Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:1902600 proton transmembrane transport	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically-inferred annotation that ATP6V0E2 is involved in proton transmembrane transport, consistent with its role as a V0-sector subunit of the V-ATPase proton pump. Strongly supported by the experimental yeast complementation data and the UniProt function description. Reason: This is the core biological process of the V-ATPase to which e2 contributes. It is independently supported by experimental (IGI) and curatorial (ISS) evidence and by the UniProt FUNCTION statement. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt a membrane integral complex (V0) that translocates protons PMID:17350184 either form of the e-subunit is essential for proper proton pump function
GO:0000220 vacuolar proton-transporting V-type ATPase, V0 domain	IBA GO_REF:0000033	ACCEPT	Summary: ATP6V0E2 is a component of the V0 membrane domain of the vacuolar V-type ATPase. This is the core complex membership for an e-subunit and is well supported. Reason: UniProt SUBUNIT explicitly places subunit e within the V0 proton translocation complex; the IBA assignment is consistent with this. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR.
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IBA GO_REF:0000033	ACCEPT	Summary: As a V0 subunit, e2 contributes to (rather than independently enables) the rotational-mechanism proton-transporting ATPase activity of the holoenzyme. The contributes_to qualifier is the precise and correct usage for an accessory subunit of a multiprotein pump. Reason: The rotational proton-pumping activity is a property of the assembled V1V0 holoenzyme; a single membrane subunit contributes to it. The contributes_to qualifier correctly captures this. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons PMID:17350184 either form of the e-subunit is essential for proper proton pump function
GO:0016020 membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: ATP6V0E2 is an integral, multi-pass membrane protein; localization to membrane is correct but very generic. Reason: True but uninformative relative to more specific compartment terms (lysosomal/endosomal/vesicle membranes). Retained as a non-core, high-level localization statement. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane protein
GO:0030665 clathrin-coated vesicle membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Localization to clathrin-coated vesicle membrane, transferred by similarity from an ortholog (Q5EB76) via UniProt subcellular location mapping. Consistent with V-ATPase distribution across the endomembrane system but not directly demonstrated for human e2. Reason: Plausible compartment for V-ATPase but based on orthology transfer rather than direct human evidence; not the core function of the subunit. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt Cytoplasmic vesicle, clathrin-coated vesicle membrane {ECO:0000250\|UniProtKB:Q5EB76}
GO:0030672 synaptic vesicle membrane	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Localization to synaptic vesicle membrane inferred by automated/orthology methods. V-ATPases acidify synaptic vesicles, so this is biologically plausible, but it derives from ortholog transfer (rat Q5EB76) rather than direct human data. Reason: Reasonable compartment annotation by analogy/orthology; not core and not directly demonstrated for human ATP6V0E2. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane {ECO:0000250\|UniProtKB:Q5EB76}
GO:0033179 proton-transporting V-type ATPase, V0 domain	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based assignment of e2 to the V0 domain of the V-type ATPase, via the e1/e2 subunit InterPro signatures. Consistent with the experimentally supported V0 membership. Reason: Correct complex/domain membership supported by InterPro family signatures (IPR008389, IPR017385) and by the UniProt SUBUNIT description. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based assignment of rotational proton-transporting ATPase activity with the enables qualifier. The activity assignment is correct at the family level, but enables is less precise than contributes_to for a single V0 subunit that cannot pump protons alone. Reason: The molecular function is correct for the V-ATPase family. The enables qualifier is the GOA convention for complex subunits via InterPro; the IBA annotation already captures the more precise contributes_to. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt a membrane integral complex (V0) that translocates protons
GO:1902600 proton transmembrane transport	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based assignment of involvement in proton transmembrane transport. Consistent with the IBA/IGI annotations to the same process. Reason: Core process of the V-ATPase, correctly inferred from InterPro family membership and corroborated by experimental evidence. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt a membrane integral complex (V0) that translocates protons
GO:0000220 vacuolar proton-transporting V-type ATPase, V0 domain	ISS GO_REF:0000024	ACCEPT	Summary: Curator-judged sequence-similarity transfer (from Q2KIB5) placing e2 in the vacuolar V0 domain. Duplicates the IBA assignment to the same term and is well supported. Reason: Correct V0 domain membership supported by orthology and by the UniProt SUBUNIT description. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9639286	KEEP AS NON CORE	Summary: Reactome pathway-context annotation placing the V-ATPase (and thus e2) on the lysosomal membrane during amino-acid/mTORC1 signaling reactions. Localization is correct; the specific reaction context is mTORC1 signaling rather than an e2-specific role. Reason: Lysosomal membrane is a major and correct V-ATPase location, but this annotation derives from a Reactome signaling reaction assigned to the whole complex, not to a unique e2 function. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640167	KEEP AS NON CORE	Summary: Reactome annotation to lysosomal membrane in the context of mTORC1 amino-acid sensing. Correct compartment, complex-level/reaction context. Reason: Duplicate lysosomal membrane localization from a Reactome signaling reaction assigned to the V-ATPase complex; correct but non-core. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640168	KEEP AS NON CORE	Summary: Reactome lysosomal membrane localization from an mTORC1/Ragulator dissociation reaction. Correct compartment for the V-ATPase complex. Reason: Correct but non-core; complex-level localization from a signaling reaction. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640175	KEEP AS NON CORE	Summary: Reactome lysosomal membrane localization (V-ATPase:Ragulator binding SLC38A9:Arginine reaction). Correct compartment, signaling context. Reason: Correct but non-core; complex-level localization from a signaling reaction. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640195	KEEP AS NON CORE	Summary: Reactome lysosomal membrane localization (RRAGA,B GTP hydrolysis reaction). Correct compartment, signaling context. Reason: Correct but non-core; complex-level localization from a signaling reaction. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9645598	KEEP AS NON CORE	Summary: Reactome lysosomal membrane localization (RRAGC,D GTP hydrolysis reaction). Correct compartment, signaling context. Reason: Correct but non-core; complex-level localization from a signaling reaction. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9645608	KEEP AS NON CORE	Summary: Reactome lysosomal membrane localization (V-ATPase:Ragulator binding mTORC1 reaction). Correct compartment, signaling context. Reason: Correct but non-core; complex-level localization from a signaling reaction. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9646468	KEEP AS NON CORE	Summary: Reactome lysosomal membrane localization (mTORC1 binding RHEB:GTP reaction). Correct compartment, signaling context. Reason: Correct but non-core; complex-level localization from a signaling reaction. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IGI PMID:17350184 Molecular cloning and characterization of a novel form of th...	ACCEPT	Summary: Experimental genetic-interaction (yeast complementation) evidence that the human e-subunit restores proton pump function in an e-subunit-deficient yeast strain, supporting its contribution to rotational proton-transporting ATPase activity. The enables qualifier is acceptable per GOA convention, though contributes_to is more precise for a single subunit. Reason: Direct functional evidence (yeast complementation, WITH ortholog Q3E7B6) that e2 is required for proper pump function; strongest support for the molecular function. Supporting Evidence: PMID:17350184 We show by complementation studies in a yeast strain deficient for the ortholog of this subunit, that either form of the e-subunit is essential for proper proton pump function.
GO:1902600 proton transmembrane transport	IGI PMID:17350184 Molecular cloning and characterization of a novel form of th...	ACCEPT	Summary: Experimental genetic-interaction (yeast complementation) evidence that e2 is required for proton pump function, supporting involvement in proton transmembrane transport. Reason: Core process supported by direct functional complementation data. Supporting Evidence: PMID:17350184 either form of the e-subunit is essential for proper proton pump function
GO:0016241 regulation of macroautophagy	NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	MARK AS OVER ANNOTATED	Summary: NAS annotation to regulation of macroautophagy citing a lipofuscin/autophagy study in senescent fibroblasts. That paper does not mention ATP6V0E2 and concerns general lysosomal/autophagy biology; assigning this process to this specific V0 subunit is an over-annotation. While V-ATPase-driven acidification is broadly upstream of autophagy, this subunit does not have a documented direct regulatory role in macroautophagy. Reason: The cited reference does not address ATP6V0E2 and provides no assertion-level support for a macroautophagy-regulation role for this subunit; the process is several steps removed from the subunit's direct function. Supporting Evidence: PMID:22982048 Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-1222516	KEEP AS NON CORE	Summary: Reactome annotation placing the V-ATPase on the phagosome membrane during intraphagosomal acidification. Correct compartment for the complex; not an e2-specific function. Reason: Plausible V-ATPase compartment derived from a Reactome complex-level pathway reaction; non-core for this subunit. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
GO:0010008 endosome membrane	TAS Reactome:R-HSA-5252133	KEEP AS NON CORE	Summary: Reactome annotation placing the V-ATPase on the endosome membrane (ATP6AP1 binds V-ATPase reaction). Correct compartment for the complex. Reason: Correct V-ATPase compartment from a Reactome complex-level reaction; non-core for this subunit. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
GO:0010008 endosome membrane	TAS Reactome:R-HSA-74723	KEEP AS NON CORE	Summary: Reactome annotation to endosome membrane in the context of endosome acidification. Correct compartment for the V-ATPase complex. Reason: Correct but non-core; complex-level localization from a Reactome acidification reaction. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917841	KEEP AS NON CORE	Summary: Reactome annotation to endosome membrane (acidification of Tf:TfR1 endosome). Correct compartment for the V-ATPase complex. Reason: Correct but non-core; complex-level localization from a Reactome acidification reaction. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
GO:0007035 vacuolar acidification	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer (from Q3E7B6) that e2 is involved in vacuolar acidification, the defining physiological output of V-ATPase proton transport. Well supported by the gene/protein name and the UniProt function. Reason: Acidification of intracellular compartments is the direct downstream consequence of the proton transport that e2 contributes to; consistent with the lysosomal e2 alternative name and UniProt FUNCTION. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
GO:0016020 membrane	NAS PMID:17350184 Molecular cloning and characterization of a novel form of th...	KEEP AS NON CORE	Summary: Membrane localization stated in the cloning paper; correct but generic. Reason: True high-level localization; superseded in informativeness by the specific compartment-membrane terms. Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane protein
GO:0042625 ATPase-coupled ion transmembrane transporter activity	ISS GO_REF:0000024	MODIFY	Summary: Generic ATPase-coupled ion transporter activity transferred by similarity. The more specific and accurate molecular function for this V-ATPase subunit is GO:0046961 (proton-transporting ATPase activity, rotational mechanism), which is already annotated. This broader term is redundant and less precise, and e2 contributes to rather than independently enables transporter activity. Reason: A more specific term that accurately captures the rotational proton-pumping mechanism of the V-ATPase is available and already used; the generic term should be replaced by it. Proposed replacements: proton-transporting ATPase activity, rotational mechanism Supporting Evidence: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt a membrane integral complex (V0) that translocates protons

Core Functions

As an accessory membrane subunit (e2) of the V0 proton-translocation sector of the vacuolar H+-ATPase, ATP6V0E2 contributes to ATP-hydrolysis-driven, rotational-mechanism proton transport across endomembranes, thereby acidifying intracellular compartments such as lysosomes and endosomes.

Molecular Function:

structural molecule activity

Directly Involved In:

proton transmembrane transport vacuolar acidification

Cellular Locations:

lysosomal membrane endosome membrane

In Complex:

vacuolar proton-transporting V-type ATPase, V0 domain

Supporting Evidence:

file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons
PMID:17350184
either form of the e-subunit is essential for proper proton pump function

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

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

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

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

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:17350184

Molecular cloning and characterization of a novel form of the human vacuolar H+-ATPase e-subunit: an essential proton pump component.

PMID:22982048

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

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

Suggested Experiments

Experiment: Targeted knockout/knockdown of ATP6V0E2 in cell types with high e2 expression (e.g., kidney or brain-derived cells) followed by ratiometric measurement of lysosomal/endosomal pH to test its specific contribution to compartment acidification relative to e1.

Experiment: Affinity purification of assembled V-ATPase from e2-expressing tissues coupled to mass spectrometry and cryo-EM to define which V0 a-subunit variant complexes incorporate e2 versus e1.

Deep Research

Falcon

(ATP6V0E2-deep-research-falcon.md)

Comprehensive Research Report: ATP6V0E2 (V-type Proton ATPase Subunit e2) Falcon

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: ATP6V0E2 (V-type Proton ATPase Subunit e2)

Gene and Protein Identity

ATP6V0E2 (UniProt ID: Q8NHE4) encodes the human V-type proton ATPase subunit e2, a component of the vacuolar H+-ATPase (V-ATPase) complex (sun2020transcriptomeprofilinganalysis pages 1-2, merkulova2015mappingtheh+ pages 1-2). This protein belongs to the V-ATPase e1/e2 subunit family and contains the ATP_synt_H domain characteristic of this protein family. The gene identity has been confirmed across multiple recent studies investigating V-ATPase function in human cells, with no ambiguity identified in the literature reviewed (sun2020transcriptomeprofilinganalysis pages 1-2, yan2025atp6ap1promotescell pages 1-2).

Structural Organization and Composition

V-ATPase Complex Architecture

V-ATPases are large, evolutionarily conserved rotary proton pumps composed of two major domains (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2). The V1 domain is a peripheral, cytosolic complex responsible for ATP hydrolysis and consists of eight different subunits: A, B, C, D, E, F, G, and H. The V0 domain is an integral membrane complex that translocates protons and comprises subunits a, c, c″, d, and e, along with two accessory proteins ATP6AP1 (Ac45) and ATP6AP2 (the pro-renin receptor) in mammalian cells (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3).

Recent cryo-electron microscopy (cryo-EM) structures of the human V-ATPase, resolved at resolutions up to 2.9 Å, have provided unprecedented detail into the complex's architecture (wang2020structuresofa pages 1-3, wang2020structuresofa pages 5-7). ATP6V0E2, as the subunit e2 isoform, is located within the V0 membrane region where it interacts with subunit a and contributes to the structural integrity of the proton-translocating machinery (abbas2020structureofvatpase pages 1-2, abbas2020structureofvatpase pages 4-5, wang2020structuresofa pages 5-7).

Rotary Mechanism and Stoichiometry

The V-ATPase operates through a rotary catalytic mechanism where ATP hydrolysis in the V1 domain drives rotation of a central rotor complex consisting of subunits D, F, and d, which is connected to the c-ring in the membrane V0 domain (wang2020structuresofa pages 1-3, kishikawa2024rotarymechanismof pages 1-3). Cryo-EM analysis of mammalian brain V-ATPase revealed that the c-ring contains nine copies of subunit c and one copy of subunit c″, establishing an ATP:H+ stoichiometry of 3:10—meaning three ATP molecules are hydrolyzed for every ten protons translocated across the membrane (abbas2020structureofvatpase pages 1-2). This stoichiometry sets a thermodynamic limit on the proton-motive force the enzyme can generate, corresponding to approximately 3 pH units or 180 mV (abbas2020structureofvatpase pages 1-2).

Primary Function and Mechanistic Role

Proton Pumping Mechanism

The primary function of the V-ATPase complex, and by extension ATP6V0E2 as a component of this complex, is ATP-driven proton translocation across cellular membranes (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, chen2022thevatpasesin pages 1-2). ATP hydrolysis at catalytic sites in the V1 A subunits induces conformational changes that drive rotation of the central rotor. This rotation, in turn, powers proton transport through the V0 domain via a half-channel mechanism in subunit a (kishikawa2024rotarymechanismof pages 1-3, abbas2020structureofvatpase pages 4-5).

During the catalytic cycle, protons enter a cytosolic half-channel formed between subunit a and the c-ring, where they protonate conserved glutamate residues on the c-ring subunits. Continued rotation carries these protonated residues through the lipid bilayer to a luminal half-channel in subunit a, where protons are released into the organelle lumen (abbas2020structureofvatpase pages 1-2, chen2022thevatpasesin pages 1-2). Recent molecular dynamics simulations on prokaryotic V-ATPase homologs have shown that protonation of specific glutamate residues triggers unidirectional Brownian motion of the c-ring, facilitating rotation and ATP synthesis in reverse mode (kishikawa2024rotarymechanismof pages 1-3).

Role of Subunit e2

While ATP6V0E2/subunit e does not directly participate in ATP hydrolysis or contain the proton-transport glutamates, it is an integral structural component of the V0 domain that helps maintain the architecture required for proton translocation (abbas2020structureofvatpase pages 4-5, wang2020structuresofa pages 5-7). High-resolution structures show that subunit e, along with subunit f and the C-terminal domain of subunit a, forms part of the membrane-embedded region surrounding the c-ring (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3). The precise molecular function of the e subunit remains less well-characterized than that of the catalytic or proton-conducting subunits, but its conservation across eukaryotic V-ATPases and presence in all functional complexes indicates an essential structural or regulatory role (wang2020structuresofa pages 5-7, wang2023structuralbasisof pages 1-2).

Subcellular Localization

Organelle-Specific Distribution

V-ATPases are found in multiple intracellular compartments and, in specialized cells, at the plasma membrane (eaton2021theh+atpase(vatpase) pages 1-5, chu2021thevatpasea3 pages 1-2, seidel2022theplantvatpase pages 1-2). The complex acidifies lysosomes, endosomes, the Golgi apparatus, the trans-Golgi network, secretory vesicles, and autophagic compartments (eaton2021theh+atpase(vatpase) pages 1-5, tuli2023thecytosolicnterminal pages 1-2, chen2024thedifferentroles pages 1-2). Each organelle maintains a characteristic pH: the endoplasmic reticulum (ER) has a pH of ~7.1, cis-Golgi ~6.8, trans-Golgi network ~6.3, late endosomes ~5.3, and lysosomes/vacuoles ~5.2 (seidel2022theplantvatpase pages 1-2).

Organelle-specific localization of V-ATPases is primarily dictated by subunit isoforms, especially the four a-subunit isoforms (a1-a4) in mammals, which exhibit tissue- and compartment-specific expression patterns (abbas2020structureofvatpase pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, tuli2023thecytosolicnterminal pages 1-2). For example, the a1 isoform is enriched in neuronal synaptic vesicles and endosomes, a2 in Golgi and early endosomes, a3 in lysosomes and the osteoclast ruffled border, and a4 in kidney intercalated cells (chu2021thevatpasea3 pages 1-2, tuli2023thecytosolicnterminal pages 1-2, chen2024thedifferentroles pages 1-2).

ATP6V0E2 Localization

Direct localization data for ATP6V0E2 (subunit e2) specifically are limited in the reviewed literature. However, as a core V0 subunit, ATP6V0E2 is expected to be present wherever fully assembled V-ATPase complexes localize—predominantly in endolysosomal compartments, the Golgi/TGN, and secretory/autophagic vesicles (eaton2021theh+atpase(vatpase) pages 1-5, seidel2022theplantvatpase pages 1-2, chen2024thedifferentroles pages 1-2). In specialized secretory cells like osteoclasts, V-ATPase complexes containing lysosome-specific isoforms (e.g., a3) traffic to and fuse with the plasma membrane to enable extracellular acidification required for bone resorption (chu2021thevatpasea3 pages 1-2).

Biological Pathways and Cellular Processes

Lysosomal Acidification and Autophagy

V-ATPase-mediated acidification is essential for lysosomal function, enabling the activation of pH-dependent hydrolases that degrade cellular macromolecules and organelles delivered via autophagy or endocytosis (eaton2021theh+atpase(vatpase) pages 1-5, sun2020transcriptomeprofilinganalysis pages 1-2, chen2022thevatpasesin pages 1-2). Defective V-ATPase activity impairs lysosomal acidification, leading to accumulation of undigested substrates, which contributes to neurodegenerative lysosomal storage disorders and other pathologies (chen2022thevatpasesin pages 1-2).

A recent study by Sun et al. (2020) demonstrated that the tyrosine kinase inhibitor anlotinib upregulates ATP6V0E2 expression in human colon cancer cells, activating lysosomal function and enhancing autophagosome-lysosome fusion (sun2020transcriptomeprofilinganalysis pages 1-2). Knockdown of either the transcription factor TFEB or ATP6V0E2 attenuated anlotinib-induced lysosomal activation and autophagy, indicating that ATP6V0E2 is functionally important for V-ATPase-dependent lysosomal acidification and autophagy in cancer cells (sun2020transcriptomeprofilinganalysis pages 1-2). The activation of lysosomal function by ATP6V0E2 was found to be mTOR-dependent and protected cancer cells from anlotinib-induced apoptosis by regulating cellular redox status (sun2020transcriptomeprofilinganalysis pages 1-2).

mTORC1 Signaling and Nutrient Sensing

Beyond its canonical proton-pumping function, V-ATPase plays non-canonical roles in nutrient sensing and mTORC1 signaling (eaton2021theh+atpase(vatpase) pages 1-5, banerjee2020regulationofvatpase pages 1-2, tuli2023thecytosolicnterminal pages 1-2). V-ATPase interacts with the Ragulator complex on lysosomal membranes, and amino acid availability modulates V-ATPase assembly state, which in turn regulates mTORC1 localization and activation (eaton2021theh+atpase(vatpase) pages 1-5, tuli2023thecytosolicnterminal pages 1-2). This positions V-ATPase as an integrator of nutritional information that couples lysosomal acidification with cellular growth and metabolic signaling (tuli2023thecytosolicnterminal pages 1-2).

Vesicle Trafficking and Membrane Fusion

V-ATPase contributes to vesicle trafficking through both acidification-dependent and acidification-independent mechanisms (eaton2021theh+atpase(vatpase) pages 1-5, tuli2023thecytosolicnterminal pages 1-2, chen2024thedifferentroles pages 1-2, wang2023structuralbasisof pages 1-2). Proper endosomal pH gradients are required for cargo sorting, receptor recycling, and progression through the endocytic pathway (chen2024thedifferentroles pages 1-2). Recent work in zebrafish microglia and mouse macrophages demonstrated that different V-ATPase a-subunit isoforms (a1 and a3) localize to early/late endosomes and lysosomes, respectively, and play distinct roles in phagosome maturation—a1 regulates early-to-late phagosome transition, while a3 controls late phagosome-lysosome fusion (chen2024thedifferentroles pages 1-2).

V-ATPase also participates in secretory lysosome trafficking in specialized cells like osteoclasts, where lysosomal V-ATPase containing the a3 subunit moves to and fuses with the plasma membrane to secrete lysosomal enzymes and acidify the extracellular space for bone resorption (chu2021thevatpasea3 pages 1-2).

Regulation by Lipids and Reversible Assembly

Phosphatidylinositol phosphate (PIP) lipids directly interact with V-ATPase subunits, particularly the a-subunit isoforms, to regulate enzyme localization and activity (banerjee2020regulationofvatpase pages 1-2). In yeast, the Golgi-enriched lipid PI(4)P binds the Golgi-specific a-subunit isoform Stv1, directing V-ATPase localization, while the lysosomal signaling lipid PI(3,5)P2 affects assembly and activity of the vacuolar a-subunit isoform Vph1 (banerjee2020regulationofvatpase pages 1-2). Similar lipid-dependent regulatory mechanisms are emerging in mammalian systems (banerjee2020regulationofvatpase pages 1-2, tuli2023thecytosolicnterminal pages 1-2).

V-ATPases can undergo reversible dissociation of the V1 and V0 domains in response to glucose deprivation or other stress signals, providing a mechanism to rapidly regulate enzyme activity (wang2023structuralbasisof pages 1-2). Recent studies suggest that this regulatory mechanism may extend to mammalian cells, particularly in the context of lysosome regeneration and autophagy (tuli2023thecytosolicnterminal pages 1-2, wang2023structuralbasisof pages 1-2).

Disease Associations

Cancer

Dysregulation of V-ATPase function is implicated in cancer progression, metastasis, and drug resistance (sun2020transcriptomeprofilinganalysis pages 1-2, chen2022thevatpasesin pages 1-2, yan2025atp6ap1promotescell pages 1-2). Cancer cells often upregulate V-ATPase expression and relocate the complex to the plasma membrane, creating an alkaline intracellular pH and acidic extracellular microenvironment that favors tumor cell proliferation, invasion, and evasion of chemotherapy (chen2022thevatpasesin pages 1-2). Specific V-ATPase subunit isoforms, such as the a3 subunit in breast cancer, are associated with enhanced invasiveness (chen2022thevatpasesin pages 1-2, chu2021thevatpasea3 pages 1-2).

ATP6V0E2 specifically has been identified as overexpressed in luminal breast cancer, where the accessory subunit ATP6AP1 promotes cell proliferation and tamoxifen resistance by activating autophagy through regulation of both lysosomal acidification and autophagosome-lysosome fusion (yan2025atp6ap1promotescell pages 1-2). In the context of anlotinib treatment in colon cancer, ATP6V0E2 upregulation enhances lysosomal function, which paradoxically protects cancer cells from drug-induced apoptosis, suggesting that combining anlotinib with lysosomal inhibitors could be a therapeutic strategy (sun2020transcriptomeprofilinganalysis pages 1-2).

Neurodegenerative Diseases

Defective lysosomal acidification due to V-ATPase dysfunction contributes to neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and lysosomal storage disorders (chen2022thevatpasesin pages 1-2, chu2021thevatpasea3 pages 1-2). In a mouse model of infantile neuronal ceroid lipofuscinosis (INCL), loss of the palmitoyl-protein thioesterase 1 (PPT1) enzyme leads to misrouting of the V0a1 subunit, reducing its lysosomal targeting and impairing V-ATPase-mediated lysosomal acidification (chen2022thevatpasesin pages 1-2). Mutations in the neuronal a1-subunit isoform (ATP6V0A1) cause developmental and epileptic encephalopathies and progressive myoclonus epilepsy through impaired autophagic and lysosomal function (chu2021thevatpasea3 pages 1-2, tuli2023thecytosolicnterminal pages 1-2).

Other Genetic Diseases

Mutations in specific V-ATPase subunit isoforms cause a range of genetic diseases reflecting the tissue-specific functions of these isoforms (eaton2021theh+atpase(vatpase) pages 1-5, chu2021thevatpasea3 pages 1-2). Mutations in the a3 isoform account for over 50% of osteopetrosis cases, a bone disease resulting from impaired osteoclast-mediated bone resorption (chu2021thevatpasea3 pages 1-2). Mutations in the a4 isoform cause distal renal tubular acidosis due to defective proton secretion in kidney intercalated cells (eaton2021theh+atpase(vatpase) pages 1-5, chu2021thevatpasea3 pages 1-2). Loss-of-function mutations in accessory proteins like ATP6AP1 and VMA21 are associated with X-linked myopathy with excessive autophagy and congenital disorders of glycosylation, respectively (wang2023structuralbasisof pages 1-2).

Structural and Bioinformatic Evidence

High-resolution cryo-EM structures of V-ATPase from mammalian brain (rat and bovine) and human sources have been determined at resolutions ranging from 2.9 to 3.9 Å, providing detailed atomic models of the entire complex in multiple rotational states (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, abbas2020structureofvatpase pages 4-5, wang2020structuresofa pages 5-7). These structures reveal that the V0 subunit e is positioned in the membrane domain adjacent to subunit a and the c-ring, contributing to the structural framework that supports proton translocation (abbas2020structureofvatpase pages 4-5, wang2020structuresofa pages 5-7).

The structural conservation of V-ATPase across eukaryotes, from yeast to humans, is remarkable despite variations in subunit isoforms (wang2020structuresofa pages 1-3, tuli2023thecytosolicnterminal pages 1-2). Sequence analysis places ATP6V0E2 in the V-ATPase e1/e2 subunit family, which is conserved across eukaryotic organisms and contains the ATP_synt_H domain characteristic of this family. Evolutionary conservation and the essential nature of V-ATPase for cellular viability underscore the fundamental importance of all core subunits, including subunit e, for proper enzyme function.

Summary Table

Category	Key Information	Citations
Gene/Protein Identity	ATP6V0E2 encodes human V-type proton ATPase subunit e2 (UniProt Q8NHE4), a component of the membrane-embedded V0 domain of the vacuolar H+-ATPase. Literature reviewed consistently refers to ATP6V0E2 as a human V-ATPase subunit associated with lysosomal function and organelle acidification; no competing gene identity emerged in the reviewed sources.	(sun2020transcriptomeprofilinganalysis pages 1-2, merkulova2015mappingtheh+ pages 1-2, yan2025atp6ap1promotescell pages 1-2)
Structural Organization	V-ATPase is a large rotary enzyme with a cytosolic V1 ATP-hydrolysis sector and a membrane V0 proton-translocating sector. Mammalian complexes contain V1 subunits A, B, C, D, E, F, G, H and V0 subunits a, c, c″, d, e, plus accessory proteins ATP6AP1 and ATP6AP2. Cryo-EM structures of mammalian V-ATPase place subunit e2 in the V0 region together with subunits a1, d1, f, ATP6AP1/Ac45, ATP6AP2/PRR, and the c-ring; V-ATPase structures support an overall ATP:H+ ratio of 3:10 in mammalian brain V-ATPase.	(abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, abbas2020structureofvatpase pages 4-5, wang2020structuresofa pages 5-7, chen2022thevatpasesin pages 1-2)
Primary Function/Mechanism	The primary function of V-ATPase is ATP-driven proton pumping to acidify intracellular organelles and, in specialized cells, the extracellular milieu. ATP hydrolysis in V1 drives rotation of the central stalk and c-ring, while the V0 sector translocates protons through offset half-channels in subunit a and protonatable glutamates in the c-ring. ATP6V0E2 itself is therefore best understood as a structural/functional V0 subunit contributing to assembly and operation of the proton pore complex, rather than as an independent catalytic enzyme with its own substrate specificity.	(abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, chen2022thevatpasesin pages 1-2, kishikawa2024rotarymechanismof pages 1-3, tuli2023thecytosolicnterminal pages 1-2, wang2023structuralbasisof pages 1-2)
Subcellular Localization	V-ATPases localize broadly to endosomes, lysosomes, Golgi/trans-Golgi network, secretory vesicles, autophagic compartments, and in specialized cells the plasma membrane. Organelle-specific localization is strongly influenced by subunit isoforms, especially the a-subunit. For ATP6V0E2 specifically, direct localization data are limited in the reviewed literature, but as a V0 subunit it is inferred to function where assembled mammalian V-ATPase complexes acidify endolysosomal and secretory compartments.	(eaton2021theh+atpase(vatpase) pages 1-5, chu2021thevatpasea3 pages 1-2, seidel2022theplantvatpase pages 1-2, tuli2023thecytosolicnterminal pages 1-2, chen2024thedifferentroles pages 1-2)
Biological Pathways	V-ATPase participates in lysosomal acidification, autophagy, endocytic trafficking, phagosome/endosome maturation, membrane trafficking, nutrient sensing, and signaling through mTORC1 and related pathways. In colon cancer cells, anlotinib upregulated ATP6V0E2, promoted TFEB nuclear activity, enhanced lysosomal function and autophagosome-lysosome fusion, and ATP6V0E2 knockdown attenuated these effects. Broader V-ATPase literature also links the complex to amino-acid sensing, Wnt-related functions via accessory subunits, and regulation by lipids and reversible assembly/disassembly.	(sun2020transcriptomeprofilinganalysis pages 1-2, banerjee2020regulationofvatpase pages 1-2, merkulova2015mappingtheh+ pages 1-2, tuli2023thecytosolicnterminal pages 1-2, chen2024thedifferentroles pages 1-2, yan2025atp6ap1promotescell pages 1-2)
Disease Associations	V-ATPase dysfunction is implicated in cancer, neurodegeneration, lysosomal storage disorders, osteopetrosis, distal renal tubular acidosis, and other disorders of trafficking or acid-base physiology. Recent reviews emphasize pathogenic roles of altered V-ATPase localization/regulation in cancer and disease-associated mutations in specific isoforms. For ATP6V0E2 specifically, the strongest direct evidence in the reviewed set is its involvement in drug-response and lysosomal adaptation in cancer cells, where ATP6V0E2 supports lysosomal activation and autophagy during anlotinib treatment; broader associations of ATP6V0E2 expression with cancer phenotypes are suggestive but less mechanistically mature than for some other V-ATPase subunits.	(sun2020transcriptomeprofilinganalysis pages 1-2, chen2022thevatpasesin pages 1-2, chu2021thevatpasea3 pages 1-2, merkulova2015mappingtheh+ pages 1-2, yan2025atp6ap1promotescell pages 1-2, tuli2023thecytosolicnterminal pages 1-2)

Table: This table summarizes the verified identity, structure, function, localization, pathways, and disease relevance of human ATP6V0E2 in the context of the V-ATPase complex. It is useful as a compact evidence map for building the final research report with source-linked claims.

Conclusions

ATP6V0E2 encodes a core structural subunit (subunit e2) of the V-ATPase proton pump, an essential molecular machine responsible for acidifying intracellular organelles in all eukaryotic cells. As part of the membrane-embedded V0 domain, ATP6V0E2 contributes to the rotary proton-pumping mechanism that couples ATP hydrolysis to the generation of pH gradients across lysosomal, endosomal, Golgi, and other organellar membranes. These pH gradients are critical for lysosomal degradation, autophagy, endocytic trafficking, protein processing, and nutrient sensing via mTORC1 signaling.

Recent research highlights ATP6V0E2's role in cancer cell biology, where its upregulation enhances lysosomal function and autophagy in response to therapeutic agents like anlotinib, and where knockdown of ATP6V0E2 impairs these adaptive responses. Broader V-ATPase dysfunction is implicated in neurodegenerative diseases, lysosomal storage disorders, osteoporosis, renal acidosis, and other pathologies arising from defective organellar acidification or trafficking.

While much of the functional understanding of V-ATPase derives from studies of catalytic subunits (A, B), regulatory accessory proteins (ATP6AP1, ATP6AP2), and organelle-targeting isoforms (especially a-subunit isoforms), the structural studies reviewed confirm that ATP6V0E2 is an integral component of the functional V0 complex. Future research defining the precise molecular interactions and regulatory inputs that target subunit e isoforms will further elucidate how V-ATPase subpopulations are assembled, localized, and regulated in health and disease.

References

(sun2020transcriptomeprofilinganalysis pages 1-2): Xin Sun, Yuhan Shu, Peiyi Yan, Hongliang Huang, Ruilan Gao, Mengting Xu, Liqin Lu, Jingkui Tian, Dongsheng Huang, and Jianbin Zhang. Transcriptome profiling analysis reveals that atp6v0e2 is involved in the lysosomal activation by anlotinib. Cell Death & Disease, Aug 2020. URL: https://doi.org/10.1038/s41419-020-02904-0, doi:10.1038/s41419-020-02904-0. This article has 26 citations and is from a peer-reviewed journal.
(merkulova2015mappingtheh+ pages 1-2): Maria Merkulova, Teodor G. Păunescu, Anie Azroyan, Vladimir Marshansky, Sylvie Breton, and Dennis Brown. Mapping the h+ (v)-atpase interactome: identification of proteins involved in trafficking, folding, assembly and phosphorylation. Scientific Reports, Oct 2015. URL: https://doi.org/10.1038/srep14827, doi:10.1038/srep14827. This article has 164 citations and is from a peer-reviewed journal.
(yan2025atp6ap1promotescell pages 1-2): Zhengwei Yan, Aidi Huang, Dongwen Ma, Chenao Hong, Shengmiao Zhang, Luling He, Hai Rao, and Shiwen Luo. Atp6ap1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy. Cell Death & Disease, Mar 2025. URL: https://doi.org/10.1038/s41419-025-07534-y, doi:10.1038/s41419-025-07534-y. This article has 6 citations and is from a peer-reviewed journal.
(wang2020structuresofa pages 1-3): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(eaton2021theh+atpase(vatpase) pages 1-5): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h⁺-atpase (v-atpase): from proton pump to signaling complex in health and disease. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.
(chen2022thevatpasesin pages 1-2): Fangquan Chen, Rui Kang, Jiao Liu, and Daolin Tang. The v-atpases in cancer and cell death. Cancer Gene Therapy, 29:1529-1541, May 2022. URL: https://doi.org/10.1038/s41417-022-00477-y, doi:10.1038/s41417-022-00477-y. This article has 129 citations and is from a peer-reviewed journal.
(abbas2020structureofvatpase pages 1-2): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(wang2020structuresofa pages 5-7): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(abbas2020structureofvatpase pages 4-5): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(kishikawa2024rotarymechanismof pages 1-3): Jun-ichi Kishikawa, Yui Nishida, Atsuki Nakano, Takayuki Kato, Kaoru Mitsuoka, Kei-ichi Okazaki, and Ken Yokoyama. Rotary mechanism of the prokaryotic vo motor driven by proton motive force. Nature Communications, Nov 2024. URL: https://doi.org/10.1038/s41467-024-53504-x, doi:10.1038/s41467-024-53504-x. This article has 7 citations and is from a highest quality peer-reviewed journal.
(wang2023structuralbasisof pages 1-2): Hanlin Wang, Stephanie A. Bueler, and John L. Rubinstein. Structural basis of v-atpase v _o region assembly by vma12p, 21p, and 22p. Proceedings of the National Academy of Sciences, Feb 2023. URL: https://doi.org/10.1073/pnas.2217181120, doi:10.1073/pnas.2217181120. This article has 18 citations and is from a highest quality peer-reviewed journal.
(chu2021thevatpasea3 pages 1-2): Anh Chu, Ralph A. Zirngibl, and Morris F. Manolson. The v-atpase a3 subunit: structure, function and therapeutic potential of an essential biomolecule in osteoclastic bone resorption. International Journal of Molecular Sciences, 22:6934, Jun 2021. URL: https://doi.org/10.3390/ijms22136934, doi:10.3390/ijms22136934. This article has 37 citations.
(seidel2022theplantvatpase pages 1-2): Thorsten Seidel. The plant v-atpase. Frontiers in Plant Science, Jun 2022. URL: https://doi.org/10.3389/fpls.2022.931777, doi:10.3389/fpls.2022.931777. This article has 60 citations.
(tuli2023thecytosolicnterminal pages 1-2): Farzana Tuli and Patricia M. Kane. The cytosolic n-terminal domain of v-atpase a-subunits is a regulatory hub targeted by multiple signals. Frontiers in Molecular Biosciences, Jun 2023. URL: https://doi.org/10.3389/fmolb.2023.1168680, doi:10.3389/fmolb.2023.1168680. This article has 10 citations.
(chen2024thedifferentroles pages 1-2): Qi Chen, Hanjing Kou, Doris Lou Demy, Wei Liu, Jianchao Li, Zilong Wen, Philippe Herbomel, Zhibin Huang, Wenqing Zhang, and Jin Xu. The different roles of v-atpase a subunits in phagocytosis/endocytosis and autophagy. Autophagy, 20:2297-2313, Jun 2024. URL: https://doi.org/10.1080/15548627.2024.2366748, doi:10.1080/15548627.2024.2366748. This article has 27 citations and is from a domain leading peer-reviewed journal.
(banerjee2020regulationofvatpase pages 1-2): Subhrajit Banerjee and Patricia M. Kane. Regulation of v-atpase activity and organelle ph by phosphatidylinositol phosphate lipids. Frontiers in Cell and Developmental Biology, Jun 2020. URL: https://doi.org/10.3389/fcell.2020.00510, doi:10.3389/fcell.2020.00510. This article has 101 citations.

📚 Additional Documentation

Notes

(ATP6V0E2-notes.md)

ATP6V0E2 (Q8NHE4) research notes

Identity

Human gene ATP6V0E2 (synonyms ATP6V0E2L, C7orf32), HGNC:21723, chromosome 7.
Encodes "V-type proton ATPase subunit e 2" (e2), an 81-aa, ~9.2 kDa integral membrane protein.
[UniProt "RecName: Full=V-type proton ATPase subunit e 2; Short=V-ATPase subunit e 2; AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2"].

Function / complex

It is one of two e-subunit forms (e1 = ATP6V0E1; e2 = ATP6V0E2) of the V0 membrane sector of the vacuolar H+-ATPase (V-ATPase).
V-ATPase is a two-sector rotary pump: peripheral V1 hydrolyzes ATP, membrane-integral V0 translocates protons.
[UniProt "Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons"].
The V0 sector includes "the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR" [UniProt SUBUNIT].
V-ATPase "is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment" [UniProt FUNCTION].
Belongs to the V-ATPase e1/e2 subunit family [UniProt SIMILARITY].

Evidence that e2 is functionally essential for the pump

PMID:17350184 cloned ATP6V0E2 and tested it functionally by yeast complementation:
PMID:17350184
This is the basis for the IGI annotations to GO:0046961 (proton-transporting ATPase activity, rotational mechanism) and GO:1902600 (proton transmembrane transport), with WITH=UniProtKB:Q3E7B6 (yeast/ortholog e-subunit).
The same paper notes the gene has a restricted tissue distribution distinct from the ubiquitous e1:
PMID:17350184
UniProt TISSUE SPECIFICITY: [UniProt "Isoform 1 is expressed at high levels in heart, brain and kidney and also detected in inner ear epithelium, vestibule, testis, epididymis and bladder."]

Localization

UniProt SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein. Cytoplasmic vesicle, clathrin-coated vesicle membrane (by similarity to Q5EB76). Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane (by similarity to Q5EB76).
[UniProt "SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane protein {ECO:0000255}. Cytoplasmic vesicle, clathrin-coated vesicle membrane {ECO:0000250|UniProtKB:Q5EB76}"].
Topology: two transmembrane helices (8-28, 36-56), N-terminus lumenal, C-terminus lumenal [UniProt FT TRANSMEM/TOPO_DOM]. (Note: UniProt "Multi-pass" but the chain shows 2 TM helices.)
Reactome places the V-ATPase (and thus this subunit) on lysosomal membrane, endosome membrane, and phagocytic (phagosome) membrane in the context of organelle acidification reactions and mTORC1/amino-acid-sensing reactions. These are TAS pathway-context annotations transferred to the whole complex.

Annotation assessment summary

Core molecular function: contribute to proton-transporting ATPase activity (rotational mechanism) as a V0 membrane subunit; core process: proton transmembrane transport / vacuolar acidification; core localization: V0 domain / membrane of acidified organelles.
IBA (GO_REF:0000033) and ISS (GO_REF:0000024 from Q2KIB5/Q3E7B6) and IGI (PMID:17350184) annotations to proton transport, V0 domain membership, and rotational ATPase activity are all consistent and well-supported by the experimental complementation data and structural family assignment.
GO:0046961 with qualifier "contributes_to"/"enables" is appropriate because a single subunit contributes to the holoenzyme activity rather than enabling it alone. The IBA uses contributes_to (correct); the IEA/IGI use enables (acceptable per GOA convention for complex subunits but contributes_to is more precise).
The various Reactome lysosomal/endosomal/phagosomal membrane TAS annotations are consistent with the known localization of V-ATPase; they are acceptable as non-core compartment annotations.
The Reactome mTORC1/amino-acid-sensing reactions (R-HSA-9639286 etc.) annotate the V-ATPase complex's location to lysosomal membrane; these are reasonable as compartment annotations but reflect the mTORC1 signaling literature, not a direct e2-specific role.
GO:0016241 regulation of macroautophagy (NAS, PMID:22982048): the cited paper (Höhn et al.) is a lipofuscin/autophagy study in senescent fibroblasts that does NOT mention ATP6V0E2 specifically; it concerns general lysosomal/autophagy biology. This is a weak/over-broad annotation for this subunit — V-ATPase acidification is upstream of autophagy generally, but assigning "regulation of macroautophagy" to this specific subunit from this reference is an over-annotation. Mark as over-annotated.
GO:0042625 (ATPase-coupled ion transmembrane transporter activity, ISS): generic; the more specific GO:0046961 (rotational-mechanism proton ATPase) is the better term, and e2 contributes to rather than enables transporter activity. Treat as a less-specific overlap; keep as non-core / over-annotated relative to GO:0046961.
No bare "protein binding" (GO:0005515) annotation present in this GOA.

Proposed actions (high level)

ACCEPT: proton transmembrane transport (IBA, IGI), V0 domain membership (IBA, ISS, IEA GO:0033179), rotational ATPase activity (IBA contributes_to; IGI), membrane (NAS/IEA), vacuolar acidification (ISS).
KEEP_AS_NON_CORE: lysosomal membrane, endosome membrane, phagocytic vesicle membrane, clathrin-coated vesicle membrane, synaptic vesicle membrane (compartment annotations).
MARK_AS_OVER_ANNOTATED: regulation of macroautophagy (NAS from non-specific ref); ATPase-coupled ion transmembrane transporter activity (generic, superseded by GO:0046961).

Falcon deep research synthesis (2026-06-21)

Falcon deep research has now completed (file:human/ATP6V0E2/ATP6V0E2-deep-research-falcon.md,
26 citations). It corroborates the e2-subunit biology above and adds one
e2-specific functional study; no change to annotation calls.

e2 is an integral structural V0 subunit (with f and the subunit-a
C-terminal domain it surrounds the c-ring); it does not hydrolyze ATP or carry
the proton-transport glutamates. Conserved and present in all functional
complexes → essential structural/regulatory role (Abbas 2020; Wang 2020). This
matches the IGI-based GO:0046961/GO:1902600 annotations from yeast
complementation already cited.
e2-specific functional evidence (Sun et al. 2020). In human colon cancer
cells, the TKI anlotinib upregulates ATP6V0E2 via TFEB, activating lysosomal
function and autophagosome–lysosome fusion; knockdown of TFEB or ATP6V0E2
attenuates this, and the effect is mTOR-dependent and cytoprotective. This is
direct evidence that e2 is functionally important for V-ATPase-dependent
lysosomal acidification/autophagy — a (cancer-context, non-core) corroboration
of the core acidification function rather than a new MF.
General regulatory context (not e2-specific MF): reversible V1/V0
dissociation under glucose/stress, and PIP-lipid (PI(4)P, PI(3,5)P2) regulation
of a-subunit isoform localization. Useful background; not e2 annotations.
Tissue distribution (heart/brain/kidney, inner ear, etc.) as already noted;
consistent with e2 being the restricted paralog vs ubiquitous e1.

Net: no change to calls — e2 is the tissue-restricted paralog of the small,
essential V0 structural subunit e, supporting organellar acidification.

Pn Notes

(ATP6V0E2-pn-notes.md)

ATP6V0E2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q8NHE4
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V0E2/ATP6V0E2-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V0E2/ATP6V0E2-ai-review.html
Gene notes: present - genes/human/ATP6V0E2/ATP6V0E2-notes.md
GOA TSV: present - genes/human/ATP6V0E2/ATP6V0E2-goa.tsv
UniProt record: present - genes/human/ATP6V0E2/ATP6V0E2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V0E2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V0E2.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

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AIGR Review Snapshot

Description: ATP6V0E2 encodes the "e2" form of the V-type proton ATPase (V-ATPase) subunit e, a small (81 aa, ~9.2 kDa) integral membrane protein with two transmembrane helices. It is one of two e-subunit paralogs in human (e1 = ATP6V0E1, e2 = ATP6V0E2) and is an accessory membrane component of the V0 proton-translocation sector of the V-ATPase. The V-ATPase is a rotary proton pump composed of a peripheral, cytoplasmic V1 sector that hydrolyzes ATP and a membrane-integral V0 sector that translocates protons across the membrane; together they acidify and maintain the pH of intracellular compartments including lysosomes, endosomes, the Golgi, secretory vesicles, synaptic vesicles, clathrin-coated vesicles and phagosomes, and in some cell types the plasma membrane. As a V0 subunit, e2 contributes to the assembly and proton-pumping function of the holoenzyme; yeast complementation studies show the e-subunit is essential for proper pump function. Unlike the ubiquitously expressed e1, ATP6V0E2 has a more restricted tissue distribution with high expression in heart, brain and kidney.
Existing/core annotation action counts: ACCEPT: 10; KEEP_AS_NON_CORE: 16; MARK_AS_OVER_ANNOTATED: 1; MODIFY: 1

PN Consistency Summary

Consistency: Review and PN agree on the core identity: e2 is an accessory V0-sector membrane subunit (PMID:17350184 yeast complementation), part_of vacuolar V0 domain (GO:0000220/GO:0033179, both ACCEPT) and involved in proton transport/vacuolar acidification. The review carries multiple TAS lysosomal-membrane annotations (Reactome), so a lysosomal context is genuinely supported here (unlike the strictly plasma-membrane isoforms). PN-projection terms GO:0046610, GO:0007042, GO:0033179 all verified real via OLS. No contradictions. Minor: PN Notes text (shared template across the V-ATPase batch) is appropriate for e2 since it is a true V0 subunit.
PN story / NEW pressure: PN asserts lysosomal V0-domain componency + lysosomal lumen acidification — more specific than the review's vacuolar-level terms. GO:0046610 (child of GO:0000220) and GO:0007042 (child of GO:0007035, which the review ACCEPTs as ISS) are defensible narrowings; e2 has lysosomal-membrane TAS support. The review did NOT add these. ADD GO:0046610 + GO:0007042 — defensible (verified real), but mark as project-context narrowings of the already-accepted vacuolar terms.
Evidence alignment: PN cites only generic V-ATPase/mTORC1 review titles; review is better-sourced with the gene-specific PMID:17350184 (e-subunit essentiality) plus Reactome lysosomal reactions. Divergence is review-favorable; no conflict.
Verdict: CONSISTENT — lysosomal projection defensible for this V0 subunit; PN terms verified real. Optional: add GO:0046610/GO:0007042 to review as conservative narrowings.

Full Consistency Review

UniProt: Q8NHE4 · batch: proteostasis-batch-2026-06-07 · review status: COMPLETE
PN placement: two ALP leaves "V0 lysosomal v-ATPase proton pump component" (under Nutrient sensing; and under Lysosomal acidification). PN-node mapping: leaf→GO:0046610 lysosomal V0 domain (more_specific_than_existing_goa); leaf→GO:0033179 V0 domain (already_in_goa_exact); type→GO:0007042 lysosomal lumen acidification (more_specific_than_existing_goa). Higher ancestors no_mapping/context_only.
Consistency: Review and PN agree on the core identity: e2 is an accessory V0-sector membrane subunit (PMID:17350184 yeast complementation), part_of vacuolar V0 domain (GO:0000220/GO:0033179, both ACCEPT) and involved in proton transport/vacuolar acidification. The review carries multiple TAS lysosomal-membrane annotations (Reactome), so a lysosomal context is genuinely supported here (unlike the strictly plasma-membrane isoforms). PN-projection terms GO:0046610, GO:0007042, GO:0033179 all verified real via OLS. No contradictions. Minor: PN Notes text (shared template across the V-ATPase batch) is appropriate for e2 since it is a true V0 subunit.
PN story / NEW pressure: PN asserts lysosomal V0-domain componency + lysosomal lumen acidification — more specific than the review's vacuolar-level terms. GO:0046610 (child of GO:0000220) and GO:0007042 (child of GO:0007035, which the review ACCEPTs as ISS) are defensible narrowings; e2 has lysosomal-membrane TAS support. The review did NOT add these. ADD GO:0046610 + GO:0007042 — defensible (verified real), but mark as project-context narrowings of the already-accepted vacuolar terms.
Mapping strategy: Gene legitimately supports both V0 leaves. Lysosomal projection is reasonable for e2 (broader tissue distribution: heart/brain/kidney; lysosomal Reactome+altname evidence). Projections narrow existing GOA, not over-broad. No node-mapping change needed.
Evidence alignment: PN cites only generic V-ATPase/mTORC1 review titles; review is better-sourced with the gene-specific PMID:17350184 (e-subunit essentiality) plus Reactome lysosomal reactions. Divergence is review-favorable; no conflict.
Verdict: CONSISTENT — lysosomal projection defensible for this V0 subunit; PN terms verified real. Optional: add GO:0046610/GO:0007042 to review as conservative narrowings.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07
review_yaml: genes/human/ATP6V0E2/ATP6V0E2-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: Q8NHE4
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: Q8NHE4
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: Q8NHE4
gene_symbol: ATP6V0E2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ATP6V0E2 encodes the "e2" form of the V-type proton ATPase (V-ATPase) subunit e,
  a small (81 aa, ~9.2 kDa) integral membrane protein with two transmembrane
  helices. It is one of two e-subunit paralogs in human (e1 = ATP6V0E1, e2 =
  ATP6V0E2) and is an accessory membrane component of the V0 proton-translocation
  sector of the V-ATPase. The V-ATPase is a rotary proton pump composed of a
  peripheral, cytoplasmic V1 sector that hydrolyzes ATP and a membrane-integral V0
  sector that translocates protons across the membrane; together they acidify and
  maintain the pH of intracellular compartments including lysosomes, endosomes,
  the Golgi, secretory vesicles, synaptic vesicles, clathrin-coated vesicles and
  phagosomes, and in some cell types the plasma membrane. As a V0 subunit, e2
  contributes to the assembly and proton-pumping function of the holoenzyme;
  yeast complementation studies show the e-subunit is essential for proper pump
  function. Unlike the ubiquitously expressed e1, ATP6V0E2 has a more restricted
  tissue distribution with high expression in heart, brain and kidney.
alternative_products:
- name: '1'
  id: Q8NHE4-1
- name: '2'
  id: Q8NHE4-2
  sequence_note: VSP_027104
- name: '3'
  id: Q8NHE4-3
  sequence_note: VSP_027105
- name: '4'
  id: Q8NHE4-4
  sequence_note: VSP_044857
existing_annotations:
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically-inferred annotation that ATP6V0E2 is involved in proton
      transmembrane transport, consistent with its role as a V0-sector subunit of
      the V-ATPase proton pump. Strongly supported by the experimental yeast
      complementation data and the UniProt function description.
    action: ACCEPT
    reason: >-
      This is the core biological process of the V-ATPase to which e2 contributes.
      It is independently supported by experimental (IGI) and curatorial (ISS)
      evidence and by the UniProt FUNCTION statement.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        a membrane integral complex (V0) that translocates protons
      reference_section_type: DATABASE_ENTRY
    - reference_id: PMID:17350184
      supporting_text: >-
        either form of the e-subunit is essential for proper proton pump function
      reference_section_type: ABSTRACT
- term:
    id: GO:0000220
    label: vacuolar proton-transporting V-type ATPase, V0 domain
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      ATP6V0E2 is a component of the V0 membrane domain of the vacuolar
      V-type ATPase. This is the core complex membership for an e-subunit and is
      well supported.
    action: ACCEPT
    reason: >-
      UniProt SUBUNIT explicitly places subunit e within the V0 proton
      translocation complex; the IBA assignment is consistent with this.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        The proton translocation complex V0 consists of the proton transport
        subunit a, a ring of proteolipid subunits c9c'', rotary subunit d,
        subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR.
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: >-
      As a V0 subunit, e2 contributes to (rather than independently enables) the
      rotational-mechanism proton-transporting ATPase activity of the holoenzyme.
      The contributes_to qualifier is the precise and correct usage for an
      accessory subunit of a multiprotein pump.
    action: ACCEPT
    reason: >-
      The rotational proton-pumping activity is a property of the assembled
      V1V0 holoenzyme; a single membrane subunit contributes to it. The
      contributes_to qualifier correctly captures this.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        a multisubunit enzyme composed of a peripheral complex (V1) that
        hydrolyzes ATP and a membrane integral complex (V0) that translocates
        protons
      reference_section_type: DATABASE_ENTRY
    - reference_id: PMID:17350184
      supporting_text: >-
        either form of the e-subunit is essential for proper proton pump function
      reference_section_type: ABSTRACT
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      ATP6V0E2 is an integral, multi-pass membrane protein; localization to
      membrane is correct but very generic.
    action: KEEP_AS_NON_CORE
    reason: >-
      True but uninformative relative to more specific compartment terms
      (lysosomal/endosomal/vesicle membranes). Retained as a non-core,
      high-level localization statement.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane protein
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0030665
    label: clathrin-coated vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Localization to clathrin-coated vesicle membrane, transferred by similarity
      from an ortholog (Q5EB76) via UniProt subcellular location mapping.
      Consistent with V-ATPase distribution across the endomembrane system but
      not directly demonstrated for human e2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible compartment for V-ATPase but based on orthology transfer rather
      than direct human evidence; not the core function of the subunit.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        Cytoplasmic vesicle, clathrin-coated vesicle membrane
        {ECO:0000250|UniProtKB:Q5EB76}
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0030672
    label: synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Localization to synaptic vesicle membrane inferred by automated/orthology
      methods. V-ATPases acidify synaptic vesicles, so this is biologically
      plausible, but it derives from ortholog transfer (rat Q5EB76) rather than
      direct human data.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reasonable compartment annotation by analogy/orthology; not core and not
      directly demonstrated for human ATP6V0E2.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane
        {ECO:0000250|UniProtKB:Q5EB76}
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0033179
    label: proton-transporting V-type ATPase, V0 domain
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: >-
      InterPro-based assignment of e2 to the V0 domain of the V-type ATPase, via
      the e1/e2 subunit InterPro signatures. Consistent with the experimentally
      supported V0 membership.
    action: ACCEPT
    reason: >-
      Correct complex/domain membership supported by InterPro family signatures
      (IPR008389, IPR017385) and by the UniProt SUBUNIT description.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        The proton translocation complex V0 consists of the proton transport
        subunit a, a ring of proteolipid subunits c9c'', rotary subunit d,
        subunits e and f
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based assignment of rotational proton-transporting ATPase activity
      with the enables qualifier. The activity assignment is correct at the
      family level, but enables is less precise than contributes_to for a single
      V0 subunit that cannot pump protons alone.
    action: ACCEPT
    reason: >-
      The molecular function is correct for the V-ATPase family. The enables
      qualifier is the GOA convention for complex subunits via InterPro; the
      IBA annotation already captures the more precise contributes_to.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        a membrane integral complex (V0) that translocates protons
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-based assignment of involvement in proton transmembrane transport.
      Consistent with the IBA/IGI annotations to the same process.
    action: ACCEPT
    reason: >-
      Core process of the V-ATPase, correctly inferred from InterPro family
      membership and corroborated by experimental evidence.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        a membrane integral complex (V0) that translocates protons
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0000220
    label: vacuolar proton-transporting V-type ATPase, V0 domain
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: >-
      Curator-judged sequence-similarity transfer (from Q2KIB5) placing e2 in the
      vacuolar V0 domain. Duplicates the IBA assignment to the same term and is
      well supported.
    action: ACCEPT
    reason: >-
      Correct V0 domain membership supported by orthology and by the UniProt
      SUBUNIT description.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9639286
  qualifier: located_in
  review:
    summary: >-
      Reactome pathway-context annotation placing the V-ATPase (and thus e2) on
      the lysosomal membrane during amino-acid/mTORC1 signaling reactions.
      Localization is correct; the specific reaction context is mTORC1 signaling
      rather than an e2-specific role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Lysosomal membrane is a major and correct V-ATPase location, but this
      annotation derives from a Reactome signaling reaction assigned to the whole
      complex, not to a unique e2 function.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640167
  qualifier: located_in
  review:
    summary: >-
      Reactome annotation to lysosomal membrane in the context of mTORC1
      amino-acid sensing. Correct compartment, complex-level/reaction context.
    action: KEEP_AS_NON_CORE
    reason: >-
      Duplicate lysosomal membrane localization from a Reactome signaling
      reaction assigned to the V-ATPase complex; correct but non-core.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640168
  qualifier: located_in
  review:
    summary: >-
      Reactome lysosomal membrane localization from an mTORC1/Ragulator
      dissociation reaction. Correct compartment for the V-ATPase complex.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but non-core; complex-level localization from a signaling reaction.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640175
  qualifier: located_in
  review:
    summary: >-
      Reactome lysosomal membrane localization (V-ATPase:Ragulator binding
      SLC38A9:Arginine reaction). Correct compartment, signaling context.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but non-core; complex-level localization from a signaling reaction.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640195
  qualifier: located_in
  review:
    summary: >-
      Reactome lysosomal membrane localization (RRAGA,B GTP hydrolysis reaction).
      Correct compartment, signaling context.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but non-core; complex-level localization from a signaling reaction.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645598
  qualifier: located_in
  review:
    summary: >-
      Reactome lysosomal membrane localization (RRAGC,D GTP hydrolysis reaction).
      Correct compartment, signaling context.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but non-core; complex-level localization from a signaling reaction.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645608
  qualifier: located_in
  review:
    summary: >-
      Reactome lysosomal membrane localization (V-ATPase:Ragulator binding
      mTORC1 reaction). Correct compartment, signaling context.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but non-core; complex-level localization from a signaling reaction.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9646468
  qualifier: located_in
  review:
    summary: >-
      Reactome lysosomal membrane localization (mTORC1 binding RHEB:GTP reaction).
      Correct compartment, signaling context.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but non-core; complex-level localization from a signaling reaction.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        AltName: Full=Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IGI
  original_reference_id: PMID:17350184
  qualifier: enables
  review:
    summary: >-
      Experimental genetic-interaction (yeast complementation) evidence that the
      human e-subunit restores proton pump function in an e-subunit-deficient
      yeast strain, supporting its contribution to rotational proton-transporting
      ATPase activity. The enables qualifier is acceptable per GOA convention,
      though contributes_to is more precise for a single subunit.
    action: ACCEPT
    reason: >-
      Direct functional evidence (yeast complementation, WITH ortholog Q3E7B6)
      that e2 is required for proper pump function; strongest support for the
      molecular function.
    supported_by:
    - reference_id: PMID:17350184
      supporting_text: >-
        We show by complementation studies in a yeast strain deficient for the
        ortholog of this subunit, that either form of the e-subunit is essential
        for proper proton pump function.
      reference_section_type: ABSTRACT
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IGI
  original_reference_id: PMID:17350184
  qualifier: involved_in
  review:
    summary: >-
      Experimental genetic-interaction (yeast complementation) evidence that e2 is
      required for proton pump function, supporting involvement in proton
      transmembrane transport.
    action: ACCEPT
    reason: >-
      Core process supported by direct functional complementation data.
    supported_by:
    - reference_id: PMID:17350184
      supporting_text: >-
        either form of the e-subunit is essential for proper proton pump function
      reference_section_type: ABSTRACT
- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: NAS
  original_reference_id: PMID:22982048
  qualifier: involved_in
  review:
    summary: >-
      NAS annotation to regulation of macroautophagy citing a lipofuscin/autophagy
      study in senescent fibroblasts. That paper does not mention ATP6V0E2 and
      concerns general lysosomal/autophagy biology; assigning this process to this
      specific V0 subunit is an over-annotation. While V-ATPase-driven
      acidification is broadly upstream of autophagy, this subunit does not have a
      documented direct regulatory role in macroautophagy.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The cited reference does not address ATP6V0E2 and provides no
      assertion-level support for a macroautophagy-regulation role for this
      subunit; the process is several steps removed from the subunit's direct
      function.
    supported_by:
    - reference_id: PMID:22982048
      supporting_text: >-
        Lipofuscin is formed independently of macroautophagy and lysosomal
        activity in stress-induced prematurely senescent human fibroblasts.
      reference_section_type: TITLE
- term:
    id: GO:0030670
    label: phagocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1222516
  qualifier: located_in
  review:
    summary: >-
      Reactome annotation placing the V-ATPase on the phagosome membrane during
      intraphagosomal acidification. Correct compartment for the complex; not an
      e2-specific function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible V-ATPase compartment derived from a Reactome complex-level
      pathway reaction; non-core for this subunit.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        V-ATPase is responsible for acidifying and maintaining the pH of
        intracellular compartments
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252133
  qualifier: located_in
  review:
    summary: >-
      Reactome annotation placing the V-ATPase on the endosome membrane
      (ATP6AP1 binds V-ATPase reaction). Correct compartment for the complex.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct V-ATPase compartment from a Reactome complex-level reaction;
      non-core for this subunit.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        V-ATPase is responsible for acidifying and maintaining the pH of
        intracellular compartments
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74723
  qualifier: located_in
  review:
    summary: >-
      Reactome annotation to endosome membrane in the context of endosome
      acidification. Correct compartment for the V-ATPase complex.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but non-core; complex-level localization from a Reactome
      acidification reaction.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        V-ATPase is responsible for acidifying and maintaining the pH of
        intracellular compartments
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917841
  qualifier: located_in
  review:
    summary: >-
      Reactome annotation to endosome membrane (acidification of Tf:TfR1
      endosome). Correct compartment for the V-ATPase complex.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but non-core; complex-level localization from a Reactome
      acidification reaction.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        V-ATPase is responsible for acidifying and maintaining the pH of
        intracellular compartments
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer (from Q3E7B6) that e2 is involved in vacuolar
      acidification, the defining physiological output of V-ATPase proton
      transport. Well supported by the gene/protein name and the UniProt function.
    action: ACCEPT
    reason: >-
      Acidification of intracellular compartments is the direct downstream
      consequence of the proton transport that e2 contributes to; consistent with
      the lysosomal e2 alternative name and UniProt FUNCTION.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        V-ATPase is responsible for acidifying and maintaining the pH of
        intracellular compartments
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0016020
    label: membrane
  evidence_type: NAS
  original_reference_id: PMID:17350184
  qualifier: located_in
  review:
    summary: >-
      Membrane localization stated in the cloning paper; correct but generic.
    action: KEEP_AS_NON_CORE
    reason: >-
      True high-level localization; superseded in informativeness by the
      specific compartment-membrane terms.
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane protein
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0042625
    label: ATPase-coupled ion transmembrane transporter activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Generic ATPase-coupled ion transporter activity transferred by similarity.
      The more specific and accurate molecular function for this V-ATPase subunit
      is GO:0046961 (proton-transporting ATPase activity, rotational mechanism),
      which is already annotated. This broader term is redundant and less precise,
      and e2 contributes to rather than independently enables transporter activity.
    action: MODIFY
    reason: >-
      A more specific term that accurately captures the rotational proton-pumping
      mechanism of the V-ATPase is available and already used; the generic term
      should be replaced by it.
    proposed_replacement_terms:
    - id: GO:0046961
      label: proton-transporting ATPase activity, rotational mechanism
    supported_by:
    - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
      supporting_text: >-
        a membrane integral complex (V0) that translocates protons
      reference_section_type: DATABASE_ENTRY
core_functions:
- description: >-
    As an accessory membrane subunit (e2) of the V0 proton-translocation sector of
    the vacuolar H+-ATPase, ATP6V0E2 contributes to ATP-hydrolysis-driven,
    rotational-mechanism proton transport across endomembranes, thereby acidifying
    intracellular compartments such as lysosomes and endosomes.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  contributes_to_molecular_function:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  directly_involved_in:
  - id: GO:1902600
    label: proton transmembrane transport
  - id: GO:0007035
    label: vacuolar acidification
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  - id: GO:0010008
    label: endosome membrane
  in_complex:
    id: GO:0000220
    label: vacuolar proton-transporting V-type ATPase, V0 domain
  supported_by:
  - reference_id: file:human/ATP6V0E2/ATP6V0E2-uniprot.txt
    supporting_text: >-
      Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit
      enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a
      membrane integral complex (V0) that translocates protons
    reference_section_type: DATABASE_ENTRY
  - reference_id: PMID:17350184
    supporting_text: >-
      either form of the e-subunit is essential for proper proton pump function
    reference_section_type: ABSTRACT
proposed_new_terms: []
suggested_questions:
- question: >-
    Do the e1 (ATP6V0E1) and e2 (ATP6V0E2) subunits confer distinct
    compartment-specific or tissue-specific V-ATPase functions, given e2's
    restricted expression in heart, brain and kidney?
- question: >-
    Is e2 incorporated into V-ATPase complexes with particular V0 a-subunit
    isoforms (ATP6V0A1-A4), as suggested by the multiple ComplexPortal variant
    complexes listing this subunit?
suggested_experiments:
- description: >-
    Targeted knockout/knockdown of ATP6V0E2 in cell types with high e2 expression
    (e.g., kidney or brain-derived cells) followed by ratiometric measurement of
    lysosomal/endosomal pH to test its specific contribution to compartment
    acidification relative to e1.
- description: >-
    Affinity purification of assembled V-ATPase from e2-expressing tissues coupled
    to mass spectrometry and cryo-EM to define which V0 a-subunit variant complexes
    incorporate e2 versus e1.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:17350184
  title: 'Molecular cloning and characterization of a novel form of the human vacuolar
    H+-ATPase e-subunit: an essential proton pump component.'
  findings: []
- id: PMID:22982048
  title: Lipofuscin is formed independently of macroautophagy and lysosomal activity
    in stress-induced prematurely senescent human fibroblasts.
  findings: []
- 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: []

ATP6V0E2

Gene Description

Existing Annotations Review

Core Functions

As an accessory membrane subunit (e2) of the V0 proton-translocation sector of the vacuolar H+-ATPase, ATP6V0E2 contributes to ATP-hydrolysis-driven, rotational-mechanism proton transport across endomembranes, thereby acidifying intracellular compartments such as lysosomes and endosomes.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: ATP6V0E2 (V-type Proton ATPase Subunit e2)

Gene and Protein Identity

Structural Organization and Composition

V-ATPase Complex Architecture

Rotary Mechanism and Stoichiometry

Primary Function and Mechanistic Role

Proton Pumping Mechanism

Role of Subunit e2

Subcellular Localization

Organelle-Specific Distribution

ATP6V0E2 Localization

Biological Pathways and Cellular Processes

Lysosomal Acidification and Autophagy

mTORC1 Signaling and Nutrient Sensing

Vesicle Trafficking and Membrane Fusion

Regulation by Lipids and Reversible Assembly

Disease Associations

Cancer

Neurodegenerative Diseases

Other Genetic Diseases

Structural and Bioinformatic Evidence

Summary Table

Conclusions

📚 Additional Documentation

Notes

ATP6V0E2 (Q8NHE4) research notes

Identity

Function / complex

Evidence that e2 is functionally essential for the pump

Localization

Annotation assessment summary

Proposed actions (high level)

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6V0E2 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