{"gene":"ATP6V1E1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2002,"finding":"Mouse ATP6V1E1 (E1 isoform) and the ubiquitous E2 isoform are bona fide V-ATPase subunit E isoforms; both functionally complemented the yeast VMA4 null mutation, and chimeric V-ATPases showed temperature-sensitive coupling between ATP hydrolysis and proton transport. The E1 isoform is expressed specifically in developing acrosomes of round spermatids and is required for acrosome acidification.","method":"Yeast complementation (Δvma4 rescue), immunohistochemistry with isoform-specific antibodies, vacuolar membrane vesicle ATPase/proton-transport assays, temperature-sensitive growth assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution via yeast complementation, in vitro ATPase/proton-transport coupling assay, isoform-specific immunolocalization, multiple orthogonal methods in one study","pmids":["11872743"],"is_preprint":false},{"year":2002,"finding":"Human ATP6E1 (ATP6V1E1) encodes a testis-specific E subunit isoform of V-ATPase that, like the ubiquitous E2 isoform, functionally complements the yeast VMA4 null mutation, confirming it is a bona fide V-ATPase subunit.","method":"Northern blotting, yeast complementation (Δvma4 rescue), chromosomal mapping","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1 / Strong — yeast complementation reconstitution with functional readout, independently corroborates mouse data from PMID:11872743","pmids":["12036578"],"is_preprint":false},{"year":2003,"finding":"The C. elegans V-ATPase E subunit ortholog (vha-8), sharing ~57% identity with human ATP6V1E1, is essential for embryogenesis, larval development, and receptor-mediated endocytosis (yolk uptake); RNAi knockdown causes embryonic/larval lethality and accumulation of endomitotic oocytes with defective endocytosis.","method":"RNAi (dsRNA injection), GFP reporter localization, whole-mount immunostaining, loss-of-function phenotypic analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with specific cellular phenotypes (embryonic lethality, endocytosis defect), ortholog ~57% identity, single lab","pmids":["12853134"],"is_preprint":false},{"year":2008,"finding":"Loss-of-function of zebrafish atp6v1e1 (one of five v-ATPase mutants studied) causes oculocutaneous albinism, defective melanosome formation/survival, RPE malformation with undigested outer segment material in vacuoles, microphthalmy with compromised retinoblast cell-cycle exit and sustained CMZ proliferation, and elevated retinal/brain apoptosis.","method":"Zebrafish forward-genetic mutant characterization, histology, BrdU incorporation, in situ hybridization, transmission electron microscopy, TUNEL","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function zebrafish model with multiple specific cellular phenotypes and ultrastructural analysis; atp6v1e1 is one of five mutants, limiting gene-specific mechanistic resolution","pmids":["18836173"],"is_preprint":false},{"year":2017,"finding":"ATM directly phosphorylates the V1 subunit ATP6V1G1, which disrupts its dimerization with ATP6V1E1 (E–G dimer), thereby impairing assembly of the V1 and V0 domains and causing lysosomal de-acidification. ATM inhibition restores E–G dimerization, promotes V-ATPase assembly, and reacidifies lysosomes.","method":"Yeast two-hybrid screen (ATM interaction with ATP6V1E1 and ATP6V1G1), co-immunoprecipitation, in vitro phosphorylation assay (ATM phosphorylates ATP6V1G1), lysosomal pH measurement, ATM inhibitor (KU-60019) treatment","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid, reciprocal Co-IP, in vitro kinase assay, functional lysosomal pH rescue; multiple orthogonal methods in one study, single lab","pmids":["28346404"],"is_preprint":false},{"year":2017,"finding":"Biallelic missense mutations in ATP6V1E1 (encoding the E1 subunit of the V-ATPase V1 domain) cause autosomal-recessive cutis laxa. Structural modeling showed substitutions affect critical inter- or intrasubunit interaction residues. Complexome profiling demonstrated mutations disturb V-ATPase complex assembly or stability. Patient fibroblasts showed abnormal vesicular trafficking (delayed retrograde transport after brefeldin A, Golgi swelling/fragmentation) and variable glycosylation defects.","method":"Whole-exome sequencing, structural homology modeling, complexome profiling (blue-native PAGE + LC-MS/MS), brefeldin A trafficking assay, transmission electron microscopy of dermis, protein glycosylation analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — complexome profiling directly demonstrates assembly/stability defect, structural modeling, functional trafficking assays, replicated across five families with multiple orthogonal methods","pmids":["28065471"],"is_preprint":false},{"year":2019,"finding":"TGF-β1 signaling in human submandibular gland (HSG) cells upregulates ATP6V1E1 expression (along with ATP6V1B2), and surface V-ATPase activity contributes to intracellular pH recovery following acidosis in a bafilomycin-sensitive manner.","method":"QRT-PCR, immunoblotting, surface biotinylation, immunofluorescence, intracellular pH recording with BCECF dye, chromatin immunoprecipitation","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (qPCR, western, ChIP, functional pH assay), single lab, ATP6V1E1 is one of several subunits studied","pmids":["30648263"],"is_preprint":false},{"year":2021,"finding":"Loss of zebrafish atp6v1e1b recapitulates human ARCL type 2C: larvae show early mortality, craniofacial dysmorphisms, vascular anomalies, cardiac dysfunction, N-glycosylation defects, hypotonia, and epidermal structural defects. Loss of atp6v1e1b alters endo(lysosomal) protein levels, interferes with non-canonical V-ATPase pathways, and disrupts oxidative phosphorylation, sphingolipid, fatty acid, and energy metabolism, as well as mitochondrial respiration.","method":"Zebrafish atp6v1e1b knockout model, transcriptomics, metabolomics, lipidomics, mitochondrial respiration assay, N-glycosylation analysis, histology/TEM","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with multi-omics (transcriptome, metabolome, lipidome) plus functional mitochondrial assay; multiple orthogonal methods replicating human disease phenotype","pmids":["34143769"],"is_preprint":false},{"year":2019,"finding":"Human antigen R (HuR) in mouse cardiomyocytes maintains ATP6V1E1 mRNA and protein expression during starvation-induced autophagy; HuR knockdown decreases ATP6V1E1 mRNA and protein, reducing lysosomal acidification. This places ATP6V1E1 downstream of HuR as a target controlling lysosomal acidification during autophagy.","method":"Western blotting, real-time RT-PCR, siRNA knockdown of HuR, lysosomal acidification assay (confocal laser scanning), immunofluorescence","journal":"Zhonghua shao shang za zhi","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with specific mRNA and protein quantification plus functional lysosomal pH assay; single lab, single paper","pmids":["30897862"],"is_preprint":false},{"year":2026,"finding":"Mycobacterium tuberculosis secreted protein Rv1184 (Chp2) promotes phosphorylation of ATP6V1E1 at Tyr56/57 by the tyrosine kinase BMX, which inhibits V-ATPase assembly and suppresses lysosomal acidification, facilitating intracellular Mtb survival. Chp2 directly binds ATP6V1E1 and facilitates its interaction with BMX. BMX inhibition impairs Mtb growth in macrophages and in mice.","method":"Co-immunoprecipitation (Chp2–ATP6V1E1–BMX interaction), site-directed mutagenesis (Tyr56/57 phosphosite), phosphorylation assays, lysosomal pH measurement, V-ATPase assembly assay, macrophage infection assay, in vivo mouse Mtb infection with BMX inhibitor","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP of ternary complex, phosphosite mutagenesis, functional assembly/acidification assay, in vitro and in vivo validation; multiple orthogonal methods in one study","pmids":["41651829"],"is_preprint":false}],"current_model":"ATP6V1E1 encodes the E1 subunit of the V1 catalytic domain of the vacuolar H⁺-ATPase (V-ATPase); it forms a critical E–G heterodimer with ATP6V1G1 required for V1–V0 domain assembly and lysosomal acidification, is phosphorylated indirectly via ATM→ATP6V1G1 to disassemble the pump during senescence, and is directly targeted by the Mycobacterium tuberculosis effector Chp2, which recruits BMX kinase to phosphorylate ATP6V1E1 at Tyr56/57 and block V-ATPase assembly, thereby suppressing lysosomal acidification to promote intracellular pathogen survival; loss-of-function mutations in humans cause autosomal-recessive cutis laxa with V-ATPase assembly defects, glycosylation abnormalities, and faulty vesicular trafficking."},"narrative":{"mechanistic_narrative":"ATP6V1E1 encodes the E1 isoform of subunit E in the V1 catalytic domain of the vacuolar H⁺-ATPase, a proton pump required for acidification of lysosomes, melanosomes, acrosomes, and other endomembrane compartments [PMID:11872743, PMID:12036578]. As a bona fide V-ATPase subunit, it functionally complements the yeast VMA4 null mutation, and the E1 isoform additionally serves a specialized role in acidifying developing acrosomes of round spermatids [PMID:11872743]. Within the V1 domain, ATP6V1E1 forms an E–G heterodimer with ATP6V1G1 that is required for productive V1–V0 assembly; disruption of this dimer de-acidifies lysosomes, as occurs when ATM phosphorylates ATP6V1G1 and blocks dimerization [PMID:28346404]. The pump is also a target of pathogen subversion: the Mycobacterium tuberculosis effector Chp2 (Rv1184) binds ATP6V1E1 and recruits the tyrosine kinase BMX to phosphorylate it at Tyr56/57, inhibiting V-ATPase assembly and suppressing lysosomal acidification to promote intracellular bacterial survival [PMID:41651829]. Biallelic missense mutations in ATP6V1E1 cause autosomal-recessive cutis laxa, with complexome profiling showing defective V-ATPase assembly/stability and patient cells displaying abnormal vesicular trafficking, Golgi fragmentation, and glycosylation defects [PMID:28065471]. Loss-of-function across orthologs produces broad developmental and metabolic phenotypes including endocytosis failure, defective melanosome and pigment formation, N-glycosylation defects, and disrupted mitochondrial respiration and lipid metabolism [PMID:12853134, PMID:18836173, PMID:34143769].","teleology":[{"year":2002,"claim":"Established that mammalian ATP6V1E1 is a genuine V-ATPase E subunit rather than a divergent paralog, and that the E1 isoform has a tissue-specialized role in acrosome acidification.","evidence":"Yeast Δvma4 complementation, isoform-specific immunohistochemistry, and vacuolar vesicle ATPase/proton-transport assays in mouse and human","pmids":["11872743","12036578"],"confidence":"High","gaps":["Did not resolve E1 vs E2 functional divergence at the structural level","Acrosome acidification role not extended to mammalian fertility phenotypes"]},{"year":2003,"claim":"Showed the V-ATPase E subunit is essential for development and receptor-mediated endocytosis, linking proton-pump function to vesicular trafficking in vivo.","evidence":"RNAi knockdown of the C. elegans ortholog vha-8 with GFP reporter and endocytosis phenotyping","pmids":["12853134"],"confidence":"Medium","gaps":["Ortholog only ~57% identical; conclusions not directly tested on human ATP6V1E1","Mechanistic link between acidification and endocytosis not dissected"]},{"year":2008,"claim":"Demonstrated that loss of atp6v1e1 disrupts organelle acidification with consequences for pigmentation, lysosomal degradation, and cell-cycle exit, extending the subunit's role to tissue morphogenesis.","evidence":"Zebrafish forward-genetic mutant characterized by histology, BrdU, in situ hybridization, TEM, and TUNEL","pmids":["18836173"],"confidence":"Medium","gaps":["atp6v1e1 was one of five mutants, limiting gene-specific resolution","Did not establish whether phenotypes arise from a single acidified compartment"]},{"year":2017,"claim":"Identified the E–G dimer as a regulatory node controlling assembly, showing that ATM-driven phosphorylation of ATP6V1G1 disrupts its dimerization with ATP6V1E1 and de-acidifies lysosomes.","evidence":"Yeast two-hybrid, reciprocal Co-IP, in vitro kinase assay, and lysosomal pH rescue with an ATM inhibitor","pmids":["28346404"],"confidence":"High","gaps":["Direct phosphorylation target is ATP6V1G1, not ATP6V1E1 itself","Physiological trigger for ATM-mediated pump disassembly not fully defined"]},{"year":2017,"claim":"Established ATP6V1E1 as a Mendelian disease gene, demonstrating that missense mutations impair V-ATPase assembly and cause cutis laxa via trafficking and glycosylation defects.","evidence":"Whole-exome sequencing across five families, complexome profiling, structural modeling, and brefeldin A trafficking assays in patient fibroblasts","pmids":["28065471"],"confidence":"High","gaps":["How assembly defects produce glycosylation abnormalities not mechanistically linked","Genotype-phenotype variability among mutations not explained"]},{"year":2019,"claim":"Placed ATP6V1E1 within regulatory networks controlling its expression, showing TGF-β1 transcriptional upregulation and HuR-dependent mRNA stabilization that tune lysosomal acidification.","evidence":"ChIP and qRT-PCR with pH recording in HSG cells; HuR siRNA knockdown with lysosomal acidification assay in mouse cardiomyocytes","pmids":["30648263","30897862"],"confidence":"Medium","gaps":["Each link rests on a single lab and one study","Direct functional consequence of expression changes on whole-organism physiology untested"]},{"year":2021,"claim":"Provided an animal model recapitulating human ARCL type 2C and revealed that ATP6V1E1 loss perturbs not only acidification but also non-canonical V-ATPase pathways, mitochondrial respiration, and lipid/energy metabolism.","evidence":"Zebrafish atp6v1e1b knockout with transcriptomics, metabolomics, lipidomics, and mitochondrial respiration assays","pmids":["34143769"],"confidence":"High","gaps":["Causal chain from V-ATPase loss to metabolic rewiring not dissected","Non-canonical V-ATPase pathways not molecularly defined"]},{"year":2026,"claim":"Revealed ATP6V1E1 as a direct target of pathogen subversion, showing that M. tuberculosis Chp2 recruits BMX to phosphorylate ATP6V1E1 at Tyr56/57 and block pump assembly to evade lysosomal killing.","evidence":"Co-IP of the Chp2–ATP6V1E1–BMX ternary complex, phosphosite mutagenesis, assembly and pH assays, and macrophage/mouse infection with a BMX inhibitor","pmids":["41651829"],"confidence":"High","gaps":["Whether Tyr56/57 phosphorylation occurs under non-infectious physiological conditions unknown","Structural basis for how phosphorylation blocks assembly not resolved"]},{"year":null,"claim":"It remains unresolved how phosphorylation of the E–G dimer interface mechanistically blocks V1–V0 assembly at the structural level and whether the various regulatory inputs (ATM, BMX, HuR, TGF-β1) converge on a common assembly checkpoint.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of phosphorylated ATP6V1E1 or the E–G dimer in the corpus","Integration of multiple regulatory pathways onto a single assembly mechanism untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4,5]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[4,8,9]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,7]}],"complexes":["V-ATPase (vacuolar H+-ATPase V1 domain)"],"partners":["ATP6V1G1","ATM","BMX","ATP6V1B2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P36543","full_name":"V-type proton ATPase subunit E 1","aliases":["V-ATPase 31 kDa subunit","p31","Vacuolar proton pump subunit E 1"],"length_aa":226,"mass_kda":26.1,"function":"Subunit of the V1 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 (PubMed:32001091, PubMed:33065002). 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 (PubMed:32001091)","subcellular_location":"Apical cell membrane; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane; Cytoplasmic vesicle, clathrin-coated vesicle membrane","url":"https://www.uniprot.org/uniprotkb/P36543/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP6V1E1","classification":"Common Essential","n_dependent_lines":1191,"n_total_lines":1208,"dependency_fraction":0.9859271523178808},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000131100","cell_line_id":"CID001931","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"golgi","grade":1}],"interactors":[{"gene":"ATP6AP2","stoichiometry":10.0},{"gene":"ATP6V1A","stoichiometry":10.0},{"gene":"ATP6V1B2","stoichiometry":10.0},{"gene":"ATP6V1D","stoichiometry":10.0},{"gene":"ATP6V1G1","stoichiometry":10.0},{"gene":"ATP6V1H","stoichiometry":10.0},{"gene":"ATP6V1F","stoichiometry":4.0},{"gene":"ATP6V0A1","stoichiometry":0.2},{"gene":"ATP6V0D1","stoichiometry":0.2},{"gene":"ATP6V1C1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001931","total_profiled":1310},"omim":[{"mim_id":"617403","title":"CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IID; ARCL2D","url":"https://www.omim.org/entry/617403"},{"mim_id":"617402","title":"CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IIC; ARCL2C","url":"https://www.omim.org/entry/617402"},{"mim_id":"617385","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, 31-KD, V1 SUBUNIT E, ISOFORM 1; ATP6V1E2","url":"https://www.omim.org/entry/617385"},{"mim_id":"607027","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, 70-KD, VI SUBUNIT A; ATP6V1A","url":"https://www.omim.org/entry/607027"},{"mim_id":"219200","title":"CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IIA; ARCL2A","url":"https://www.omim.org/entry/219200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATP6V1E1"},"hgnc":{"alias_symbol":["P31","Vma4","ATP6E2"],"prev_symbol":["ATP6E","ATP6V1E"]},"alphafold":{"accession":"P36543","domains":[{"cath_id":"3.30.2320.30","chopping":"98-213","consensus_level":"high","plddt":95.2236,"start":98,"end":213}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P36543","model_url":"https://alphafold.ebi.ac.uk/files/AF-P36543-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P36543-F1-predicted_aligned_error_v6.png","plddt_mean":94.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP6V1E1","jax_strain_url":"https://www.jax.org/strain/search?query=ATP6V1E1"},"sequence":{"accession":"P36543","fasta_url":"https://rest.uniprot.org/uniprotkb/P36543.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P36543/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P36543"}},"corpus_meta":[{"pmid":"28346404","id":"PMC_28346404","title":"Chemical 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The E1 isoform is expressed specifically in developing acrosomes of round spermatids and is required for acrosome acidification.\",\n      \"method\": \"Yeast complementation (Δvma4 rescue), immunohistochemistry with isoform-specific antibodies, vacuolar membrane vesicle ATPase/proton-transport assays, temperature-sensitive growth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution via yeast complementation, in vitro ATPase/proton-transport coupling assay, isoform-specific immunolocalization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11872743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Human ATP6E1 (ATP6V1E1) encodes a testis-specific E subunit isoform of V-ATPase that, like the ubiquitous E2 isoform, functionally complements the yeast VMA4 null mutation, confirming it is a bona fide V-ATPase subunit.\",\n      \"method\": \"Northern blotting, yeast complementation (Δvma4 rescue), chromosomal mapping\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — yeast complementation reconstitution with functional readout, independently corroborates mouse data from PMID:11872743\",\n      \"pmids\": [\"12036578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The C. elegans V-ATPase E subunit ortholog (vha-8), sharing ~57% identity with human ATP6V1E1, is essential for embryogenesis, larval development, and receptor-mediated endocytosis (yolk uptake); RNAi knockdown causes embryonic/larval lethality and accumulation of endomitotic oocytes with defective endocytosis.\",\n      \"method\": \"RNAi (dsRNA injection), GFP reporter localization, whole-mount immunostaining, loss-of-function phenotypic analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with specific cellular phenotypes (embryonic lethality, endocytosis defect), ortholog ~57% identity, single lab\",\n      \"pmids\": [\"12853134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss-of-function of zebrafish atp6v1e1 (one of five v-ATPase mutants studied) causes oculocutaneous albinism, defective melanosome formation/survival, RPE malformation with undigested outer segment material in vacuoles, microphthalmy with compromised retinoblast cell-cycle exit and sustained CMZ proliferation, and elevated retinal/brain apoptosis.\",\n      \"method\": \"Zebrafish forward-genetic mutant characterization, histology, BrdU incorporation, in situ hybridization, transmission electron microscopy, TUNEL\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function zebrafish model with multiple specific cellular phenotypes and ultrastructural analysis; atp6v1e1 is one of five mutants, limiting gene-specific mechanistic resolution\",\n      \"pmids\": [\"18836173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATM directly phosphorylates the V1 subunit ATP6V1G1, which disrupts its dimerization with ATP6V1E1 (E–G dimer), thereby impairing assembly of the V1 and V0 domains and causing lysosomal de-acidification. ATM inhibition restores E–G dimerization, promotes V-ATPase assembly, and reacidifies lysosomes.\",\n      \"method\": \"Yeast two-hybrid screen (ATM interaction with ATP6V1E1 and ATP6V1G1), co-immunoprecipitation, in vitro phosphorylation assay (ATM phosphorylates ATP6V1G1), lysosomal pH measurement, ATM inhibitor (KU-60019) treatment\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid, reciprocal Co-IP, in vitro kinase assay, functional lysosomal pH rescue; multiple orthogonal methods in one study, single lab\",\n      \"pmids\": [\"28346404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biallelic missense mutations in ATP6V1E1 (encoding the E1 subunit of the V-ATPase V1 domain) cause autosomal-recessive cutis laxa. Structural modeling showed substitutions affect critical inter- or intrasubunit interaction residues. Complexome profiling demonstrated mutations disturb V-ATPase complex assembly or stability. Patient fibroblasts showed abnormal vesicular trafficking (delayed retrograde transport after brefeldin A, Golgi swelling/fragmentation) and variable glycosylation defects.\",\n      \"method\": \"Whole-exome sequencing, structural homology modeling, complexome profiling (blue-native PAGE + LC-MS/MS), brefeldin A trafficking assay, transmission electron microscopy of dermis, protein glycosylation analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — complexome profiling directly demonstrates assembly/stability defect, structural modeling, functional trafficking assays, replicated across five families with multiple orthogonal methods\",\n      \"pmids\": [\"28065471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TGF-β1 signaling in human submandibular gland (HSG) cells upregulates ATP6V1E1 expression (along with ATP6V1B2), and surface V-ATPase activity contributes to intracellular pH recovery following acidosis in a bafilomycin-sensitive manner.\",\n      \"method\": \"QRT-PCR, immunoblotting, surface biotinylation, immunofluorescence, intracellular pH recording with BCECF dye, chromatin immunoprecipitation\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (qPCR, western, ChIP, functional pH assay), single lab, ATP6V1E1 is one of several subunits studied\",\n      \"pmids\": [\"30648263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of zebrafish atp6v1e1b recapitulates human ARCL type 2C: larvae show early mortality, craniofacial dysmorphisms, vascular anomalies, cardiac dysfunction, N-glycosylation defects, hypotonia, and epidermal structural defects. Loss of atp6v1e1b alters endo(lysosomal) protein levels, interferes with non-canonical V-ATPase pathways, and disrupts oxidative phosphorylation, sphingolipid, fatty acid, and energy metabolism, as well as mitochondrial respiration.\",\n      \"method\": \"Zebrafish atp6v1e1b knockout model, transcriptomics, metabolomics, lipidomics, mitochondrial respiration assay, N-glycosylation analysis, histology/TEM\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with multi-omics (transcriptome, metabolome, lipidome) plus functional mitochondrial assay; multiple orthogonal methods replicating human disease phenotype\",\n      \"pmids\": [\"34143769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human antigen R (HuR) in mouse cardiomyocytes maintains ATP6V1E1 mRNA and protein expression during starvation-induced autophagy; HuR knockdown decreases ATP6V1E1 mRNA and protein, reducing lysosomal acidification. This places ATP6V1E1 downstream of HuR as a target controlling lysosomal acidification during autophagy.\",\n      \"method\": \"Western blotting, real-time RT-PCR, siRNA knockdown of HuR, lysosomal acidification assay (confocal laser scanning), immunofluorescence\",\n      \"journal\": \"Zhonghua shao shang za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with specific mRNA and protein quantification plus functional lysosomal pH assay; single lab, single paper\",\n      \"pmids\": [\"30897862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Mycobacterium tuberculosis secreted protein Rv1184 (Chp2) promotes phosphorylation of ATP6V1E1 at Tyr56/57 by the tyrosine kinase BMX, which inhibits V-ATPase assembly and suppresses lysosomal acidification, facilitating intracellular Mtb survival. Chp2 directly binds ATP6V1E1 and facilitates its interaction with BMX. BMX inhibition impairs Mtb growth in macrophages and in mice.\",\n      \"method\": \"Co-immunoprecipitation (Chp2–ATP6V1E1–BMX interaction), site-directed mutagenesis (Tyr56/57 phosphosite), phosphorylation assays, lysosomal pH measurement, V-ATPase assembly assay, macrophage infection assay, in vivo mouse Mtb infection with BMX inhibitor\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP of ternary complex, phosphosite mutagenesis, functional assembly/acidification assay, in vitro and in vivo validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"41651829\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V1E1 encodes the E1 subunit of the V1 catalytic domain of the vacuolar H⁺-ATPase (V-ATPase); it forms a critical E–G heterodimer with ATP6V1G1 required for V1–V0 domain assembly and lysosomal acidification, is phosphorylated indirectly via ATM→ATP6V1G1 to disassemble the pump during senescence, and is directly targeted by the Mycobacterium tuberculosis effector Chp2, which recruits BMX kinase to phosphorylate ATP6V1E1 at Tyr56/57 and block V-ATPase assembly, thereby suppressing lysosomal acidification to promote intracellular pathogen survival; loss-of-function mutations in humans cause autosomal-recessive cutis laxa with V-ATPase assembly defects, glycosylation abnormalities, and faulty vesicular trafficking.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATP6V1E1 encodes the E1 isoform of subunit E in the V1 catalytic domain of the vacuolar H\\u207a-ATPase, a proton pump required for acidification of lysosomes, melanosomes, acrosomes, and other endomembrane compartments [#0, #1]. As a bona fide V-ATPase subunit, it functionally complements the yeast VMA4 null mutation, and the E1 isoform additionally serves a specialized role in acidifying developing acrosomes of round spermatids [#0]. Within the V1 domain, ATP6V1E1 forms an E\\u2013G heterodimer with ATP6V1G1 that is required for productive V1\\u2013V0 assembly; disruption of this dimer de-acidifies lysosomes, as occurs when ATM phosphorylates ATP6V1G1 and blocks dimerization [#4]. The pump is also a target of pathogen subversion: the Mycobacterium tuberculosis effector Chp2 (Rv1184) binds ATP6V1E1 and recruits the tyrosine kinase BMX to phosphorylate it at Tyr56/57, inhibiting V-ATPase assembly and suppressing lysosomal acidification to promote intracellular bacterial survival [#9]. Biallelic missense mutations in ATP6V1E1 cause autosomal-recessive cutis laxa, with complexome profiling showing defective V-ATPase assembly/stability and patient cells displaying abnormal vesicular trafficking, Golgi fragmentation, and glycosylation defects [#5]. Loss-of-function across orthologs produces broad developmental and metabolic phenotypes including endocytosis failure, defective melanosome and pigment formation, N-glycosylation defects, and disrupted mitochondrial respiration and lipid metabolism [#2, #3, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that mammalian ATP6V1E1 is a genuine V-ATPase E subunit rather than a divergent paralog, and that the E1 isoform has a tissue-specialized role in acrosome acidification.\",\n      \"evidence\": \"Yeast \\u0394vma4 complementation, isoform-specific immunohistochemistry, and vacuolar vesicle ATPase/proton-transport assays in mouse and human\",\n      \"pmids\": [\n        \"11872743\",\n        \"12036578\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not resolve E1 vs E2 functional divergence at the structural level\",\n        \"Acrosome acidification role not extended to mammalian fertility phenotypes\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed the V-ATPase E subunit is essential for development and receptor-mediated endocytosis, linking proton-pump function to vesicular trafficking in vivo.\",\n      \"evidence\": \"RNAi knockdown of the C. elegans ortholog vha-8 with GFP reporter and endocytosis phenotyping\",\n      \"pmids\": [\n        \"12853134\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ortholog only ~57% identical; conclusions not directly tested on human ATP6V1E1\",\n        \"Mechanistic link between acidification and endocytosis not dissected\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that loss of atp6v1e1 disrupts organelle acidification with consequences for pigmentation, lysosomal degradation, and cell-cycle exit, extending the subunit's role to tissue morphogenesis.\",\n      \"evidence\": \"Zebrafish forward-genetic mutant characterized by histology, BrdU, in situ hybridization, TEM, and TUNEL\",\n      \"pmids\": [\n        \"18836173\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"atp6v1e1 was one of five mutants, limiting gene-specific resolution\",\n        \"Did not establish whether phenotypes arise from a single acidified compartment\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified the E\\u2013G dimer as a regulatory node controlling assembly, showing that ATM-driven phosphorylation of ATP6V1G1 disrupts its dimerization with ATP6V1E1 and de-acidifies lysosomes.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, in vitro kinase assay, and lysosomal pH rescue with an ATM inhibitor\",\n      \"pmids\": [\n        \"28346404\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct phosphorylation target is ATP6V1G1, not ATP6V1E1 itself\",\n        \"Physiological trigger for ATM-mediated pump disassembly not fully defined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established ATP6V1E1 as a Mendelian disease gene, demonstrating that missense mutations impair V-ATPase assembly and cause cutis laxa via trafficking and glycosylation defects.\",\n      \"evidence\": \"Whole-exome sequencing across five families, complexome profiling, structural modeling, and brefeldin A trafficking assays in patient fibroblasts\",\n      \"pmids\": [\n        \"28065471\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How assembly defects produce glycosylation abnormalities not mechanistically linked\",\n        \"Genotype-phenotype variability among mutations not explained\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed ATP6V1E1 within regulatory networks controlling its expression, showing TGF-\\u03b21 transcriptional upregulation and HuR-dependent mRNA stabilization that tune lysosomal acidification.\",\n      \"evidence\": \"ChIP and qRT-PCR with pH recording in HSG cells; HuR siRNA knockdown with lysosomal acidification assay in mouse cardiomyocytes\",\n      \"pmids\": [\n        \"30648263\",\n        \"30897862\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Each link rests on a single lab and one study\",\n        \"Direct functional consequence of expression changes on whole-organism physiology untested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided an animal model recapitulating human ARCL type 2C and revealed that ATP6V1E1 loss perturbs not only acidification but also non-canonical V-ATPase pathways, mitochondrial respiration, and lipid/energy metabolism.\",\n      \"evidence\": \"Zebrafish atp6v1e1b knockout with transcriptomics, metabolomics, lipidomics, and mitochondrial respiration assays\",\n      \"pmids\": [\n        \"34143769\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Causal chain from V-ATPase loss to metabolic rewiring not dissected\",\n        \"Non-canonical V-ATPase pathways not molecularly defined\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed ATP6V1E1 as a direct target of pathogen subversion, showing that M. tuberculosis Chp2 recruits BMX to phosphorylate ATP6V1E1 at Tyr56/57 and block pump assembly to evade lysosomal killing.\",\n      \"evidence\": \"Co-IP of the Chp2\\u2013ATP6V1E1\\u2013BMX ternary complex, phosphosite mutagenesis, assembly and pH assays, and macrophage/mouse infection with a BMX inhibitor\",\n      \"pmids\": [\n        \"41651829\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Tyr56/57 phosphorylation occurs under non-infectious physiological conditions unknown\",\n        \"Structural basis for how phosphorylation blocks assembly not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how phosphorylation of the E\\u2013G dimer interface mechanistically blocks V1\\u2013V0 assembly at the structural level and whether the various regulatory inputs (ATM, BMX, HuR, TGF-\\u03b21) converge on a common assembly checkpoint.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of phosphorylated ATP6V1E1 or the E\\u2013G dimer in the corpus\",\n        \"Integration of multiple regulatory pathways onto a single assembly mechanism untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0140657\",\n        \"supporting_discovery_ids\": [\n          0,\n          1\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [\n          0,\n          4,\n          5\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005764\",\n        \"supporting_discovery_ids\": [\n          4,\n          8,\n          9\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [\n          6\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-382551\",\n        \"supporting_discovery_ids\": [\n          0,\n          1\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-5653656\",\n        \"supporting_discovery_ids\": [\n          2,\n          5\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-1643685\",\n        \"supporting_discovery_ids\": [\n          5,\n          7\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"V-ATPase (vacuolar H+-ATPase V1 domain)\"\n    ],\n    \"partners\": [\n      \"ATP6V1G1\",\n      \"ATM\",\n      \"BMX\",\n      \"ATP6V1B2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}