ATP6V0E2

Summary

ATP6V0E2 (ATPase H+ transporting V0 subunit e2, HGNC:21723) is a protein-coding gene on chromosome 7q36.1, encoding V-type proton ATPase subunit e 2 (Q8NHE4). 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.

Multisubunit vacuolar-type proton pumps, or H(+)-ATPases, acidify various intracellular compartments, such as vacuoles, clathrin-coated and synaptic vesicles, endosomes, lysosomes, and chromaffin granules. H(+)-ATPases are also found in plasma membranes of specialized cells, where they play roles in urinary acidification, bone resorption, and sperm maturation. Multiple subunits form H(+)-ATPases, with proteins of the V1 class hydrolyzing ATP for energy to transport H+, and proteins of the V0 class forming an integral membrane domain through which H+ is transported. ATP6V0E2 encodes an isoform of the H(+)-ATPase V0 e subunit, an essential proton pump component (Blake-Palmer et al., 2007 [PubMed 17350184]).

Source: NCBI Gene 155066 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 31 total
• MANE Select transcript: NM_145230

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21723
Approved symbol	ATP6V0E2
Name	ATPase H+ transporting V0 subunit e2
Location	7q36.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000171130
Ensembl biotype	protein_coding
OMIM	611019
Entrez	155066

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 10 protein_coding, 3 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000421974, ENST00000425642, ENST00000456496, ENST00000464662, ENST00000464683, ENST00000471877, ENST00000479613, ENST00000483478, ENST00000490092, ENST00000495408, ENST00000606024, ENST00000649866, ENST00000887566, ENST00000887567, ENST00000938384, ENST00000958031

RefSeq mRNA: 12 — MANE Select: NM_145230 NM_001100592, NM_001289990, NM_001367788, NM_001367789, NM_001367791, NM_001367792, NM_001367793, NM_001367794, NM_001367795, NM_001367796, NM_001367797, NM_145230

CCDS: CCDS47742, CCDS55181, CCDS94229

Canonical transcript exons

ENST00000425642 — 4 exons

Exon	Start	End
ENSE00002322041	149879335	149880695
ENSE00003603505	149878678	149878790
ENSE00003700762	149873969	149874169
ENSE00003702416	149875598	149875645

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 55.4912 / max 1385.6562, expressed in 1788 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
81913	53.6043	1785
81912	1.0870	292
81916	0.4312	181
81911	0.3277	152
81914	0.0278	11
81915	0.0133	5

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 10	UBERON:0013541	99.69	gold quality
paraflocculus	UBERON:0005351	99.64	gold quality
frontal pole	UBERON:0002795	99.45	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.45	gold quality
pons	UBERON:0000988	99.42	gold quality
cerebellar hemisphere	UBERON:0002245	99.39	gold quality
cerebellar cortex	UBERON:0002129	99.38	gold quality
cerebellum	UBERON:0002037	99.32	gold quality
superior vestibular nucleus	UBERON:0007227	99.29	gold quality
ventral tegmental area	UBERON:0002691	99.27	gold quality
right frontal lobe	UBERON:0002810	99.23	gold quality
prefrontal cortex	UBERON:0000451	99.14	gold quality
amygdala	UBERON:0001876	99.10	gold quality
Ammon’s horn	UBERON:0001954	99.09	gold quality
frontal cortex	UBERON:0001870	99.04	gold quality
cingulate cortex	UBERON:0003027	99.04	gold quality
anterior cingulate cortex	UBERON:0009835	99.04	gold quality
cerebellar vermis	UBERON:0004720	99.02	gold quality
CA1 field of hippocampus	UBERON:0003881	99.00	gold quality
hypothalamus	UBERON:0001898	98.98	gold quality
putamen	UBERON:0001874	98.93	gold quality
medulla oblongata	UBERON:0001896	98.92	gold quality
temporal lobe	UBERON:0001871	98.91	gold quality
neocortex	UBERON:0001950	98.91	gold quality
middle frontal gyrus	UBERON:0002702	98.90	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.90	gold quality
parietal lobe	UBERON:0001872	98.88	gold quality
nucleus accumbens	UBERON:0001882	98.88	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.88	gold quality
substantia nigra pars compacta	UBERON:0001965	98.87	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9154	no	828.63
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HDAC3

miRNA regulators (miRDB)

45 targeting ATP6V0E2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-3619-5P	99.00	68.87	2308

Literature-anchored findings (GeneRIF, showing 1)

• The identification of this novel form of the e-subunit lends further support to the hypothesis that subunit differences may play a key role in the structure, site and function of H(+)-ATPases within the cell.[ATPV0E2] (PMID:17350184)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	atpv0e2	ENSDARG00000059057
mus_musculus	Atp6v0e2	ENSMUSG00000039347
rattus_norvegicus	Atp6v0e2	ENSRNOG00000008218
drosophila_melanogaster	VhaM9.7-b	FBGN0028663
drosophila_melanogaster	VhaM9.7-c	FBGN0028664
drosophila_melanogaster	VhaM9.7-a	FBGN0035521
drosophila_melanogaster	VhaM9.7-d	FBGN0038458
caenorhabditis_elegans		WBGENE00009882

Paralogs (1): ATP6V0E1 (ENSG00000113732)

Protein

Protein identifiers

V-type proton ATPase subunit e 2 — Q8NHE4 (reviewed: Q8NHE4)

Alternative names: Lysosomal 9 kDa H(+)-transporting ATPase V0 subunit e2, Vacuolar proton pump subunit e 2

All UniProt accessions (3): E9PAS2, Q8NHE4, F8WDM2

UniProt curated annotations — full annotation on UniProt →

Function. 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. 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.

Subunit / interactions. V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex. The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H. 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.

Subcellular location. Membrane. Cytoplasmic vesicle. Clathrin-coated vesicle membrane. Secretory vesicle. Synaptic vesicle membrane.

Tissue specificity. Isoform 1 is expressed at high levels in heart, brain and kidney and also detected in inner ear epithelium, vestibule, testis, epididymis and bladder. Isoform 2 is expressed in heart, kidney, placenta and pancreas. Isoform 2 is not detected in frontal cortex, but is prevalent in all other brain areas.

Miscellaneous. May be due to a competing donor splice site.

Similarity. Belongs to the V-ATPase e1/e2 subunit family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8NHE4-1	1	yes
Q8NHE4-2	2
Q8NHE4-3	3
Q8NHE4-4	4

RefSeq proteins (12): NP_001094062, NP_001276919, NP_001354717, NP_001354718, NP_001354720, NP_001354721, NP_001354722, NP_001354723, NP_001354724, NP_001354725, NP_001354726, NP_660265* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008389	ATPase_V0-cplx_e1/e2_su	Family
IPR017385	ATPase_V0-cplx_e1/e2_su_met	Family

Pfam: PF05493

UniProt features (10 total): topological domain 3, splice variant 3, transmembrane region 2, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NHE4-F1	94.71	0.94

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (1): 70

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1222556	ROS and RNS production in phagocytes
R-HSA-77387	Insulin receptor recycling
R-HSA-917977	Transferrin endocytosis and recycling
R-HSA-9639288	Amino acids regulate mTORC1
R-HSA-983712	Ion channel transport
R-HSA-9857377	Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy

MSigDB gene sets: 215 (showing top): REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_REGULATION_OF_AUTOPHAGY, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOCC_VACUOLAR_MEMBRANE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MACROAUTOPHAGY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOCC_COATED_VESICLE, GOBP_VACUOLAR_ACIDIFICATION

GO Biological Process (5): vacuolar acidification (GO:0007035), regulation of macroautophagy (GO:0016241), transmembrane transport (GO:0055085), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811)

GO Molecular Function (2): ATPase-coupled ion transmembrane transporter activity (GO:0042625), proton-transporting ATPase activity, rotational mechanism (GO:0046961)

GO Cellular Component (10): vacuolar proton-transporting V-type ATPase, V0 domain (GO:0000220), lysosomal membrane (GO:0005765), endosome membrane (GO:0010008), membrane (GO:0016020), clathrin-coated vesicle membrane (GO:0030665), phagocytic vesicle membrane (GO:0030670), synaptic vesicle membrane (GO:0030672), cytoplasmic vesicle (GO:0031410), proton-transporting V-type ATPase, V0 domain (GO:0033179), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Innate Immune System	1
Signaling by Insulin receptor	1
Iron uptake and transport	1
Cellular response to starvation	1
Transport of small molecules	1
MITF-M-dependent gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
intracellular pH reduction	1
regulation of autophagy	1
macroautophagy	1
cellular process	1
monoatomic cation transmembrane transport	1
ATPase-coupled transmembrane transporter activity	1
proton transmembrane transporter activity	1
ATPase-coupled monoatomic cation transmembrane transporter activity	1
ATPase activity, coupled to transmembrane movement of ions, rotational mechanism	1
vacuolar membrane	1
vacuolar proton-transporting V-type ATPase complex	1
proton-transporting V-type ATPase, V0 domain	1
lysosome	1
lytic vacuole membrane	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
cellular anatomical structure	1
clathrin-coated vesicle	1
coated vesicle membrane	1
endocytic vesicle membrane	1
phagocytic vesicle	1
synaptic vesicle	1
exocytic vesicle membrane	1
cytoplasm	1
intracellular vesicle	1
proton-transporting V-type ATPase complex	1
proton-transporting two-sector ATPase complex, proton-transporting domain	1
cell junction	1

Protein interactions and networks

STRING

610 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP6V0E2	ATP6V0B	Q99437	800
ATP6V0E2	ATP4A	P20648	794
ATP6V0E2	ATP12A	P54707	770
ATP6V0E2	ATP6V1H	Q9UI12	722
ATP6V0E2	ATP6AP1	Q15904	709
ATP6V0E2	ATP6V1G1	O75348	671
ATP6V0E2	ATP6V0D2	Q8N8Y2	616
ATP6V0E2	ATP6V1C2	Q8NEY4	570
ATP6V0E2	LUC7L2	Q9Y383	545
ATP6V0E2	A0A0A6YYJ8	A0A0A6YYJ8	544
ATP6V0E2	ATP6V1E2	Q96A05	536
ATP6V0E2	ATP6V0C	P27449	491
ATP6V0E2	ATP6V1F	Q16864	475
ATP6V0E2	ATP6V1G2	O95670	470
ATP6V0E2	ATP6V0A1	Q93050	452

IntAct

2 interactions, top by confidence:

A	B	Type	Score
ATP6V0E2	MC4R	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (2): ATP6V0E2 (Two-hybrid), ATP6V0E2 (Two-hybrid)

ESM2 similar proteins: A4FVW3, A5GL35, A6UQK6, A6UQK8, A6VHF0, D0VWR4, O07380, O27231, O29047, O78444, P04126, P19057, P20205, P23317, P35092, P49779, P51370, P58583, P72575, P72712, P74564, P75041, P80186, P80651, P80653, Q12VU4, Q1XDB7, Q2KIB5, Q31KG3, Q31LM3, Q49176, Q49606, Q58257, Q58258, Q5EB76, Q5N0A1, Q5N1F0, Q6B8M4, Q6LWZ2, Q6LWZ3

Diamond homologs: O15342, P81103, Q20591, Q2KIB5, Q5EB76, Q5K8S8, Q5RAV0, Q69Z14, Q794C0, Q8NHE4, Q91XE7, Q9BDP4, Q9CQD8, Q9FLN5, Q9SZ13, Q3E7B6, Q75EU0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HDAC3	“down-regulates quantity by repression”	ATP6V0E2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

31 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	20
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

625 predictions. Top by Δscore:

Variant	Effect	Δscore
7:149874166:GCGG:G	donor_gain	1.0000
7:149874168:GG:G	donor_gain	1.0000
7:149874169:GG:G	donor_gain	1.0000
7:149874169:GGTAA:G	donor_loss	1.0000
7:149874170:G:C	donor_loss	1.0000
7:149874171:T:G	donor_loss	1.0000
7:149874176:A:T	donor_gain	1.0000
7:149875596:A:AG	acceptor_gain	1.0000
7:149875597:G:GG	acceptor_gain	1.0000
7:149875597:GA:G	acceptor_gain	1.0000
7:149875641:CTCTT:C	donor_gain	1.0000
7:149875644:TT:T	donor_gain	1.0000
7:149875646:G:GG	donor_gain	1.0000
7:149874170:G:GG	donor_gain	0.9900
7:149875595:CAG:C	acceptor_gain	0.9900
7:149875596:AGA:A	acceptor_gain	0.9900
7:149875596:AGAGT:A	acceptor_gain	0.9900
7:149875597:GAG:G	acceptor_gain	0.9900
7:149875597:GAGT:G	acceptor_gain	0.9900
7:149875597:GAGTG:G	acceptor_gain	0.9900
7:149875642:TCTT:T	donor_gain	0.9900
7:149875643:CTT:C	donor_gain	0.9900
7:149875644:TTG:T	donor_loss	0.9900
7:149875645:TG:T	donor_loss	0.9900
7:149875646:GTAA:G	donor_loss	0.9900
7:149878491:G:GT	donor_gain	0.9800
7:149874165:CGCGG:C	donor_gain	0.9700
7:149874166:GCGGG:G	donor_gain	0.9700
7:149875592:CTGCA:C	acceptor_loss	0.9700
7:149875594:GCA:G	acceptor_loss	0.9700

AlphaMissense

516 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:149874114:T:A	W17R	0.998
7:149874114:T:C	W17R	0.998
7:149875632:T:C	C47R	0.998
7:149875635:T:C	C48R	0.998
7:149878719:G:A	G65E	0.998
7:149874117:G:C	G18R	0.997
7:149874126:G:C	G21R	0.997
7:149874127:G:A	G21D	0.997
7:149878679:T:A	W52R	0.997
7:149878679:T:C	W52R	0.997
7:149878718:G:A	G65R	0.997
7:149878718:G:C	G65R	0.997
7:149875627:C:A	A45D	0.996
7:149878718:G:T	G65W	0.996
7:149875637:T:G	C48W	0.995
7:149878765:G:C	W80C	0.995
7:149878765:G:T	W80C	0.995
7:149874118:G:A	G18D	0.994
7:149875636:G:A	C48Y	0.994
7:149874166:G:C	R34P	0.993
7:149878719:G:T	G65V	0.993
7:149878763:T:A	W80R	0.993
7:149878763:T:C	W80R	0.993
7:149874124:T:A	V20D	0.992
7:149874135:G:A	G24R	0.992
7:149874135:G:C	G24R	0.992
7:149874148:T:A	V28E	0.992
7:149878683:T:C	L53P	0.992
7:149878709:C:T	P62S	0.992
7:149878728:T:C	L68P	0.992

dbSNP variants (sampled 300 via entrez): RS1000094367 (7:149873555 C>T), RS1000155146 (7:149874503 A>C), RS1000333868 (7:149878775 G>A,C,T), RS1001914392 (7:149876712 A>T), RS1001945750 (7:149874473 T>C), RS1002169856 (7:149872269 A>G), RS1002759665 (7:149880319 C>T), RS1003111054 (7:149873845 G>A,C,T), RS1003495548 (7:149872486 C>T), RS1003906236 (7:149873722 T>A,C,G), RS1003935055 (7:149873816 C>G,T), RS1003987422 (7:149879872 A>C), RS1005580799 (7:149872535 A>T), RS1005643975 (7:149872863 C>A), RS1005732143 (7:149878347 G>T)

Disease associations

OMIM: gene MIM:611019 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004029_4	Angiotensin-converting enzyme inhibitor intolerance	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005325	response to angiotensin-converting enzyme inhibitor

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — V-type ATPase

CTD chemical–gene interactions

44 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation, affects cotreatment, increases expression	9
sodium arsenite	decreases expression, increases expression	4
Benzo(a)pyrene	decreases expression, increases expression, affects methylation	4
Tetrachlorodibenzodioxin	affects expression, increases expression	3
Cyclosporine	decreases expression, decreases methylation	3
bisphenol A	affects expression, decreases methylation	2
Acetaminophen	decreases expression, affects response to substance	2
Aflatoxin B1	affects expression, decreases expression	2
methylmercuric chloride	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
manganese chloride	increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	decreases expression, increases abundance	1
Azathioprine	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects binding, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Gallic Acid	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.