation supported by multiple lines of evidence. Duplicates are acceptable as they represent independent evidence sources.
GO:0030670 phagocytic vesicle membrane	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: V-ATPases are present in phagocytic vesicle membranes where they acidify the phagosome, and Reactome also projects ATP6V0D2 to a phagosomal acidification event. For ATP6V0D2 specifically, however, the strongest primary human evidence emphasizes kidney/osteoclast plasma membrane pumps, V0-domain complex membership, and lysosomal/autophagy functions rather than a directly tested phagocytic-vesicle localization. Reason: Keep as a plausible non-core V-ATPase localization from automated inference, but do not treat it as a defining ATP6V0D2 cellular component.
GO:0033179 proton-transporting V-type ATPase, V0 domain	IEA GO_REF:0000002	ACCEPT	Summary: ATP6V0D2 is definitively part of the V0 domain of the V-ATPase. The V0 domain is the membrane-integral portion responsible for proton translocation. This annotation is derived from InterPro domain annotations which correctly identify ATP6V0D2 as a V0 d subunit [PMID:18752060 "The V0 d subunit is one of the least characterized of all the H+-ATPase components"]. Reason: This is the most precise cellular component annotation for ATP6V0D2 - it is specifically a subunit of the V0 domain. This annotation correctly distinguishes it from V1 domain subunits. Supporting Evidence: PMID:18752060 The V0 d subunit is one of the least characterized of all the H+-ATPase components
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate of IBA annotation. This IEA from InterPro correctly assigns the molecular function of the V-ATPase complex to which ATP6V0D2 belongs. As with the IBA row, this should be understood as ATP6V0D2 contributing to the assembled complex activity rather than independently enabling ATPase activity. Reason: Correct annotation from InterPro mapping. The d2 subunit is integral to the rotational mechanism of the V-ATPase, but the biologically appropriate qualifier for this structural subunit is contributes_to.
GO:1902600 proton transmembrane transport	IEA GO_REF:0000120	ACCEPT	Summary: ATP6V0D2 as part of the V-ATPase is involved in proton transmembrane transport. This is the core function of the V-ATPase complex. The annotation is derived from combined automated methods and is correct. Reason: Core biological process annotation for ATP6V0D2 as a V-ATPase subunit involved in proton pumping across membranes.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: This annotation comes from the HuRI (Human Reference Interactome) high-throughput yeast two-hybrid study. While ATP6V0D2 certainly binds proteins (it interacts with other V-ATPase subunits, RAB7, HOPS components, etc.), the generic term "protein binding" provides no information about the specific functional interactions. Reason: "Protein binding" is an uninformative annotation that does not describe the specific molecular function. This high-throughput interaction data does not add functional understanding beyond what is captured by more specific annotations (V-ATPase complex membership, interactions with D/F subunits, RAB7, etc.).
GO:0005768 endosome	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: V-ATPases are present in endosomes for acidification. However, ATP6V0D2 specifically shows tissue-restricted expression and is primarily characterized at the plasma membrane of specialized cells and lysosomes rather than general endosomal localization. Reason: While V-ATPases containing d2 may be present in endosomes, the primary literature focuses on other localizations (plasma membrane, lysosomes). This is an acceptable but non-core annotation.
GO:0005769 early endosome	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Duplicate early endosome annotation from Ensembl Compara ortholog transfer. Same considerations as the IBA annotation for early endosome. Reason: Not a primary localization for ATP6V0D2 based on available literature. Retain as non-core.
GO:0016324 apical plasma membrane	IEA GO_REF:0000107	ACCEPT	Summary: This annotation is transferred from orthologs but is consistent with experimental data showing ATP6V0D2 at the apical plasma membrane of kidney intercalated cells [PMID:15800125]. Reason: Consistent with direct experimental evidence showing d2 at the apical plasma membrane of intercalated cells in human kidney. Supporting Evidence: PMID:15800125 high-intensity d2 staining was observed only in intercalated cells of the collecting duct
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9639286	ACCEPT	Summary: Reactome places ATP6V0D2-containing V-ATPase events at the lysosomal membrane. The lysosomal interpretation is also consistent with ccRCC evidence that ATP6V0D2 increases lysosomal acidification/activity during autophagic degradation [PMID:39477683]. Reason: Lysosomal membrane localization is a core annotation for ATP6V0D2, supported by multiple Reactome entries and primary literature. Supporting Evidence: PMID:39477683 ATP6V0D2 promoted autolysosome degradation by increasing the acidification and activity of lysosomes during the later stages of macroautophagy/autophagy.
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640167	ACCEPT	Summary: Duplicate lysosomal membrane annotation from Reactome pathway (RRAG GTP exchange). Same evidence and rationale as above. Reason: Core localization annotation, multiple Reactome pathway entries support this.
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640168	ACCEPT	Summary: Duplicate lysosomal membrane annotation from Reactome (V-ATPase:Ragulator complex). Reason: Core localization annotation for ATP6V0D2.
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640175	ACCEPT	Summary: Duplicate lysosomal membrane annotation from Reactome pathway. Reason: Core localization annotation for ATP6V0D2.
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640195	ACCEPT	Summary: Duplicate lysosomal membrane annotation from Reactome pathway. Reason: Core localization annotation for ATP6V0D2.
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9645598	ACCEPT	Summary: Duplicate lysosomal membrane annotation from Reactome pathway. Reason: Core localization annotation for ATP6V0D2.
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9645608	ACCEPT	Summary: Duplicate lysosomal membrane annotation from Reactome (mTORC1 signaling). Reason: Core localization annotation for ATP6V0D2.
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9646468	ACCEPT	Summary: Duplicate lysosomal membrane annotation from Reactome pathway. Reason: Core localization annotation for ATP6V0D2.
GO:0016241 regulation of macroautophagy	NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	KEEP AS NON CORE	Summary: The referenced paper [PMID:22982048] studies lipofuscin formation and autophagy but does not specifically address ATP6V0D2. It examines general V-ATPase inhibition effects. However, PMID:39477683 provides direct evidence in ccRCC models that ATP6V0D2 promotes autophagosome-lysosome fusion and later autolysosome degradation. Reason: Keep the annotation because there is newer ATP6V0D2-specific evidence for late macroautophagy/autophagosome-lysosome fusion, but classify it as non-core because the original NAS citation is not ATP6V0D2-specific and the best-established core function remains V-ATPase-mediated acidification. Supporting Evidence: PMID:39477683 Mechanistically, ATP6V0D2 directly bound to RAB7 and VPS41 and promoted the RAB7-HOPS interaction, facilitating SNARE complex assembly and autophagosome-lysosome fusion.
GO:0016324 apical plasma membrane	IDA PMID:15800125 Vacuolar H+-ATPase d2 subunit: molecular characterization, d...	ACCEPT	Summary: Direct experimental evidence from immunohistochemistry showing ATP6V0D2 at the apical plasma membrane of kidney intercalated cells [PMID:15800125 "high-intensity d2 staining was observed only in intercalated cells of the collecting duct in fresh-frozen human kidney, where it co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern"]. Reason: Strong experimental evidence from direct immunolocalization in human kidney tissue. Supporting Evidence: PMID:15800125 high-intensity d2 staining was observed only in intercalated cells of the collecting duct in fresh-frozen human kidney, where it co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: This annotation is from a high-throughput proteomics study of urinary exosomes [PMID:19056867]. ATP6V0D2 was identified in exosome preparations. Given d2's expression in kidney, its presence in urinary exosomes is plausible. However, this may reflect contamination or non-specific association rather than functional localization. Reason: High-throughput proteomics identification in exosomes. While technically valid, this does not represent a functional localization and may be incidental. Retain as non-core.
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-1222516	KEEP AS NON CORE	Summary: From Reactome pathway "Intraphagosomal pH is lowered to 5 by V-ATPase". V-ATPases including ATP6V0D2 function in phagosome acidification. This is consistent with d2's role in osteoclasts (which have specialized phagocytic activity) and macrophages. Reason: Reactome pathway context makes this plausible, but it is a generalized V-ATPase/phagosome localization rather than a primary ATP6V0D2-defining localization. Keep as a non-core compartmental context.
GO:0010008 endosome membrane	TAS Reactome:R-HSA-5252133	KEEP AS NON CORE	Summary: From Reactome pathway showing ATP6AP1 binding to V-ATPase. Endosome membrane localization is consistent with V-ATPase function in endosomal acidification. Reason: V-ATPases function at endosome membranes for acidification, so this is reasonable. For ATP6V0D2 specifically, the better-supported core locations are lysosomal membrane and specialized apical/plasma membrane V-ATPases.
GO:0010008 endosome membrane	TAS Reactome:R-HSA-74723	KEEP AS NON CORE	Summary: From Reactome pathway "Endosome acidification". Core function of V-ATPase. Reason: Consistent with V-ATPase function in endosomal acidification, but retained as non-core for ATP6V0D2 because the direct evidence emphasizes lysosomal and specialized plasma membrane contexts.
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917841	KEEP AS NON CORE	Summary: From Reactome pathway "Acidification of Tf:TfR1 containing endosome". V-ATPases acidify endosomes containing transferrin receptor. Reason: Consistent with V-ATPase function in endosomal acidification, but retained as non-core for ATP6V0D2 because the direct evidence emphasizes lysosomal and specialized plasma membrane contexts.
GO:0005515 protein binding	IPI PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	REMOVE	Summary: From the study demonstrating that d2 directly interacts with V-ATPase D and F subunits [PMID:18752060 "d1 and d2 interact directly with the D and F subunits"]. While the IPI evidence supports protein binding, the generic term is uninformative. Reason: Generic "protein binding" annotation does not convey functional information. The specific interactions (with D and F subunits, RAB7, HOPS components) are better captured by complex membership and process annotations.
GO:0016020 membrane	IDA PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	ACCEPT	Summary: Very general membrane localization annotation. ATP6V0D2 is a peripheral membrane protein that associates with the V0 domain of the V-ATPase [PMID:18752060 "It associates with the membrane bound V0 domain, probably by protein-protein interactions rather than being directly anchored in the membrane"]. Reason: Correct but very general annotation. More specific membrane localizations (lysosomal membrane, plasma membrane, etc.) are more informative but this is not incorrect. Supporting Evidence: PMID:18752060 It associates with the membrane bound V0 domain, probably by protein-protein interactions rather than being directly anchored in the membrane
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IDA PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	ACCEPT	Summary: Direct experimental evidence from pull-down experiments showing ATP6V0D2 is part of the V-ATPase complex [PMID:18752060 "d1-GST and d2-GST, but not GST alone, are each able to pull down the H+-ATPase D and F subunits from solubilized human kidney membrane preparations"]. Reason: Strong experimental evidence confirming ATP6V0D2 as a V-ATPase complex component through direct biochemical interaction studies. Supporting Evidence: PMID:18752060 d1-GST and d2-GST, but not GST alone, are each able to pull down the H+-ATPase D and F subunits from solubilized human kidney membrane preparations
GO:0007042 lysosomal lumen acidification	NAS PMID:39477683 Atractylenolide I inhibits angiogenesis and reverses sunitin...	NEW	Summary: NEW annotation proposed from the Proteostasis Network projection. ATP6V0D2 already has the broader GO:0007035 vacuolar acidification annotation, and the PN autophagy-lysosome mapping projects the lysosomal acidification branch to GO:0007042. PMID:39477683 provides ATP6V0D2-specific support for increased lysosomal acidification/activity in late autophagy. Reason: This is a conservative PN projection because it is more specific than the existing vacuolar acidification GOA term and is supported by ATP6V0D2's lysosomal V-ATPase context. It should be added as a lysosome-specific acidification annotation rather than as a broad proteostasis-process claim. Supporting Evidence: PMID:39477683 ATP6V0D2 promoted autolysosome degradation by increasing the acidification and activity of lysosomes during the later stages of macroautophagy/autophagy.
GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain	IC PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	NEW	Summary: NEW annotation proposed from the Proteostasis Network projection. ATP6V0D2 is already annotated to the V0 domain (GO:0033179), the V-ATPase complex (GO:0016471), and lysosomal membrane (GO:0005765). The PN mapping recommends the more specific lysosomal V0-domain component term GO:0046610 for V0-sector lysosomal V-ATPase components. No single supporting source directly demonstrates a d2-containing lysosomal V0-domain complex; this recommendation combines the accepted GO:0033179 V0-domain annotation with accepted GO:0005765 lysosomal-membrane annotations. Reason: This is a conservative compositional refinement of existing GOA rather than a novel mechanistic claim. ATP6V0D2 is the d2 V0-domain subunit and is represented in lysosomal V-ATPase Reactome contexts; GO:0046610 captures that lysosomal V0-domain component role more precisely than the existing separate V0-domain and lysosomal-membrane annotations. The supporting literature establishes the pieces of this inference rather than directly testing lysosomal GO:0046610 membership for the d2 isoform. Supporting Evidence: PMID:18752060 The multi-subunit vacuolar-type H(+)-ATPase consists of a V(1) domain (A-H subunits) catalyzing ATP hydrolysis and a V(0) domain (a, c, c', c", d, e) responsible for H(+) translocation. PMID:39477683 it promoted autophagic degradation of EPAS1 by upregulating the ATPase subunit ATP6V0D2 (ATPase H+ transporting V0 subunit d2) to increase lysosomal function

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