ATP6V1E1

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).

1. 2002 High

   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

   PMID:11872743 PMID:12036578

   Open questions at the time

   • Did not resolve E1 vs E2 functional divergence at the structural level
   • Acrosome acidification role not extended to mammalian fertility phenotypes
2. 2003 Medium

   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

   PMID:12853134

   Open questions at the time

   • Ortholog only ~57% identical; conclusions not directly tested on human ATP6V1E1
   • Mechanistic link between acidification and endocytosis not dissected
3. 2008 Medium

   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

   PMID:18836173

   Open questions at the time

   • atp6v1e1 was one of five mutants, limiting gene-specific resolution
   • Did not establish whether phenotypes arise from a single acidified compartment
4. 2017 High

   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

   PMID:28346404

   Open questions at the time

   • Direct phosphorylation target is ATP6V1G1, not ATP6V1E1 itself
   • Physiological trigger for ATM-mediated pump disassembly not fully defined
5. 2017 High

   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

   PMID:28065471

   Open questions at the time

   • How assembly defects produce glycosylation abnormalities not mechanistically linked
   • Genotype-phenotype variability among mutations not explained
6. 2019 Medium

   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

   PMID:30648263 PMID:30897862

   Open questions at the time

   • Each link rests on a single lab and one study
   • Direct functional consequence of expression changes on whole-organism physiology untested
7. 2021 High

   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

   PMID:34143769

   Open questions at the time

   • Causal chain from V-ATPase loss to metabolic rewiring not dissected
   • Non-canonical V-ATPase pathways not molecularly defined
8. 2026 High

   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

   PMID:41651829

   Open questions at the time

   • Whether Tyr56/57 phosphorylation occurs under non-infectious physiological conditions unknown
   • Structural basis for how phosphorylation blocks assembly not resolved

• 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.
• 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