Affinage

VMA21

Vacuolar ATPase assembly integral membrane protein VMA21 · UniProt Q3ZAQ7

Length
101 aa
Mass
11.4 kDa
Annotated
2026-04-28
30 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VMA21 is an endoplasmic reticulum-resident assembly chaperone essential for biogenesis of the vacuolar H⁺-ATPase (V-ATPase), the principal mammalian proton pump, and its deficiency impairs lysosomal acidification, autophagic degradation, and cellular amino acid homeostasis. VMA21 exists as a ubiquitous short isoform (VMA21-101) and a muscle-specific long isoform (VMA21-120) that is upregulated during myogenic differentiation; both isoforms localize to the sarcoplasmic reticulum and interact with V-ATPase subunits, and XMEA-causing mutations ablate both isoforms (PMID:37756622). Hypomorphic VMA21 mutations cause X-linked myopathy with excessive autophagy (XMEA) through reduced V-ATPase assembly, elevated lysosomal pH, mTORC1 downregulation, and compensatory macroautophagy leading to cell vacuolation, while distinct pathogenic variants produce a congenital disorder of glycosylation with autophagic liver disease featuring lipid droplet accumulation, ER stress, and SREBP-mediated cholesterol dysregulation (PMID:19379691, PMID:32145091). A follicular lymphoma-associated truncation removes a C-terminal ER retrieval signal, mislocalizing VMA21 to lysosomes and creating an autophagy-dependent survival vulnerability targetable by ULK1 inhibitors, and VMA21 additionally stabilizes the V-ATPase subunit TCIRG1 by inhibiting its ubiquitination-mediated degradation (PMID:35287545, PMID:39267677).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2000 Medium

    Mapping the XMEA disease locus to Xq28 established the chromosomal region harboring VMA21, enabling its subsequent identification as the causative gene.

    Evidence Linkage analysis with 32 X-chromosome markers in XMEA families

    PMID:10757644

    Open questions at the time
    • Gene itself not yet identified
    • No functional characterization of the locus product
  2. 2009 High

    Identification of hypomorphic VMA21 mutations as the cause of XMEA established VMA21 as the mammalian V-ATPase assembly chaperone and revealed the mechanistic cascade from impaired proton pump assembly through lysosomal alkalinization, autophagy blockade, amino acid depletion, mTOR dysregulation, and compensatory macroautophagy to cell vacuolation.

    Evidence Genetic mapping, V-ATPase assembly assays, lysosomal pH measurement, autophagy flux, mTOR pathway analysis, yeast ortholog complementation

    PMID:19379691

    Open questions at the time
    • Tissue-specific mechanisms of skeletal muscle selectivity unknown
    • Structural basis of VMA21-V0 interaction not determined
    • No isoform-level characterization
  3. 2013 High

    Replication and extension of the XMEA mechanism confirmed VMA21 as the diverged human ortholog of yeast Vma21p and solidified the pathway from V-ATPase misassembly through mTORC1 downregulation to autophagic overcompensation and atrophy.

    Evidence Patient mutation analysis, V-ATPase assembly and lysosomal pH assays, mTORC1 and autophagy flux measurements, muscle biopsy histology

    PMID:23315026

    Open questions at the time
    • No explanation for why only skeletal muscle is affected despite ubiquitous V-ATPase expression
    • No non-coding mutation analysis
  4. 2014 Medium

    Discovery that non-coding VMA21 microdeletions cause severe XMEA demonstrated that VMA21 protein level is directly proportional to disease severity and lysosomal function.

    Evidence Genetic sequencing of intronic and 3ʹUTR deletions with clinical correlation

    PMID:25683699

    Open questions at the time
    • Precise regulatory elements disrupted not mapped
    • No quantitative dose–response curve for VMA21 levels versus lysosomal pH established
  5. 2020 High

    Identification of VMA21 variants causing congenital disorder of glycosylation with liver disease revealed that V-ATPase dysfunction extends beyond muscle to produce hepatic steatosis, ER stress, lysosomal cholesterol sequestration, and SREBP-mediated lipogenesis.

    Evidence Patient variant analysis, V-ATPase assembly assays, lipid droplet imaging, cholesterol trafficking, ER stress marker quantification, SREBP pathway analysis

    PMID:32145091

    Open questions at the time
    • Genotype–phenotype rules distinguishing muscle versus liver presentations unclear
    • Whether glycosylation defect is primary or secondary to lysosomal pH change not resolved
  6. 2022 High

    Characterization of the follicular lymphoma hotspot mutation p.93X revealed a C-terminal non-canonical ER retrieval signal whose loss mislocalizes VMA21 to lysosomes, impairing V-ATPase activity and creating an autophagy-dependent survival vulnerability targetable by ULK1 inhibition.

    Evidence Subcellular localization imaging, lysosomal metabolomics (Lyso-IP), V-ATPase activity assays, autophagy flux assays, high-throughput drug screen, yeast functional assays

    PMID:35287545 PMID:37389034

    Open questions at the time
    • In vivo FL therapeutic efficacy of ULK1 inhibition not tested
    • Whether mislocalized VMA21 has dominant-negative or loss-of-function behavior in lymphocytes not distinguished
  7. 2023 High

    Discovery of two VMA21 isoforms — ubiquitous VMA21-101 and muscle-specific VMA21-120 — explained the tissue-selective vulnerability in XMEA: VMA21-120 is upregulated during myogenic differentiation and muscle regeneration, and XMEA mutations eliminate both isoforms.

    Evidence RT-PCR, Western blot, immunofluorescence, co-immunoprecipitation with V-ATPase, muscle differentiation and in vivo mouse models

    PMID:37756622

    Open questions at the time
    • Distinct functional contributions of VMA21-101 versus VMA21-120 to V-ATPase assembly not dissected
    • No structural data on either isoform
  8. 2023 Medium

    Demonstration that aerobic exercise upregulates VMA21 via ADRB2–AMPK–mTOR signaling in an Alzheimer's disease mouse model linked VMA21-dependent V-ATPase function to amyloid-β clearance through the autophagy–lysosome pathway.

    Evidence APP-PSEN1 mouse model, propranolol-mediated ADRB2 blockade, VMA21/V-ATPase activity measurement, autophagy and Aβ quantification

    PMID:37964627

    Open questions at the time
    • Mechanism by which ADRB2 signaling transcriptionally or post-transcriptionally regulates VMA21 not defined
    • Not replicated in independent AD cohorts or models
  9. 2024 Medium

    VMA21 was shown to stabilize the V-ATPase a3 subunit TCIRG1 by direct binding and inhibition of its ubiquitination-mediated degradation, linking VMA21 to tumor proliferation and immune evasion in triple-negative breast cancer.

    Evidence Co-immunoprecipitation, ubiquitination assay, VMA21 knockdown in TNBC cell lines, CD8⁺ T cell co-culture, xenograft model

    PMID:39267677

    Open questions at the time
    • Whether VMA21-TCIRG1 stabilization is independent of canonical V-ATPase assembly chaperone function not clarified
    • No identification of the E3 ligase antagonized by VMA21
    • Single-lab finding awaiting independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of VMA21's interaction with V0 subunits, the distinct functional roles of VMA21-101 versus VMA21-120 in V-ATPase assembly, and the genotype–phenotype rules governing muscle versus liver disease remain unresolved.
  • No crystal or cryo-EM structure of mammalian VMA21 or VMA21–V0 complex
  • Isoform-specific V-ATPase assembly contributions not dissected
  • Determinants of tissue-selective pathology (muscle vs liver vs lymphoma) undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 4
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005764 lysosome 1
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-382551 Transport of small molecules 3 R-HSA-162582 Signal Transduction 2
Partners
ATP6V0A1ATP6V0D1TCIRG1
Complex memberships
V-ATPase (V0 sector assembly intermediate)

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 VMA21 is an essential assembly chaperone of the vacuolar ATPase (V-ATPase), the principal mammalian proton pump complex; decreased VMA21 raises lysosomal pH, reduces lysosomal degradative ability, blocks autophagy, reduces cellular free amino acids, upregulates mTOR-dependent macroautophagy, and results in proliferation of large ineffective autolysosomes that vacuolate the cell, causing X-linked myopathy with excessive autophagy (XMEA). Genetic mapping of XMEA mutations to hypomorphic VMA21 alleles, V-ATPase assembly assays, lysosomal pH measurement, autophagy flux assays, mTOR pathway analysis, yeast ortholog functional comparison Cell High 19379691
2013 VMA21 is the diverged human ortholog of yeast Vma21p and functions as an essential V-ATPase assembly chaperone; hypomorphic XMEA mutations reduce VMA21 expression, raising lysosomal pH, impairing lysosomal degradation, blocking autophagy, reducing free amino acids, downregulating mTORC1, and causing macroautophagic overcompensation leading to cell vacuolation and atrophy. Patient mutation analysis, V-ATPase assembly assays, lysosomal pH measurements, mTORC1 pathway assays, autophagy flux assays, muscle biopsy histology Acta neuropathologica High 23315026
2014 Non-coding (intronic and 3'UTR) microdeletions in VMA21 reduce VMA21 expression and cause a more severe XMEA phenotype, confirming that VMA21 protein levels are directly proportional to disease severity and lysosomal pH dysregulation. Genetic sequencing of non-coding VMA21 deletions, patient clinical characterization, mutation-expression correlation Neuromuscular disorders : NMD Medium 25683699
2020 VMA21 pathogenic variants cause V-ATPase misassembly and dysfunction, impairing lysosomal acidification, leading to lipid droplet accumulation in autolysosomes, ER stress, sequestration of unesterified cholesterol in lysosomes, and activation of SREBP-mediated cholesterol synthesis, resulting in a congenital disorder of glycosylation with autophagic liver disease. Patient variant identification, V-ATPase assembly assays, lysosomal acidification assays, lipid droplet imaging, cholesterol trafficking assays, ER stress markers, SREBP pathway analysis Hepatology (Baltimore, Md.) High 32145091
2022 Follicular lymphoma-associated VMA21 hotspot mutation p.93X removes a C-terminal non-canonical ER retrieval signal, causing VMA21 mislocalization from ER to lysosomes, impairing V-ATPase activity, preventing full lysosomal acidification, depleting cytoplasmic amino acids, and activating compensatory autophagy that creates a survival dependency targetable by ULK1 inhibitors. Mutation analysis, subcellular localization (fluorescence microscopy), lysosomal metabolomics (Lyso-IP), V-ATPase activity assays, autophagy flux assays (multiple complementary assays), high-throughput drug screening, yeast functional assays Autophagy High 35287545
2022 The FL-associated VMA21 Vma21[Δ66-77] mutation (corresponding to p.93X) impairs V-ATPase assembly as shown by decreased vacuolar levels of V0 subunits and a Vph1 stability assay, and significantly reduces vacuolar levels of histidine, lysine, and arginine. Yeast genetic model, V0 subunit localization, Vph1 stability assay, vacuolar amino acid metabolomics Autophagy reports Medium 37389034
2023 VMA21 encodes two protein isoforms: a ubiquitous short isoform (VMA21-101) and a muscle-specific long isoform (VMA21-120); VMA21-120 is predominantly expressed in skeletal muscle, rapidly upregulated upon muscle differentiation, accumulated during development/regeneration/denervation, and both isoforms localize to the sarcoplasmic reticulum of muscle cells and interact with the V-ATPase; XMEA mutations cause loss of both isoforms. RT-PCR and Western blot isoform identification, immunofluorescence localization, co-immunoprecipitation with V-ATPase, muscle differentiation assays, mouse and human muscle precursor cell models, in vivo mouse muscle analysis Human molecular genetics High 37756622
2023 Aerobic exercise reverses V-ATPase dysfunction and autophagy-lysosomal deficits in Alzheimer's disease mice by upregulating VMA21 levels via ADRB2/β2-adrenergic receptor and AMPK-mTOR signaling, enhancing Aβ clearance through the autophagy-lysosomal pathway. Mouse AD model (APP-PSEN1), pharmacological ADRB2 inhibition with propranolol, VMA21 protein level measurement, V-ATPase activity assay, autophagy flux assays, Aβ pathology quantification, cognitive testing Autophagy Medium 37964627
2024 VMA21 stabilizes TCIRG1 protein expression by binding to TCIRG1 and inhibiting its ubiquitination-mediated degradation, thereby promoting proliferation, invasion, and immune escape in triple-negative breast cancer cells. Co-immunoprecipitation, ubiquitination assay, VMA21 knockdown in TNBC cell lines, CD8+ T cell co-culture assay, xenograft mouse model American journal of cancer research Medium 39267677
2000 X-linked myopathy with excessive autophagy (XMEA) was genetically mapped to the Xq28 region, establishing the chromosomal locus of the VMA21 gene and ruling out allelic identity with Emery-Dreifuss muscular dystrophy. Linkage analysis with 32 polymorphic X-chromosome markers, multipoint LOD score analysis, Sanger sequencing of emerin gene European journal of human genetics : EJHG Medium 10757644

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Circular RNA VMA21 protects against intervertebral disc degeneration through targeting miR-200c and X linked inhibitor-of-apoptosis protein. Annals of the rheumatic diseases 243 29343508
2013 VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy. Acta neuropathologica 111 23315026
2020 Circular RNA VMA21 ameliorates sepsis-associated acute kidney injury by regulating miR-9-3p/SMG1/inflammation axis and oxidative stress. Journal of cellular and molecular medicine 66 32827242
2019 lncRNA ZFPM2-AS1 promotes proliferation via miR-18b-5p/VMA21 axis in lung adenocarcinoma. Journal of cellular biochemistry 51 31297866
2009 VMA21 deficiency causes an autophagic myopathy by compromising V-ATPase activity and lysosomal acidification. Cell 51 19379691
2020 Mutations in the V-ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease. Hepatology (Baltimore, Md.) 43 32145091
2020 Non-coding RNA LOXL1-AS1 exhibits oncogenic activity in ovarian cancer via regulation of miR-18b-5p/VMA21 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 32058209
2014 Non-coding VMA21 deletions cause X-linked myopathy with excessive autophagy. Neuromuscular disorders : NMD 30 25683699
2023 Aerobic exercise attenuates autophagy-lysosomal flux deficits by ADRB2/β2-adrenergic receptor-mediated V-ATPase assembly factor VMA21 signaling in APP-PSEN1/PS1 mice. Autophagy 24 37964627
2019 Protective impacts of circular RNA VMA21 on lipopolysaccharide-engendered WI-38 cells injury via mediating microRNA-142-3p. BioFactors (Oxford, England) 24 31793712
2000 Linkage of X-linked myopathy with excessive autophagy (XMEA) to Xq28. European journal of human genetics : EJHG 22 10757644
2021 Hsa_circ_0001361 facilitates the progress of lung adenocarcinoma cells via targeting miR-525-5p/VMA21 axis. Journal of translational medicine 18 34507559
2020 Long non-coding RNA LINC00665 promotes melanoma cell growth and migration via regulating the miR-224-5p/VMA21 axis. Experimental dermatology 16 33247967
2022 Circular RNA VMA21 ameliorates lung injury in septic rat via targeting microRNA-497-5p/CD2-associated protein axis. Bioengineered 15 35172672
2022 Follicular lymphoma-associated mutations in the V-ATPase chaperone VMA21 activate autophagy creating a targetable dependency. Autophagy 15 35287545
2021 LncRNA LINC00858 enhances cervical cancer cell growth through miR-3064-5p/ VMA21 axis. Cancer biomarkers : section A of Disease markers 13 34275889
2022 Circular RNA VMA21 ameliorates IL-1β-engendered chondrocyte injury through the miR-495-3p/FBWX7 signaling axis. Clinical immunology (Orlando, Fla.) 10 35378300
2021 circ_VMA21 protects WI-38 cells against LPS-induced apoptotic and inflammatory injury by acting on the miR-409-3p/KLF4 axis. General physiology and biophysics 10 34350833
2022 Novel Intronic Mutation in VMA21 Causing Severe Phenotype of X-Linked Myopathy with Excessive Autophagy-Case Report. Genes 8 36553512
2023 Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis. Human molecular genetics 5 37756622
2009 VMA21 deficiency: a case of myocyte indigestion. Cell 5 19379689
2017 Prenatal diagnosis of X-linked myopathy associated with a VMA21 gene mutation afforded through a novel targeted exome sequencing strategy applied in fetuses with abnormal ultrasound findings. Clinical case reports 4 28265396
2022 Circular RNA Derived from Vacuolar ATPase Assembly Factor VMA21 Suppresses Lipopolysaccharide-Induced Apoptosis of Chondrocytes in Osteoarthritis (OA) by Decreasing Mature miR-103 Production. Molecular biotechnology 3 35138580
2024 Identification of a Novel Intronic Mutation in VMA21 Associated with a Classical Form of X-Linked Myopathy with Autophagy. Global medical genetics 2 38736558
2022 Follicular lymphoma-associated mutations in the V-ATPase chaperone Vma21 activate autophagy by dysfunctional V-ATPase assembly. Autophagy reports 1 37389034
2026 Clinical, morphological, and molecular characterization of patients with X-linked myopathy with excessive autophagy (XMEA). Journal of neuropathology and experimental neurology 0 41307411
2025 Recent advances in the clinical spectrum and pathomechanisms associated with X-linked myopathy with excessive autophagy and other VMA21-related disorders. Journal of neuromuscular diseases 0 40033998
2024 XMEA: A New Hybrid Diamond Multielectrode Array for the In Situ Assessment of the Radiation Dose Enhancement by Nanoparticles. Sensors (Basel, Switzerland) 0 38676026
2024 VMA21: unveiling a novel oncogene that facilitates immune evasion in triple-negative breast cancer through TCIRG1 protein stability regulation. American journal of cancer research 0 39267677
2024 A novel variant in VMA21 causing adult-onset phenotype of X-linked myopathy with excessive autophagy with cardiac involvement in a Chinese patient. Journal of neuromuscular diseases 0 39973400