Affinage

ATP6V0A2

V-type proton ATPase 116 kDa subunit a 2 · UniProt Q9Y487

Length
856 aa
Mass
98.1 kDa
Annotated
2026-06-09
22 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP6V0A2 encodes the a2 subunit of the vacuolar H+-ATPase, a six-transmembrane membrane protein that drives bafilomycin-sensitive proton translocation into intracellular organelles and localizes to the Golgi apparatus (PMID:16113235, PMID:22773132). Through this acidifying activity it maintains Golgi structural integrity and membrane dynamics: loss of function distends Golgi cisternae, produces abnormal lysosomes and multivesicular bodies, and delays brefeldin A-induced Golgi collapse, while impairing secretion of tropoelastin and extracellular deposition of mature elastin and increasing apoptosis of elastogenic cells (PMID:19321599, PMID:22773132). By sustaining luminal pH, ATP6V0A2 supports Golgi-dependent glycosylation, and its reduction in senescent fibroblasts reproduces senescence-associated glycosylation changes (PMID:26611489). The disease-causing P405L missense mutation destabilizes the protein and disrupts post-ER Golgi trafficking without affecting its association with the V0 assembly factor VMA21 (PMID:29311258). Beyond the Golgi, ATP6V0A2 maintains lysosomal acidification in cardiomyocytes, where its loss triggers ferroptosis and its re-expression restores lysosomal pH and protects against oxidative cardiotoxicity (PMID:39048556). Loss-of-function mutations in ATP6V0A2 cause autosomal recessive cutis laxa type 2 (PMID:19321599, PMID:29311258).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2005 Medium

    Established that ATP6V0A2 is a functional proton pump subunit rather than merely a membrane protein of unknown role, by showing its overexpression increases organellar H+ uptake.

    Evidence Overexpression in HEK 293 cells with H+ uptake assay and bafilomycin inhibition, plus sequence/topology analysis

    PMID:16113235

    Open questions at the time
    • Endogenous proton-pumping role not tested by loss-of-function
    • Functional relevance of the putative ITAM left unresolved
    • No native organellar localization shown in this study
  2. 2009 High

    Connected ATP6V0A2 loss to a defined cellular phenotype, showing it is required for Golgi/lysosome integrity and for tropoelastin secretion and elastin deposition.

    Evidence siRNA knockdown, pulse-chase secretion assays, immunostaining, insoluble elastin assays, TUNEL, and electron microscopy of patient fibroblasts

    PMID:19321599

    Open questions at the time
    • Did not establish how luminal pH controls tropoelastin trafficking mechanistically
    • Specificity for tropoelastin over other secreted cargo only partially addressed
  3. 2012 High

    Localized ATP6V0A2 to the Golgi and implicated it in Golgi membrane dynamics distinct from other cutis laxa genes, while linking its loss to elevated TGF-beta signaling.

    Evidence Immunostaining, brefeldin A-induced Golgi collapse assay, genetic epistasis with GORAB/PYCR1-deficient cells, and TGF-beta signaling assays

    PMID:22773132

    Open questions at the time
    • Molecular basis of the membrane-fusion/Golgi-dynamics defect not defined
    • Causal link between TGF-beta elevation and disease phenotype not established
  4. 2015 Medium

    Tied ATP6V0A2 to maintenance of Golgi-dependent glycosylation and cellular senescence, showing its reduction recapitulates senescence-associated glycosylation changes.

    Evidence Differential proteomics, siRNA knockdown, FITC-lectin staining, glycoblotting, and Golgi immunostaining in human diploid fibroblasts

    PMID:26611489

    Open questions at the time
    • Which glycosyltransferases are pH-affected not identified
    • Causal role in driving senescence versus correlation not fully separated
  5. 2018 High

    Defined the molecular consequence of a disease mutation, showing P405L destabilizes the protein and blocks post-ER Golgi trafficking without altering VMA21 binding.

    Evidence Cycloheximide chase, endoglycosidase treatment, immunofluorescence, and co-immunoprecipitation in HEK 293 cells

    PMID:29311258

    Open questions at the time
    • Why instability manifests at Golgi trafficking rather than ER not mechanistically resolved
    • Generalizability to other missense alleles untested
  6. 2018 Low

    Extended the phenotypic spectrum of ATP6V0A2 loss to platelet/bleeding and acrosomal acidification defects, though mechanism was inferred from genetics/proteomics rather than functional manipulation.

    Evidence Exome/linkage analysis with patient EM (bleeding diathesis); 2D-DIGE/MS proteomic correlation in asthenozoospermic sperm

    PMID:30474613 PMID:30550884

    Open questions at the time
    • No direct functional manipulation of ATP6V0A2 in these tissues
    • Causal versus correlative role in platelet and sperm phenotypes unresolved
  7. 2024 Medium

    Demonstrated a protective role for ATP6V0A2 in lysosomal acidification, showing its re-expression rescues lysosomal pH and blocks ferroptosis in drug-injured cardiomyocytes.

    Evidence Microarray, immunoblotting, ATP6V0A2 overexpression with lysosomal acidification and lipid peroxidation assays, ferroptosis inhibitor rescue, in vitro and in vivo mouse model

    PMID:39048556

    Open questions at the time
    • Mechanistic link between lysosomal pH and ferroptosis pathway not fully delineated
    • Whether endogenous loss alone is sufficient to drive cardiac ferroptosis not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ATP6V0A2-dependent luminal acidification is mechanistically coupled to specific glycosyltransferase activities, membrane fusion machinery, and cargo selectivity across distinct tissues remains unresolved.
  • No structural model of the a2-containing V-ATPase complex in the timeline
  • Tissue-specific cargo and pH-sensitive effector enzymes not enumerated
  • Direct molecular partners beyond VMA21 association not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005794 Golgi apparatus 3 GO:0005764 lysosome 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-1430728 Metabolism 1
Partners
VMA21
Complex memberships
V-ATPase

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Human TJ6 (ATP6V0A2) encodes a membrane protein with six predicted transmembrane-spanning regions; overexpression in HEK 293 cells increased H+ uptake into intracellular organelles in a bafilomycin-sensitive manner, establishing it as a functional vacuolar ATPase (V-ATPase) proton pump regulatory subunit (a2 subunit). The protein also contains a putative ITAM sequence (residues 452–466), but it was a poor substrate for tyrosine-phosphorylating enzymes, suggesting the ITAM is non-functional in PTK-mediated signaling. Overexpression in HEK 293 cells with H+ uptake assay, bafilomycin inhibition, Northern blot, immunolocalization, sequence analysis International immunology Medium 16113235
2009 Loss-of-function mutations in ATP6V0A2 (via siRNA knockdown or patient ARCL2 cells) result in distended Golgi cisternae, accumulation of abnormal lysosomes and multivesicular bodies, impaired secretion and intracellular retention of tropoelastin (TE) in the Golgi, reduced extracellular deposition of mature elastin, and increased apoptosis of elastogenic cells. Fibrillin-1 microfibril assembly and secreted lysyl oxidase activity were unaffected. siRNA knockdown, pulse-chase secretion assays, immunostaining, insoluble elastin assays, TUNEL staining, electron microscopy of patient fibroblasts Human molecular genetics High 19321599
2012 ATP6V0A2 localizes to the Golgi apparatus; loss of ATP6V0A2 protein in patient dermal fibroblasts or ATP6V0A2-deficient HeLa cells delays brefeldin A-induced Golgi collapse, implicating ATP6V0A2 in membrane fusion/Golgi dynamics. Patient fibroblasts also displayed elevated TGF-β signaling and increased TGF-β1 secretion. This Golgi collapse delay was not observed in cells deficient for ARCL-associated proteins GORAB or PYCR1, placing ATP6V0A2 in a distinct pathway. Immunostaining (localization to Golgi), brefeldin A-induced Golgi collapse assay in patient fibroblasts and ATP6V0A2-deficient HeLa cells, genetic epistasis with GORAB/PYCR1-deficient cells, TGF-β ELISA and signaling assays Human genetics High 22773132
2015 Reduced ATP6V0A2 expression in senescent human diploid fibroblasts (TIG-1) causes Golgi dispersal and altered glycosylation patterns (detected by FITC-lectin staining and glycoblotting). siRNA-mediated reduction of ATP6V0A2 in young TIG-1 cells recapitulated the glycosylation changes seen in senescent cells, establishing ATP6V0A2 as a mediator of Golgi-dependent glycosylation maintenance and a regulator of cellular senescence. Differential proteomic analysis, siRNA knockdown, FITC-lectin staining, glycoblotting, immunostaining for Golgi structure Scientific reports Medium 26611489
2018 The disease-causing missense mutation a2P405L (causing cutis laxa) renders the ATP6V0A2 protein unstable (shown by cycloheximide chase), degraded through both proteasomal and lysosomal pathways, and causes defective Golgi trafficking. The protein remains fully N-glycosylated. Co-immunoprecipitation showed no significant change in its association with the V0 assembly factor VMA21 (unlike a4R449H). This places P405L-induced instability at the level of post-ER Golgi trafficking failure. Cycloheximide chase assay, endoglycosidase treatment, immunofluorescence, co-immunoprecipitation, transient expression in HEK 293 cells The Journal of biological chemistry High 29311258
2018 ATP6V0A2 is required for acrosomal acidification in sperm; lower expression of ATP6V0A2 was found in asthenozoospermic males by 2D-DIGE/mass spectrometry and confirmed by western blot and ELISA, and is proposed to be responsible for acrosomal de-acidification and reduced sperm motility. 2D-DIGE, mass spectrometry, western blot, ELISA, qRT-PCR in patient vs. control sperm proteomes Life sciences Low 30550884
2024 ATP6V0A2 is required for lysosomal acidification in cardiomyocytes; epirubicin downregulates ATP6V0A2, disrupts lysosomal acidification, and triggers ferroptosis. Overexpression of ATP6V0A2 restored lysosomal acidification, reduced oxidative stress and lipid peroxidation accumulation, and protected cardiomyocytes from ferroptosis-driven epirubicin-induced cardiotoxicity both in vitro and in vivo. Microarray screening, qRT-PCR, immunoblotting, ATP6V0A2 overexpression in primary cardiomyocytes and mouse hearts, lysosomal acidification assay, ferroptosis inhibitor (Ferrostatin-1) rescue, in vivo mouse model Cell death discovery Medium 39048556
2018 ATP6V0A2 mutations increase pH in secretory vesicles, thereby impairing glycosyltransferase activity and organelle trafficking. A novel frameshift mutation (c.2085_2088del) in ATP6V0A2 was identified in patients with bleeding diathesis and defective wound healing, expanding the known functional consequences of ATP6V0A2 loss beyond glycosylation and elastic fiber defects to include platelet abnormalities. Linkage analysis, exome sequencing, electron microscopy of patient fibroblasts and epidermal basal cells, clinical and histological analysis Turkish journal of haematology Low 30474613
2024 A non-canonical splicing-site variant (c.117+5G>T) in ATP6V0A2 was shown by minigene assay to disrupt pre-mRNA splicing, establishing that splicing integrity is required for normal ATP6V0A2 function. Whole-exome sequencing, Sanger sequencing, bioinformatics analysis, minigene splicing assay Molecular biology reports Low 38598037

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival. Human molecular genetics 111 19321599
2012 Further characterization of ATP6V0A2-related autosomal recessive cutis laxa. Human genetics 63 22773132
2021 Mechanisms of Enterobacter bugandensis TJ6 immobilization of heavy metals and inhibition of Cd and Pb uptake by wheat based on metabolomics and proteomics. Chemosphere 42 33714158
1995 Reciprocal alteration in circulating TJ6+ CD19+ and TJ6+ CD56+ leukocytes in early pregnancy predicts success or miscarriage. American journal of reproductive immunology (New York, N.Y. : 1989) 32 8579758
1994 Expression of a membrane form of the pregnancy-associated protein TJ6 on lymphocytes. Cellular immunology 32 7513260
2015 Impaired ATP6V0A2 expression contributes to Golgi dispersion and glycosylation changes in senescent cells. Scientific reports 27 26611489
2018 Molecular mechanisms of cutis laxa- and distal renal tubular acidosis-causing mutations in V-ATPase a subunits, ATP6V0A2 and ATP6V0A4. The Journal of biological chemistry 24 29311258
1996 TJ6: the pregnancy-associated cytokine. American journal of reproductive immunology (New York, N.Y. : 1989) 19 8739450
1995 Purification and characterization of a pregnancy-associated protein: TJ6s. American journal of reproductive immunology (New York, N.Y. : 1989) 19 7619235
2018 Proteomic analyses reveal lower expression of TEX40 and ATP6V0A2 proteins related to calcium ion entry and acrosomal acidification in asthenozoospermic males. Life sciences 17 30550884
2018 A Novel ATP6V0A2 Mutation Causing Recessive Cutis Laxa with Unusual Manifestations of Bleeding Diathesis and Defective Wound Healing. Turkish journal of haematology : official journal of Turkish Society of Haematology 11 30474613
2014 ATP6V0A2 mutations present in two Mexican Mestizo children with an autosomal recessive cutis laxa syndrome type IIA. Molecular genetics and metabolism reports 11 27896089
2005 Cloning, expression and functional characterization of the putative regeneration and tolerance factor (RTF/TJ6) as a functional vacuolar ATPase proton pump regulatory subunit with a conserved sequence of immunoreceptor tyrosine-based activation motif. International immunology 9 16113235
2024 Epirubicin induces cardiotoxicity through disrupting ATP6V0A2-dependent lysosomal acidification and triggering ferroptosis in cardiomyocytes. Cell death discovery 8 39048556
1997 Expression of TJ6 during pregnancy. American journal of reproductive immunology (New York, N.Y. : 1989) 7 9325490
1996 Expression of membrane form of the pregnancy associated protein TJ6 on decidual lymphocytes in the first trimester of pregnancy. Journal of reproductive immunology 6 8920165
2022 A novel deletion mutation in the ATP6V0A2 gene in an Iranian patient affected by autosomal recessive cutis laxa. Irish journal of medical science 4 36520350
2024 Identification of a novel intronic variant of ATP6V0A2 in a Han-Chinese family with cutis laxa. Molecular biology reports 1 38598037
2023 Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families. The journal of gene medicine 1 37119015
1996 Transforming growth factor-beta 2-related-decidual suppressor factor is not related to TJ6 protein. American journal of reproductive immunology (New York, N.Y. : 1989) 1 8739451
2026 ATP6V0A2-Related Cutis Laxa: Identification of a Recurrent Exon 16 Deletion With Founder Effect in Southeastern Türkiye and a Novel Frameshift Variant. American journal of medical genetics. Part A 0 41732832
2022 [Analysis of clinical features and genetic variants in a child with autosomal recessive cutis laxa due to variants of ATP6V0A2 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 36184099

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