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

Core Functions

ATP6V0D2 is a structural component of the V0 domain of the vacuolar H+-ATPase, serving as the d2 isoform of the d subunit. It links the V1 central stalk (D and F subunits) to the V0 proteolipid ring, playing a critical role in coupling ATP hydrolysis to proton translocation. Direct biochemical evidence from pull-down and in vitro binding experiments [PMID:18752060]; structural modeling showing d2 is orthologous to bacterial A-ATPase subunit C.

In Complex:

vacuolar proton-transporting V-type ATPase complex

As part of the V-ATPase, ATP6V0D2 contributes to acidification of intracellular compartments (lysosomes, endosomes) and extracellular spaces (in specialized cells like kidney intercalated cells and osteoclasts). Immunolocalization in kidney intercalated cells [PMID:15800125]; ccRCC autophagy experiments showing ATP6V0D2-dependent lysosomal acidification/activity [PMID:39477683].

Directly Involved In:

vacuolar acidification lysosomal lumen acidification

Cellular Locations:

lysosomal membrane apical plasma membrane

Supporting Evidence:

file:human/ATP6V0D2/ATP6V0D2-deep-research-falcon.md
Lysosomal acidification and degradation in human cells: The same study shows ATP6V0D2 enhances lysosomal acidification and activity

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000107

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

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:15800125

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

ATP6V0D2 shows tissue-restricted expression in kidney and bone
d2 localizes to apical plasma membrane of intercalated cells in kidney collecting duct
d2 co-localizes with a4 subunit in kidney and a3 subunit in osteoclasts

PMID:18752060

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

d2 directly interacts with V1 subunits D and F
d2 is structurally similar to bacterial A-ATPase subunit C
d2 forms part of the pump's central stalk and is important in rotary mechanism

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

ATP6V0D2 identified in urinary exosome proteome

PMID:22982048

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

General study of autophagy and lysosomal function, not specific to ATP6V0D2

PMID:32296183

A reference map of the human binary protein interactome.

High-throughput interactome study, identifies ATP6V0D2 protein interactions

Reactome:R-HSA-1222516

Intraphagosomal pH is lowered to 5 by V-ATPase

Reactome:R-HSA-5252133

ATP6AP1 binds V-ATPase

Reactome:R-HSA-74723

Endosome acidification

Reactome:R-HSA-917841

Acidification of Tf:TfR1 containing endosome

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

PMID:39477683

Atractylenolide I inhibits angiogenesis and reverses sunitinib resistance in clear cell renal cell carcinoma through ATP6V0D2-mediated autophagic degradation of EPAS1/HIF2alpha.

ATP6V0D2 promotes autophagosome-lysosome fusion through RAB7/HOPS and SNARE-complex assembly in ccRCC models.
ATP6V0D2 increases lysosomal acidification and activity during late autophagy in ccRCC models.

file:human/ATP6V0D2/ATP6V0D2-deep-research-falcon.md

Falcon deep research report for ATP6V0D2

ATP6V0D2 is a V-ATPase V0 d2 subunit with evidence for specialized kidney, osteoclast, lysosomal, and late-autophagy roles.

file:human/ATP6V0D2/ATP6V0D2-notes.md

ATP6V0D2 PN curation notes

Manual PN review treated lysosomal acidification and lysosomal V0-domain projection as conservative new annotation candidates, while keeping broader proteostasis/autophagy claims non-core.

file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml

Proteostasis Network autophagy-lysosome pathway mappings

PN mappings project the lysosomal acidification node to GO:0007042 and the V0 lysosomal V-ATPase component node to GO:0046610.

Suggested Experiments

Experiment: Test whether ATP6V0D2 mutants that cannot interact with D/F subunits (and thus cannot assemble into V-ATPase) retain autophagosome-lysosome fusion activity. This would distinguish V-ATPase-dependent from V-ATPase-independent functions of ATP6V0D2 in autophagy.

Experiment: Generate tissue-specific d2 knockout mice (kidney intercalated cell-specific, osteoclast-specific) to define physiological roles. This would clarify whether d2 has unique functions not compensated by d1 in specialized cell types.

Deep Research

Falcon

(ATP6V0D2-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 21 citations 2026-02-08T20:34:15.599052

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

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

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

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

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

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

Comprehensive Research Report: Human ATP6V0D2 (UniProt Q8N8Y2)

Plan status
- Identity verification: ATP6V0D2 encodes the V‑ATPase V0 sector d-subunit isoform 2 in human; literature below is restricted to human V‑ATPase and human cell systems where noted (completed). (chen2024vatpaseincancer pages 1-3)
- Evidence collection: Recent primary and review literature prioritizing 2023–2025 identified and synthesized (completed). (chen2024vatpaseincancer pages 1-3, chen2025theemergingroles pages 2-5, li2025atractylenolideiinhibits pages 11-14, li2025atractylenolideiinhibits pages 7-9, li2025atractylenolideiinhibits pages 16-17)

1) Key concepts and definitions (current understanding)
- Molecular identity and complex membership: ATP6V0D2 is a subunit of the membrane-embedded V0 sector of the vacuolar-type H+‑ATPase (V‑ATPase). The V‑ATPase consists of a cytosolic catalytic V1 sector (A–H subunits) and a membrane V0 sector (a, c/cʺ, d, e); the V1 central shaft (D/F) couples to V0 through the small d subunit. ATP6V0D2 encodes the d2 isoform of this V0 d subunit and participates in proton pumping through its structural role in the assembled holoenzyme. Isoform specialization is a hallmark of the V‑ATPase, with cell-type and organelle-specific distributions across subunits. (Cell Communication and Signaling, Dec 2024; URL: https://doi.org/10.1186/s12964-024-01998-9). (chen2024vatpaseincancer pages 1-3)
- Subcellular localization: In human cells, ATP6V0D2 localizes to lysosomes/acidic vesicles, where it contributes to lysosomal acidification and degradative capacity (Autophagy, Nov 2025; URL: https://doi.org/10.1080/15548627.2024.2421699). (li2025atractylenolideiinhibits pages 11-14, li2025atractylenolideiinhibits pages 7-9)
- Functional role (general): As part of V‑ATPase, ATP6V0D2 supports organelle acidification that underpins autophagic flux, cargo degradation, and, when situated at specialized membranes, extracellular acidification-dependent processes. Reviews emphasize subunit/isoform diversity and regulation (e.g., reversible V1–V0 assembly, subcellular trafficking) as core determinants of activity. (Biomolecules, Apr 2025; URL: https://doi.org/10.3390/biom15040525). (chen2025theemergingroles pages 2-5)

2) Recent developments and latest research (prioritize 2023–2024+)
- Autophagosome–lysosome fusion mechanism linked to ATP6V0D2 (human tumor cells): A 2025 study in clear‑cell renal cell carcinoma (ccRCC) reports that ATP6V0D2 directly promotes autophagosome–lysosome fusion by physically interacting with RAB7 and HOPS complex components (e.g., VPS41), thereby facilitating HOPS assembly and SNARE complex formation. Co‑IP, GST pulldown with recombinant proteins (GST‑ATP6V0D2, His‑RAB7, His‑VPS41), and confocal colocalization in 786O and 293T cells support direct or complex-mediated binding. Knockdown of ATP6V0D2 reduced RAB7–VPS41 colocalization and impaired fusion, while pharmacologic upregulation of ATP6V0D2 restored fusion and autophagic flux (Autophagy, Nov 2025; URL: https://doi.org/10.1080/15548627.2024.2421699). (li2025atractylenolideiinhibits pages 11-14, li2025atractylenolideiinhibits pages 16-17)
- Lysosomal acidification and degradation in human cells: The same study shows ATP6V0D2 enhances lysosomal acidification and activity: depletion increased RFP+GFP+ LC3 puncta (indicating impaired fusion/degradation) and stabilized a lysosome‑degraded substrate (EPAS1/HIF2α). Chloroquine (lysosomal inhibitor) phenocopied the effect and eliminated differences between control and ATP6V0D2‑depleted cells, consistent with a role in the degradative step. Quantitatively, in vitro assays used ATL‑I at 80 μM for 48 h and xenografts used ATL‑I 50 mg/kg (with or without 20 mg/kg sunitinib) to modulate ATP6V0D2‑dependent autophagy and tumor phenotypes. Overexpression of ATP6V0D2 modestly increased apoptosis (~10% in 786O) while reducing tumor burden in xenografts. Publication date: Nov 2025. (li2025atractylenolideiinhibits pages 7-9)
- Immune/macrophage context (recent reviews citing primary work): Reviews summarizing macrophage studies indicate that ATP6V0D2 facilitates autophagosome–lysosome fusion to restrain inflammasome activation and bacterial infection, situating ATP6V0D2 as an immune-regulatory V‑ATPase subunit with cell-type preferential expression (Biomolecules, Apr 2025; URL: https://doi.org/10.3390/biom15040525). (chen2025theemergingroles pages 26-26)
- Structural/architectural updates on V‑ATPase relevant to ATP6V0D2: A 2024 review details human V‑ATPase subunit composition, regulation (assembly/disassembly), and roles in pH homeostasis and disease microenvironments, reinforcing the placement of ATP6V0D2 within V0 and its potential to shape organelle acidity and flux (Cell Communication and Signaling, Dec 2024; URL: https://doi.org/10.1186/s12964-024-01998-9). (chen2024vatpaseincancer pages 1-3)

3) Current applications and real-world implementations
- Oncology: Targeting the autophagy–lysosome system via ATP6V0D2 shows translational potential in ccRCC. Pharmacologic upregulation of ATP6V0D2 with atractylenolide I (ATL‑I) promoted autophagic degradation of EPAS1/HIF2α, reduced VEGF signaling outputs, and overcame sunitinib resistance in xenografts, suggesting a route to modulate lysosomal flux and angiogenesis in therapy-resistant settings. Dosing in mice (ATL‑I 50 mg/kg; sunitinib 20 mg/kg) and cell-based ATL‑I exposure (80 μM, 48 h) are reported, providing actionable parameters for preclinical replication (Autophagy, Nov 2025; URL: https://doi.org/10.1080/15548627.2024.2421699). (li2025atractylenolideiinhibits pages 7-9)
- Immunology/infection: Reviews highlight that in macrophages ATP6V0D2 aids autophagosome–lysosome fusion to limit inflammasome activation and bacterial burdens, indicating potential for host-directed therapies enhancing lysosomal fusion/acidification in infection and inflammatory states (Biomolecules, Apr 2025; URL: https://doi.org/10.3390/biom15040525). (chen2025theemergingroles pages 26-26)
- Broad V‑ATPase targeting: State-of-the-art reviews discuss V‑ATPase as a therapeutic axis (e.g., cancer metabolism, tumor microenvironment acidity, autophagy dependence), providing the rationale for modulating specific subunits/isoforms, including d2, in a context-dependent manner (Cell Communication and Signaling, Dec 2024; URL: https://doi.org/10.1186/s12964-024-01998-9). (chen2024vatpaseincancer pages 1-3)

4) Expert opinions and analysis (authoritative sources)
- V‑ATPase architecture and isoform specialization underscore ATP6V0D2’s context-specific biology: Expert reviews emphasize that subunit isoforms (including d2) confer organelle and tissue specificity to V‑ATPase function, affecting localization, activity, and signaling crosstalk (e.g., mTORC1/AMPK at lysosomes). This supports interpreting ATP6V0D2 phenotypes as isoform-dependent tuning of acidification and degradative flux in select cell types. Publication: Dec 2024; URL: https://doi.org/10.1186/s12964-024-01998-9. (chen2024vatpaseincancer pages 1-3)
- Lysosomal energy-sensing platforms: Reviews place V‑ATPase at the core of lysosomal signaling hubs that integrate nutrient status with autophagy and inflammatory outputs, strengthening the view that ATP6V0D2 may influence not only proton pumping mechanics but also upstream assembly and downstream fusion/flux control in disease states (Biomolecules, Jul 2025; URL: https://doi.org/10.3390/biom15070997; Biomolecules, Apr 2025; URL: https://doi.org/10.3390/biom15040525). (yang2025vatpaseandlysosomal pages 6-7, chen2025theemergingroles pages 2-5)

5) Relevant statistics and data from recent studies
- Human ccRCC systems: ATL‑I upregulated ATP6V0D2 and restored autophagosome–lysosome fusion; ATP6V0D2 knockdown increased RFP+GFP+ LC3 puncta, stabilized EPAS1/HIF2α (relative to control), and reduced RAB7–VPS41 colocalization; ATL‑I at 80 μM (48 h) used for in vitro; xenograft dosing at 50 mg/kg for ATL‑I with or without 20 mg/kg sunitinib; ATP6V0D2 overexpression increased apoptosis by ~10% in 786O cells (Autophagy, Nov 2025; URL: https://doi.org/10.1080/15548627.2024.2421699). (li2025atractylenolideiinhibits pages 11-14, li2025atractylenolideiinhibits pages 7-9, li2025atractylenolideiinhibits pages 16-17)
- System-level context: Reviews synthesize that V‑ATPase-dependent lysosomal pH typically falls in the 4.5–5.0 range in human cells and that isoform composition, assembly state, and subcellular targeting regulate acidification and flux, providing quantitative context for interpreting ATP6V0D2 perturbations (Biomolecules, Apr 2025; URL: https://doi.org/10.3390/biom15040525). (chen2025theemergingroles pages 2-5)

Mechanistic model (integrated)
- ATP6V0D2 functions as a V0 d‑subunit isoform in the V‑ATPase, promoting lysosomal acidification and autophagic cargo degradation. Beyond proton pumping, it facilitates autophagosome–lysosome fusion by engaging RAB7–HOPS machinery and enabling SNARE assembly at the fusion stage. In human tumor cells, this supports degradation of disease-relevant substrates (EPAS1/HIF2α), modulates angiogenic signaling, and can influence therapy resistance. In immune cells (macrophages), ATP6V0D2’s role in fusion/acidification contributes to dampening inflammasome activation and restricting intracellular pathogens. Collectively, ATP6V0D2 is best understood as an isoform-specific enabler of lysosomal function and fusion, with disease-relevant consequences in cancer and infection. (chen2024vatpaseincancer pages 1-3, chen2025theemergingroles pages 26-26, li2025atractylenolideiinhibits pages 11-14, li2025atractylenolideiinhibits pages 7-9)

Identity cross-check and ambiguity safeguards
- Gene symbol and protein match: Literature consistently places ATP6V0D2 as the human V‑ATPase V0 d‑subunit isoform 2 within the V‑ATPase complex, distinct from catalytic V1 subunits and other V0 components; no conflicting gene/protein symbol usage was detected in 2024–2025 reviews and the cited human cell studies. (chen2024vatpaseincancer pages 1-3)
- Organism: Human-focused reviews and the ccRCC experimental systems (786O, 293T) confirm human context for functional claims. (li2025atractylenolideiinhibits pages 11-14, li2025atractylenolideiinhibits pages 7-9)
- Protein family: Placement within the V0 d-subunit family is consistent across structural/functional reviews, aligning with expected V‑ATPase domain architecture. (chen2024vatpaseincancer pages 1-3, chen2025theemergingroles pages 2-5)

Key evidence table
| Concept/Claim | Mechanistic detail | Experimental system (species/cell type) | Year | Key methods | Outcome / quantitative notes | Source URL | Citation ID |
|---|---|---|---:|---|---|---|---|
| Identity / complex membership | ATP6V0D2 encodes the V-ATPase V0 sector d‑subunit isoform 2 ("d2"); a membrane V0 component that links the V1 rotor to the proton-translocating pore; isoform-specific expression vs d1 (ubiquitous) | Human / mammalian (reviewed annotation and structural descriptions) | 2024–2025 | Protein family/domain annotation; structural reviews | Classified as V0 d‑subunit with tissue‑preferential isoform expression (d2 vs d1) | https://doi.org/10.1186/s12964-024-01998-9; https://doi.org/10.3390/biom15070997 | (chen2024vatpaseincancer pages 1-3, yang2025vatpaseandlysosomal pages 6-7) |
| Subcellular localization | Localizes to lysosomes / acidic vesicles (colocalizes with LAMP1); reported lysosomal membrane association and contribution to organellar acidification | Human cell lines (ccRCC 786O, 293T) and reviewed mammalian datasets | 2025 | IHC / IF, LysoTracker, colocalization, WB | Shows lysosomal localization and functional role in organelle acidification/activity | https://doi.org/10.1080/15548627.2024.2421699 | (li2025atractylenolideiinhibits pages 11-14, li2025atractylenolideiinhibits pages 7-9) |
| Autophagosome–lysosome fusion (RAB7–HOPS–SNARE axis) | Physically interacts with RAB7 and HOPS components (e.g., VPS41); promotes RAB7–HOPS interaction and facilitates SNARE complex assembly to drive autophagosome–lysosome fusion | Human 786O / SU‑R‑786O tumor cells, 293T transfections; recombinant protein pulldowns | 2025 | co‑IP, GST pulldown, mass spectrometry, confocal colocalization, RFP‑GFP‑LC3 flux, TEM | ATP6V0D2 knockdown reduces RAB7–VPS41 colocalization and impairs fusion; ATL‑I upregulates ATP6V0D2 and restores fusion | https://doi.org/10.1080/15548627.2024.2421699 | (li2025atractylenolideiinhibits pages 11-14, li2025atractylenolideiinhibits pages 16-17) |
| Lysosomal acidification & degradative activity | Promotes lysosomal acidification and degradative flux; loss impairs autophagic degradation (increased LC3/SQSTM1, more RFP+GFP+ LC3 puncta), stabilizes lysosome‑targeted substrates (e.g., EPAS1/HIF2α) | Human ccRCC cell lines; pharmacologic perturbations (chloroquine, rapamycin) | 2025 | LysoTracker, RFP‑GFP‑LC3 assay, western blot, cycloheximide chase, chloroquine inhibition, TEM | ATP6V0D2 depletion impairs autophagic flux and increases target stability; chloroquine phenocopies impaired degradation | https://doi.org/10.1080/15548627.2024.2421699 | (li2025atractylenolideiinhibits pages 7-9) |
| Osteoclast fusion / bone resorption roles | Expressed in osteoclast lineage; implicated in pre‑osteoclast fusion and the V‑ATPase‑dependent acidification steps required for bone resorption (works alongside fusion regulators such as DC‑STAMP) | Mouse and human osteoclast studies summarized in reviews and primary literature | 2023–2024 | Osteoclast differentiation assays, gene expression profiling, in vivo bone phenotyping (reviewed evidence) | Reviewed evidence links ATP6V0D2 to osteoclast fusion and resorptive function; loss/reduction reported to impair fusion and modulate bone remodeling (see primary studies cited in reviews) | https://doi.org/10.1186/s12964-024-01998-9; https://doi.org/10.3390/cells12212576 | (chen2024vatpaseincancer pages 1-3, chen2025theemergingroles pages 2-5) |
| Immune / macrophage roles & disease relevance | Macrophage‑specific functions include facilitating autophagosome–lysosome fusion to restrict inflammasome activation and bacterial infection; disease links reported in cancer (modulates degradation of oncogenic factors and therapy resistance), infection models, and links to atherosclerosis via autophagy–lysosome pathways | Macrophage studies, infection models, ccRCC cell lines, mouse models and transcriptomic analyses | 2024–2025 | Gene knockdown/overexpression, infection assays, xenografts, transcriptomics / bioinformatics | ATP6V0D2 modulates immune responses and infection outcomes; upregulation can enhance lysosomal degradation of disease‑relevant substrates and affect tumor progression / drug response | https://doi.org/10.3390/biom15040525; https://doi.org/10.1080/15548627.2024.2421699 | (chen2025theemergingroles pages 26-26, li2025atractylenolideiinhibits pages 11-14, chen2024vatpaseincancer pages 1-3) |

Table: Compact summary table mapping key claims about human ATP6V0D2 to mechanistic details, experimental systems, methods, outcomes and source literature (2024–2025). Useful for quickly tracing major functional assertions to the supporting references.

References (with URLs and dates)
- Chen T, Lin X, Lu S, Li B. V‑ATPase in cancer: mechanistic insights and therapeutic potentials. Cell Communication and Signaling. Dec 2024. URL: https://doi.org/10.1186/s12964-024-01998-9 (chen2024vatpaseincancer pages 1-3)
- Chen Y‑Y, Liu C‑X, Liu H‑X, Wen S‑Y. The emerging roles of V‑ATPase‑dependent lysosomal acidification in cardiovascular disease. Biomolecules. Apr 2025. URL: https://doi.org/10.3390/biom15040525 (chen2025theemergingroles pages 2-5)
- Yang X, Holliday LS. V‑ATPase and lysosomal energy sensing in periodontitis and MRONJ. Biomolecules. Jul 2025. URL: https://doi.org/10.3390/biom15070997 (yang2025vatpaseandlysosomal pages 6-7, yang2025vatpaseandlysosomal pages 4-6)
- Li Q et al. Atractylenolide I inhibits angiogenesis and reverses sunitinib resistance in clear cell renal cell carcinoma through ATP6V0D2‑mediated autophagic degradation of EPAS1/HIF2α. Autophagy. Nov 2025. URL: https://doi.org/10.1080/15548627.2024.2421699 (li2025atractylenolideiinhibits pages 11-14, li2025atractylenolideiinhibits pages 7-9, li2025atractylenolideiinhibits pages 16-17)
- Biomolecules review citing macrophage-specific ATP6V0D2 restraining inflammasome activation and bacterial infection via autophagosome–lysosome fusion. Apr 2025. URL: https://doi.org/10.3390/biom15040525 (chen2025theemergingroles pages 26-26)

Notes on evidence scope
- Osteoclast-specific primary mechanistic data were not directly captured in the 2023–2024 items retrieved here; however, expert reviews consistently assign ATP6V0D2 to osteoclast/acidification pathways through its role as a V0 d‑subunit and isoform specialization. Where osteoclast fusion/resorption roles are mentioned, they are supported here via reviews rather than newly retrieved 2023–2024 primary articles. Future updates should incorporate osteoclast-focused primary studies as they become available in 2023–2024 if accessible. (chen2024vatpaseincancer pages 1-3, chen2025theemergingroles pages 2-5)

References

(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 15 citations.
(chen2025theemergingroles pages 2-5): Yan-Yan Chen, Cai-Xia Liu, Hai-Xin Liu, and Shi-Yuan Wen. The emerging roles of vacuolar-type atpase-dependent lysosomal acidification in cardiovascular disease. Biomolecules, 15:525, Apr 2025. URL: https://doi.org/10.3390/biom15040525, doi:10.3390/biom15040525. This article has 9 citations and is from a poor quality or predatory journal.
(li2025atractylenolideiinhibits pages 11-14): Qinyu Li, Kai Zeng, Qian Chen, Chenglin Han, Xi Wang, Beining Li, Jianping Miao, Bolong Zheng, Jihong Liu, Xianglin Yuan, and Bo Liu. Atractylenolide i inhibits angiogenesis and reverses sunitinib resistance in clear cell renal cell carcinoma through atp6v0d2-mediated autophagic degradation of epas1/hif2α. Autophagy, 21:619-638, Nov 2025. URL: https://doi.org/10.1080/15548627.2024.2421699, doi:10.1080/15548627.2024.2421699. This article has 20 citations and is from a domain leading peer-reviewed journal.
(li2025atractylenolideiinhibits pages 7-9): Qinyu Li, Kai Zeng, Qian Chen, Chenglin Han, Xi Wang, Beining Li, Jianping Miao, Bolong Zheng, Jihong Liu, Xianglin Yuan, and Bo Liu. Atractylenolide i inhibits angiogenesis and reverses sunitinib resistance in clear cell renal cell carcinoma through atp6v0d2-mediated autophagic degradation of epas1/hif2α. Autophagy, 21:619-638, Nov 2025. URL: https://doi.org/10.1080/15548627.2024.2421699, doi:10.1080/15548627.2024.2421699. This article has 20 citations and is from a domain leading peer-reviewed journal.
(li2025atractylenolideiinhibits pages 16-17): Qinyu Li, Kai Zeng, Qian Chen, Chenglin Han, Xi Wang, Beining Li, Jianping Miao, Bolong Zheng, Jihong Liu, Xianglin Yuan, and Bo Liu. Atractylenolide i inhibits angiogenesis and reverses sunitinib resistance in clear cell renal cell carcinoma through atp6v0d2-mediated autophagic degradation of epas1/hif2α. Autophagy, 21:619-638, Nov 2025. URL: https://doi.org/10.1080/15548627.2024.2421699, doi:10.1080/15548627.2024.2421699. This article has 20 citations and is from a domain leading peer-reviewed journal.
(chen2025theemergingroles pages 26-26): Yan-Yan Chen, Cai-Xia Liu, Hai-Xin Liu, and Shi-Yuan Wen. The emerging roles of vacuolar-type atpase-dependent lysosomal acidification in cardiovascular disease. Biomolecules, 15:525, Apr 2025. URL: https://doi.org/10.3390/biom15040525, doi:10.3390/biom15040525. This article has 9 citations and is from a poor quality or predatory journal.
(yang2025vatpaseandlysosomal pages 6-7): Xianrui Yang and Lexie Shannon Holliday. V-atpase and lysosomal energy sensing in periodontitis and medicine-related osteonecrosis of the jaw. Biomolecules, 15:997, Jul 2025. URL: https://doi.org/10.3390/biom15070997, doi:10.3390/biom15070997. This article has 1 citations and is from a poor quality or predatory journal.
(yang2025vatpaseandlysosomal pages 4-6): Xianrui Yang and Lexie Shannon Holliday. V-atpase and lysosomal energy sensing in periodontitis and medicine-related osteonecrosis of the jaw. Biomolecules, 15:997, Jul 2025. URL: https://doi.org/10.3390/biom15070997, doi:10.3390/biom15070997. This article has 1 citations and is from a poor quality or predatory journal.

Citations

chen2024vatpaseincancer pages 1-3
chen2025theemergingroles pages 2-5
li2025atractylenolideiinhibits pages 7-9
chen2025theemergingroles pages 26-26
li2025atractylenolideiinhibits pages 11-14
li2025atractylenolideiinhibits pages 16-17
yang2025vatpaseandlysosomal pages 6-7
yang2025vatpaseandlysosomal pages 4-6
https://doi.org/10.1186/s12964-024-01998-9
https://doi.org/10.1080/15548627.2024.2421699
https://doi.org/10.3390/biom15040525
https://doi.org/10.1186/s12964-024-01998-9.
https://doi.org/10.3390/biom15070997;
https://doi.org/10.1186/s12964-024-01998-9;
https://doi.org/10.3390/biom15070997
https://doi.org/10.3390/cells12212576
https://doi.org/10.3390/biom15040525;
https://doi.org/10.1186/s12964-024-01998-9,
https://doi.org/10.3390/biom15040525,
https://doi.org/10.1080/15548627.2024.2421699,
https://doi.org/10.3390/biom15070997,

📚 Additional Documentation

Notes

(ATP6V0D2-notes.md)

ATP6V0D2 review notes

Core function

ATP6V0D2 encodes the d2 isoform of the V-ATPase V0 d subunit. The core function
is as a structural V0-sector component that contributes to the assembled
V-ATPase rotary proton pump, not as an independently catalytic ATPase. Smith et
al. show that the mammalian V0 d subunit has d1 and d2 forms and that d2 is
predominantly expressed in kidney and osteoclast PMID:18752060.
The same paper supports a central-stalk/rotary mechanism role because the human
d subunits pull down V1 D and F subunits and the authors conclude that the d
subunit is centrally located in the pump PMID:18752060.

The direct tissue-localization evidence supports specialized plasma membrane
V-ATPases in kidney intercalated cells and osteoclasts. Smith et al. report
human collecting-duct intercalated-cell staining that co-localized with the a4
subunit PMID:15800125 and bone
osteoclast co-localization with a3 PMID:15800125.

PN projection

Falcon deep research already existed as
genes/human/ATP6V0D2/ATP6V0D2-deep-research-falcon.md, so this was handled as
a PN-context re-review rather than a new deep-research run.

The PN projection has two ATP6V0D2 candidate additions from
projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv:
GO:0007042 lysosomal lumen acidification and GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain.
I treated both as conservative action: NEW recommendations. GO:0007042 is
a specific child/refinement of the existing GOA GO:0007035 vacuolar acidification and is supported by the ATP6V0D2-specific Autophagy abstract,
which states that ATP6V0D2 promoted autolysosome degradation by increasing
lysosomal acidification/activity PMID:39477683.

GO:0046610 is a compositional PN refinement, not a single direct experiment:
ATP6V0D2 is already in GOA as V0 domain, V-ATPase complex, and lysosomal
membrane, and the PN mapping
Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V0 lysosomal v-ATPase proton pump component
targets GO:0046610 [file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml].
Because this depends on combining existing GOA/Reactome context with V0-subunit
identity, I recorded it as a conservative proposed annotation and added an expert
question about whether direct d2-specific lysosomal V0-domain evidence should be
required.

Conservative annotation decisions

Kept GO:0007035 vacuolar acidification, V-ATPase complex, V0 domain, and
plasma membrane V-ATPase complex as core.
Added PN-projected GO:0007042 and GO:0046610 as NEW recommendations.
Moved broad GO:0007034 vacuolar transport to non-core because acidification
is the cleaner core process.
Kept macroautophagy regulation as non-core. PMID:39477683 supports a real
late-autophagy/fusion role, but the original GOA citation PMID:22982048 is not
ATP6V0D2-specific and instead addresses lipofuscin/autophagy generally
PMID:22982048.
Kept phagocytic vesicle membrane and endosome membrane localizations as
non-core Reactome/automated contexts rather than ATP6V0D2-defining locations.
Removed generic GO:0005515 protein binding annotations because they are less
informative than V-ATPase complex membership and specific mechanistic process
annotations.

Description cleanup note

The YAML description was kept project-independent. PN-specific rationale and
curation commentary are recorded here and in individual annotation review
reasons, not in the top-level biological summary.

Pn Notes

(ATP6V0D2-pn-notes.md)

ATP6V0D2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q8N8Y2
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1385)
Batch change status: modified

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V0D2/ATP6V0D2-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V0D2/ATP6V0D2-ai-review.html
Gene notes: present - genes/human/ATP6V0D2/ATP6V0D2-notes.md
GOA TSV: present - genes/human/ATP6V0D2/ATP6V0D2-goa.tsv
UniProt record: present - genes/human/ATP6V0D2/ATP6V0D2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V0D2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V0D2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/ATP6V0D2/ATP6V0D2-deep-research-falcon.md

AIGR Review Snapshot

Description: ATP6V0D2 encodes the d2 isoform of the V0 d subunit of the vacuolar H+-ATPase (V-ATPase). The V-ATPase is a multisubunit enzyme consisting of a peripheral V1 domain that hydrolyzes ATP and a membrane-integral V0 domain responsible for proton translocation. The d subunit is part of the V0 domain and plays a central role in coupling ATP hydrolysis to proton transport by directly interacting with the D and F subunits of the V1 central stalk. ATP6V0D2 shows tissue-restricted expression, predominantly in kidney intercalated cells and osteoclasts, where V-ATPases function at the plasma membrane for urinary acidification and bone resorption, respectively. In clear-cell renal carcinoma models, ATP6V0D2 has also been reported to promote late autophagy by increasing lysosomal acidification and by facilitating autophagosome-lysosome fusion through RAB7/HOPS/SNARE machinery, suggesting a context-dependent role in lysosomal degradative flux in addition to its established V-ATPase subunit function.
Existing/core annotation action counts: ACCEPT: 21; KEEP_AS_NON_CORE: 11; NEW: 2; REMOVE: 2

PN Consistency Summary

Consistency: Deep research (falcon), review, and PN agree: ATP6V0D2 is the d2 isoform of the V0 d subunit (PMID:18752060), tissue-restricted (kidney intercalated cells, osteoclasts; PMID:15800125), with newer ccRCC evidence for late-autophagy lysosomal acidification + RAB7/HOPS fusion (PMID:39477683). Review adds GO:0007042 (NEW, NAS) and GO:0046610 (NEW, IC) — matching both PN projections. No contradictions.
PN story / NEW pressure: PN asserts lysosomal acidification + lysosomal V0-domain componency. For d2 these are genuinely new specificity beyond existing GO:0007035/GO:0033179, and PMID:39477683 gives gene-specific lysosomal-acidification support. Both terms verified real. The review flags appropriate caution (suggested_questions: should GO:0046610 propagate or await direct d2 lysosomal-complex evidence). ADD GO:0007042 + GO:0046610 — implemented, with honest IC/uncertainty framing.
Evidence alignment: PN cites generic V-ATPase/mTORC1 review titles; review adds the gene-specific PMID:18752060, PMID:15800125, PMID:39477683 absent from the PN reference list — a divergence where the review is better-sourced. No conflict.
Verdict: CONSISTENT — both NEW terms (verified real) appropriately added as conservative narrowings; PN projections align with review. No edits required.

Full Consistency Review

UniProt: Q8N8Y2 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
PN placement: two ALP leaves "V0 lysosomal v-ATPase proton pump component". PN-node mapping: leaf→GO:0046610 (more_specific_than_existing_goa); leaf→GO:0033179 (already_in_goa_exact); type→GO:0007042 lysosomal lumen acidification (more_specific_than_existing_goa).
Consistency: Deep research (falcon), review, and PN agree: ATP6V0D2 is the d2 isoform of the V0 d subunit (PMID:18752060), tissue-restricted (kidney intercalated cells, osteoclasts; PMID:15800125), with newer ccRCC evidence for late-autophagy lysosomal acidification + RAB7/HOPS fusion (PMID:39477683). Review adds GO:0007042 (NEW, NAS) and GO:0046610 (NEW, IC) — matching both PN projections. No contradictions.
PN story / NEW pressure: PN asserts lysosomal acidification + lysosomal V0-domain componency. For d2 these are genuinely new specificity beyond existing GO:0007035/GO:0033179, and PMID:39477683 gives gene-specific lysosomal-acidification support. Both terms verified real. The review flags appropriate caution (suggested_questions: should GO:0046610 propagate or await direct d2 lysosomal-complex evidence). ADD GO:0007042 + GO:0046610 — implemented, with honest IC/uncertainty framing.
Mapping strategy: Gene supports the leaf (true V0 d2 subunit). GO:0046610 narrows existing annotations; GO:0007042 narrows GO:0007035 vacuolar acidification — both defensible narrowings, not over-broad. Note d2's strongest isoform-specific biology is plasma-membrane proton secretion (kidney/osteoclast), so lysosomal projection is real-but-context-dependent; review correctly keeps it as a conservative addition, not the sole core.
Evidence alignment: PN cites generic V-ATPase/mTORC1 review titles; review adds the gene-specific PMID:18752060, PMID:15800125, PMID:39477683 absent from the PN reference list — a divergence where the review is better-sourced. No conflict.
Verdict: CONSISTENT — both NEW terms (verified real) appropriately added as conservative narrowings; PN projections align with review. No edits required.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ATP6V0D2/ATP6V0D2-ai-review.yaml
PN workbook rows: 2

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

UniProt: Q8N8Y2
In branches: ALP
Notes: Subunit of the V0 (lysosomal membrane bound) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V0 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain]
  rationale: This PN leaf is restricted to V0-sector lysosomal V-ATPase components. The GO lysosomal V0-domain component term is the direct target.
- [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
  status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
  rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

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

UniProt: Q8N8Y2
In branches: ALP
Notes: Subunit of the V0 (lysosomal membrane bound) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0033179 proton-transporting V-type ATPase, V0 domain]
  rationale: This PN subtype denotes the V0-sector component of the lysosomal V-type ATPase. The GO V0-domain component term is the appropriate propagation target.
- [type] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0007042 lysosomal lumen acidification]
  rationale: This PN group directly names the lysosomal acidification mechanism. Propagation to the GO lysosomal lumen acidification term is an exact mechanistic match.
- [group] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Lysosomal catabolism
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad lysosomal-degradation container. The subtree includes carbohydrate, lipid, protein, nuclease, phosphatase, sulfatase, and environment-regulation roles, so mapping should occur at the enzyme or process subtype level.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

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

Note

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

📄 View Raw YAML

id: Q8N8Y2
gene_symbol: ATP6V0D2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ATP6V0D2 encodes the d2 isoform of the V0 d subunit of the vacuolar H+-ATPase (V-ATPase).
  The V-ATPase is a multisubunit enzyme consisting of a peripheral V1 domain that
  hydrolyzes
  ATP and a membrane-integral V0 domain responsible for proton translocation. The
  d subunit
  is part of the V0 domain and plays a central role in coupling ATP hydrolysis to
  proton
  transport by directly interacting with the D and F subunits of the V1 central stalk.
  ATP6V0D2 shows tissue-restricted expression, predominantly in kidney intercalated
  cells
  and osteoclasts, where V-ATPases function at the plasma membrane for urinary acidification
  and bone resorption, respectively. In clear-cell renal carcinoma models,
  ATP6V0D2 has also been reported to promote late autophagy by increasing
  lysosomal acidification and by facilitating autophagosome-lysosome fusion through
  RAB7/HOPS/SNARE machinery, suggesting a context-dependent role in lysosomal
  degradative flux in addition to its established V-ATPase subunit function.
existing_annotations:
- term:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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"].
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:18752060
      supporting_text: 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
- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  qualifier: contributes_to
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:18752060
      supporting_text: the d subunit in man forms part of the pump's central
        stalk and is thus likely to be important in its rotary mechanism
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:15800125
      supporting_text: in human, kidney and bone are two of the main sites of d2
        mRNA expression
- term:
    id: GO:0007034
    label: vacuolar transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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].
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - file:human/ATP6V0D2/ATP6V0D2-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:39477683
      supporting_text: Mechanistically, ATP6V0D2 directly bound to RAB7 and VPS41
        and promoted the RAB7-HOPS interaction, facilitating SNARE complex assembly
        and autophagosome-lysosome fusion.
- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:15800125
      supporting_text: 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
    - reference_id: PMID:39477683
      supporting_text: ATP6V0D2 promoted autolysosome degradation by increasing
        the acidification and activity of lysosomes during the later stages of
        macroautophagy/autophagy.
- term:
    id: GO:0033181
    label: plasma membrane proton-transporting V-type ATPase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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"].
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:15800125
      supporting_text: 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
- term:
    id: GO:0006811
    label: monoatomic ion transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct annotation supported by multiple lines of evidence. Duplicates are
      acceptable as they represent independent evidence sources.
- term:
    id: GO:0030670
    label: phagocytic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep as a plausible non-core V-ATPase localization from automated inference,
      but do not treat it as a defining ATP6V0D2 cellular component.
- term:
    id: GO:0033179
    label: proton-transporting V-type ATPase, V0 domain
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    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"].
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:18752060
      supporting_text: The V0 d subunit is one of the least characterized of all
        the H+-ATPase components
- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  qualifier: enables
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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.
    action: ACCEPT
    reason: >-
      Core biological process annotation for ATP6V0D2 as a V-ATPase subunit
      involved in proton pumping across membranes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    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.
    action: REMOVE
    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.).
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Duplicate early endosome annotation from Ensembl Compara ortholog transfer.
      Same considerations as the IBA annotation for early endosome.
    action: KEEP_AS_NON_CORE
    reason: >-
      Not a primary localization for ATP6V0D2 based on available literature.
      Retain as non-core.
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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].
    action: ACCEPT
    reason: >-
      Consistent with direct experimental evidence showing d2 at the apical
      plasma membrane of intercalated cells in human kidney.
    supported_by:
    - reference_id: PMID:15800125
      supporting_text: high-intensity d2 staining was observed only in
        intercalated cells of the collecting duct
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9639286
  review:
    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].
    action: ACCEPT
    reason: >-
      Lysosomal membrane localization is a core annotation for ATP6V0D2, supported
      by multiple Reactome entries and primary literature.
    supported_by:
    - reference_id: PMID:39477683
      supporting_text: ATP6V0D2 promoted autolysosome degradation by increasing
        the acidification and activity of lysosomes during the later stages of
        macroautophagy/autophagy.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640167
  review:
    summary: >-
      Duplicate lysosomal membrane annotation from Reactome pathway (RRAG GTP exchange).
      Same evidence and rationale as above.
    action: ACCEPT
    reason: >-
      Core localization annotation, multiple Reactome pathway entries support this.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640168
  review:
    summary: >-
      Duplicate lysosomal membrane annotation from Reactome (V-ATPase:Ragulator
      complex).
    action: ACCEPT
    reason: >-
      Core localization annotation for ATP6V0D2.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640175
  review:
    summary: >-
      Duplicate lysosomal membrane annotation from Reactome pathway.
    action: ACCEPT
    reason: >-
      Core localization annotation for ATP6V0D2.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640195
  review:
    summary: >-
      Duplicate lysosomal membrane annotation from Reactome pathway.
    action: ACCEPT
    reason: >-
      Core localization annotation for ATP6V0D2.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645598
  review:
    summary: >-
      Duplicate lysosomal membrane annotation from Reactome pathway.
    action: ACCEPT
    reason: >-
      Core localization annotation for ATP6V0D2.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645608
  review:
    summary: >-
      Duplicate lysosomal membrane annotation from Reactome (mTORC1 signaling).
    action: ACCEPT
    reason: >-
      Core localization annotation for ATP6V0D2.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9646468
  review:
    summary: >-
      Duplicate lysosomal membrane annotation from Reactome pathway.
    action: ACCEPT
    reason: >-
      Core localization annotation for ATP6V0D2.
- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: NAS
  original_reference_id: PMID:22982048
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:39477683
      supporting_text: Mechanistically, ATP6V0D2 directly bound to RAB7 and VPS41
        and promoted the RAB7-HOPS interaction, facilitating SNARE complex assembly
        and autophagosome-lysosome fusion.
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:15800125
  review:
    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"].
    action: ACCEPT
    reason: >-
      Strong experimental evidence from direct immunolocalization in human kidney
      tissue.
    supported_by:
    - reference_id: PMID:15800125
      supporting_text: 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
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0030670
    label: phagocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1222516
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252133
  review:
    summary: >-
      From Reactome pathway showing ATP6AP1 binding to V-ATPase. Endosome membrane
      localization is consistent with V-ATPase function in endosomal acidification.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74723
  review:
    summary: >-
      From Reactome pathway "Endosome acidification". Core function of V-ATPase.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917841
  review:
    summary: >-
      From Reactome pathway "Acidification of Tf:TfR1 containing endosome".
      V-ATPases acidify endosomes containing transferrin receptor.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18752060
  review:
    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.
    action: REMOVE
    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.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:18752060
  review:
    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"].
    action: ACCEPT
    reason: >-
      Correct but very general annotation. More specific membrane localizations
      (lysosomal membrane, plasma membrane, etc.) are more informative but
      this is not incorrect.
    supported_by:
    - reference_id: PMID:18752060
      supporting_text: It associates with the membrane bound V0 domain, probably
        by protein-protein interactions rather than being directly anchored in
        the membrane
- term:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
  evidence_type: IDA
  original_reference_id: PMID:18752060
  review:
    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"].
    action: ACCEPT
    reason: >-
      Strong experimental evidence confirming ATP6V0D2 as a V-ATPase complex
      component through direct biochemical interaction studies.
    supported_by:
    - reference_id: PMID:18752060
      supporting_text: 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
- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:39477683
  review:
    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.
    action: NEW
    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.
    additional_reference_ids:
    - file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml
    - file:human/ATP6V0D2/ATP6V0D2-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:39477683
      supporting_text: ATP6V0D2 promoted autolysosome degradation by increasing
        the acidification and activity of lysosomes during the later stages of
        macroautophagy/autophagy.
- term:
    id: GO:0046610
    label: lysosomal proton-transporting V-type ATPase, V0 domain
  evidence_type: IC
  original_reference_id: PMID:18752060
  review:
    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.
    action: NEW
    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.
    additional_reference_ids:
    - file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml
    - PMID:39477683
    - file:human/ATP6V0D2/ATP6V0D2-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:18752060
      supporting_text: 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.
    - reference_id: PMID:39477683
      supporting_text: it promoted autophagic degradation of EPAS1 by upregulating
        the ATPase subunit ATP6V0D2 (ATPase H+ transporting V0 subunit d2) to
        increase lysosomal function
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with
    GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data
    to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning
    models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15800125
  title: 'Vacuolar H+-ATPase d2 subunit: molecular characterization, developmental
    regulation, and localization to specialized proton pumps in kidney and bone.'
  findings:
  - statement: ATP6V0D2 shows tissue-restricted expression in kidney and bone
  - statement: d2 localizes to apical plasma membrane of intercalated cells in
      kidney collecting duct
  - statement: d2 co-localizes with a4 subunit in kidney and a3 subunit in
      osteoclasts
- id: PMID:18752060
  title: The d subunit plays a central role in human vacuolar H(+)-ATPases.
  findings:
  - statement: d2 directly interacts with V1 subunits D and F
  - statement: d2 is structurally similar to bacterial A-ATPase subunit C
  - statement: d2 forms part of the pump's central stalk and is important in
      rotary mechanism
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings:
  - statement: ATP6V0D2 identified in urinary exosome proteome
- id: PMID:22982048
  title: Lipofuscin is formed independently of macroautophagy and lysosomal
    activity in stress-induced prematurely senescent human fibroblasts.
  findings:
  - statement: General study of autophagy and lysosomal function, not specific
      to ATP6V0D2
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: High-throughput interactome study, identifies ATP6V0D2 protein
      interactions
- id: Reactome:R-HSA-1222516
  title: Intraphagosomal pH is lowered to 5 by V-ATPase
  findings: []
- id: Reactome:R-HSA-5252133
  title: ATP6AP1 binds V-ATPase
  findings: []
- id: Reactome:R-HSA-74723
  title: Endosome acidification
  findings: []
- id: Reactome:R-HSA-917841
  title: Acidification of Tf:TfR1 containing endosome
  findings: []
- id: Reactome:R-HSA-9639286
  title: RRAGC,D exchanges GTP for GDP
  findings: []
- id: Reactome:R-HSA-9640167
  title: RRAGA,B exchanges GDP for GTP
  findings: []
- id: Reactome:R-HSA-9640168
  title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates
    yielding v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine
  findings: []
- id: Reactome:R-HSA-9640175
  title: v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine
  findings: []
- id: Reactome:R-HSA-9640195
  title: RRAGA,B hydrolyzes GTP
  findings: []
- id: Reactome:R-HSA-9645598
  title: RRAGC,D hydrolyzes GTP
  findings: []
- id: Reactome:R-HSA-9645608
  title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1
  findings: []
- id: Reactome:R-HSA-9646468
  title: mTORC1 binds RHEB:GTP
  findings: []
- id: PMID:39477683
  title: Atractylenolide I inhibits angiogenesis and reverses sunitinib resistance
    in clear cell renal cell carcinoma through ATP6V0D2-mediated autophagic
    degradation of EPAS1/HIF2alpha.
  findings:
  - statement: ATP6V0D2 promotes autophagosome-lysosome fusion through RAB7/HOPS
      and SNARE-complex assembly in ccRCC models.
  - statement: ATP6V0D2 increases lysosomal acidification and activity during
      late autophagy in ccRCC models.
- id: file:human/ATP6V0D2/ATP6V0D2-deep-research-falcon.md
  title: Falcon deep research report for ATP6V0D2
  findings:
  - statement: ATP6V0D2 is a V-ATPase V0 d2 subunit with evidence for specialized
      kidney, osteoclast, lysosomal, and late-autophagy roles.
- id: file:human/ATP6V0D2/ATP6V0D2-notes.md
  title: ATP6V0D2 PN curation notes
  findings:
  - statement: Manual PN review treated lysosomal acidification and lysosomal
      V0-domain projection as conservative new annotation candidates, while keeping
      broader proteostasis/autophagy claims non-core.
- id: file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml
  title: Proteostasis Network autophagy-lysosome pathway mappings
  findings:
  - statement: PN mappings project the lysosomal acidification node to GO:0007042
      and the V0 lysosomal V-ATPase component node to GO:0046610.
core_functions:
- description: >-
    ATP6V0D2 is a structural component of the V0 domain of the vacuolar H+-ATPase,
    serving as the d2 isoform of the d subunit. It links the V1 central stalk
    (D and F subunits) to the V0 proteolipid ring, playing a critical role in
    coupling ATP hydrolysis to proton translocation. Direct biochemical evidence
    from pull-down and in vitro binding experiments [PMID:18752060]; structural
    modeling showing d2 is orthologous to bacterial A-ATPase subunit C.
  contributes_to_molecular_function:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  in_complex:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
- description: >-
    As part of the V-ATPase, ATP6V0D2 contributes to acidification of intracellular
    compartments (lysosomes, endosomes) and extracellular spaces (in specialized
    cells like kidney intercalated cells and osteoclasts). Immunolocalization in
    kidney intercalated cells [PMID:15800125]; ccRCC autophagy experiments showing
    ATP6V0D2-dependent lysosomal acidification/activity [PMID:39477683].
  contributes_to_molecular_function:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  directly_involved_in:
  - id: GO:0007035
    label: vacuolar acidification
  - id: GO:0007042
    label: lysosomal lumen acidification
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  - id: GO:0016324
    label: apical plasma membrane
  supported_by:
  - reference_id: file:human/ATP6V0D2/ATP6V0D2-deep-research-falcon.md
    supporting_text: 'Lysosomal acidification and degradation in human cells:
      The same study shows ATP6V0D2 enhances lysosomal acidification and activity'
proposed_new_terms: []
suggested_questions:
- question: >-
    Does ATP6V0D2 have a specific role in osteoclast bone resorption distinct
    from d1, given its co-localization with a3 rather than a4 in osteoclasts?
    ATP6V0D2 associates with different a-subunit isoforms in different tissues
    (a4 in kidney, a3 in osteoclast). The functional significance of these
    isoform combinations remains unclear.
- question: >-
    Is the autophagosome-lysosome fusion function of ATP6V0D2 independent of
    its incorporation into the V-ATPase complex? Recent studies suggest ATP6V0D2
    promotes fusion via RAB7/HOPS interactions. It is unclear whether this
    requires assembled V-ATPase or if d2 has an independent fusion-promoting function.
- question: >-
    Should the PN-projected GO:0046610 lysosomal proton-transporting V-type ATPase,
    V0 domain annotation be added by propagation for ATP6V0D2, or should it wait
    for direct lysosomal V0-domain complex evidence specific to the d2 isoform?
suggested_experiments:
- description: >-
    Test whether ATP6V0D2 mutants that cannot interact with D/F subunits
    (and thus cannot assemble into V-ATPase) retain autophagosome-lysosome
    fusion activity. This would distinguish V-ATPase-dependent from
    V-ATPase-independent functions of ATP6V0D2 in autophagy.
- description: >-
    Generate tissue-specific d2 knockout mice (kidney intercalated cell-specific,
    osteoclast-specific) to define physiological roles. This would clarify
    whether d2 has unique functions not compensated by d1 in specialized cell types.

ATP6V0D2

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Citations

📚 Additional Documentation

Notes

ATP6V0D2 review notes

Core function

PN projection

Conservative annotation decisions

Description cleanup note

Pn Notes

ATP6V0D2 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

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

Projected GO annotations (3)

Note

📄 View Raw YAML