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.