Affinage

VMA21

Vacuolar ATPase assembly integral membrane protein VMA21 · UniProt Q3ZAQ7

Length
101 aa
Mass
11.4 kDa
Annotated
2026-06-11
30 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VMA21 is an endoplasmic/sarcoplasmic reticulum-resident assembly chaperone essential for the proper assembly of the vacuolar H+-ATPase (V-ATPase) proton pump, the principal driver of lysosomal acidification (PMID:19379691, PMID:23315026). Loss of VMA21 function causes V-ATPase misassembly that raises lysosomal pH, impairs lysosomal degradation and autophagic flux, depletes cytoplasmic free amino acids, and dysregulates mTORC1, driving compensatory macroautophagy (PMID:19379691, PMID:23315026, PMID:35287545). This core defect underlies X-linked myopathy with excessive autophagy (XMEA), caused by hypomorphic VMA21 alleles, in which the resulting failure of autolysosomal degradation produces vacuolating autolysosomes in skeletal muscle (PMID:19379691, PMID:23315026); distinct pathogenic variants instead produce a liver-specific congenital disorder of glycosylation marked by lysosomal lipid and unesterified cholesterol accumulation, ER stress, and SREBP-driven cholesterol synthesis (PMID:32145091). The protein carries a C-terminal non-canonical ER retrieval signal whose loss (the follicular-lymphoma hotspot p.93X) mislocalizes VMA21 to lysosomes, impairing V-ATPase activity and creating a compensatory-autophagy dependence on ULK1 (PMID:35287545). VMA21 is expressed as a ubiquitous short isoform (VMA21-101) and a muscle-specific long isoform (VMA21-120) that is upregulated during muscle differentiation, regeneration, and denervation; both localize to the sarcoplasmic reticulum and interact with the V-ATPase (PMID:37756622). Beyond V-ATPase chaperoning, VMA21 stabilizes TCIRG1 by binding it and blocking its ubiquitination-mediated degradation (PMID:39267677).

Mechanistic history

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

    Before any gene was identified, the question was where the XMEA disease locus resided; mapping it established the genomic interval that would later pinpoint VMA21.

    Evidence Two-point and multipoint linkage analysis with X-chromosome markers in four XMEA families

    PMID:10757644

    Open questions at the time
    • Localizes the locus to Xq28 but does not identify the causative gene or any protein mechanism
    • No functional or molecular characterization
  2. 2009 High

    Identified VMA21 as the XMEA gene and defined its molecular role as a V-ATPase assembly chaperone, linking proton-pump assembly failure to a defined autophagy-lysosomal disease mechanism.

    Evidence Genetic identification of hypomorphic alleles in XMEA patients plus lysosomal pH, autophagic flux, amino acid, and mTOR assays in patient cells

    PMID:19379691

    Open questions at the time
    • Does not define the structural basis of VMA21–V-ATPase interaction
    • Isoform diversity not resolved
    • Tissue-specific manifestations not yet explained
  3. 2013 High

    Independently confirmed VMA21 as the diverged human ortholog of yeast Vma21p and reproduced the lysosomal-pH/autophagy/mTORC1 cascade in patient muscle, solidifying the disease mechanism.

    Evidence Analysis of XMEA patient muscle biopsies and cells with hypomorphic alleles; lysosomal pH, autophagy, and mTORC1 assays

    PMID:23315026

    Open questions at the time
    • Does not address non-muscle phenotypes
    • No direct biochemical reconstitution of assembly chaperone activity
  4. 2020 High

    Extended the VMA21 phenotypic spectrum by showing distinct pathogenic variants cause a liver CDG, revealing how impaired lysosomal acidification feeds into lipid and cholesterol dysregulation and ER stress.

    Evidence Patient-derived cells with VMA21 variants; V-ATPase assembly, lysosomal acidification, lipidomics, ER-stress, and cholesterol-trafficking assays

    PMID:32145091

    Open questions at the time
    • Does not explain why these variants give a liver rather than muscle phenotype
    • SREBP activation mechanism downstream of cholesterol sequestration not fully dissected
  5. 2022 High

    Defined a C-terminal non-canonical ER retrieval signal and showed its loss (p.93X) mislocalizes VMA21 to lysosomes and creates a therapeutically exploitable ULK1 dependency in follicular lymphoma.

    Evidence FL patient mutation analysis, localization studies, lysosomal metabolomics, V-ATPase activity and autophagy assays in human and yeast cells, ULK1 inhibitor sensitivity

    PMID:35287545

    Open questions at the time
    • Retrieval-signal receptor/machinery not identified
    • ULK1 dependency tested in a limited set of models
  6. 2022 Medium

    Reconstituted the FL-associated mutation in yeast to causally link reduced V0-subunit assembly to depletion of specific vacuolar amino acids, providing cross-species mechanistic support for autophagy activation.

    Evidence Yeast Vma21[Δ66-77] model; V0 vacuolar fractionation, Vph1 stability assay, vacuolar amino-acid metabolomics

    PMID:37389034

    Open questions at the time
    • Single lab; yeast surrogate of the human mutation
    • Does not establish direct chaperone binding stoichiometry
  7. 2023 High

    Resolved VMA21 isoform diversity, identifying a muscle-specific long isoform regulated by differentiation and denervation, addressing why VMA21 loss particularly affects skeletal muscle.

    Evidence Molecular cloning, immunofluorescence/fractionation for sarcoplasmic reticulum localization, reciprocal Co-IP with V-ATPase, muscle differentiation models, XMEA patient samples

    PMID:37756622

    Open questions at the time
    • Functional difference between VMA21-101 and VMA21-120 not defined
    • Whether the long isoform has V-ATPase-independent roles unknown
  8. 2023 Medium

    Placed VMA21 downstream of a regulable signaling axis, showing aerobic exercise upregulates VMA21 via ADRB2 and AMPK-MTOR to restore V-ATPase function and reduce amyloid pathology, suggesting VMA21 is a tunable node in neurodegeneration.

    Evidence Aerobic exercise and propranolol intervention in APP-PSEN1 mice; VMA21 protein, V-ATPase activity, autophagy flux, and Aβ pathology readouts

    PMID:37964627

    Open questions at the time
    • Direct transcriptional/post-translational mechanism of VMA21 induction not defined
    • Single lab; correlative coupling between VMA21 levels and Aβ reduction
  9. 2024 Medium

    Uncovered a V-ATPase-assembly-independent role: VMA21 binds and stabilizes TCIRG1 by inhibiting its ubiquitination, promoting tumor cell proliferation, invasion, and immune evasion in TNBC.

    Evidence Co-IP of VMA21 and TCIRG1, ubiquitination assay after VMA21 knockdown, functional and xenograft assays with CD8+ T-cell infiltration analysis

    PMID:39267677

    Open questions at the time
    • Single lab, single study
    • Whether stabilization is direct or via the V-ATPase complex not resolved
    • E3 ligase acting on TCIRG1 not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural mechanism by which VMA21 chaperones V-ATPase assembly, and how distinct mutations and isoforms produce tissue-specific muscle, liver, lymphoma, and neurodegenerative phenotypes, remains unresolved.
  • No structural model of the VMA21–V-ATPase assembly intermediate
  • Mechanistic basis of tissue-specific phenotypes not defined
  • Functional distinction between isoforms unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-9612973 Autophagy 3 R-HSA-392499 Metabolism of proteins 2
Partners
TCIRG1
Complex memberships
V-ATPase

Evidence

Reading pass · 9 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 — establishing the disease mechanism of XMEA. Genetic identification of hypomorphic VMA21 alleles in XMEA patients, functional studies in patient cells including lysosomal pH measurement, autophagic flux assays, amino acid quantification, and mTOR pathway analysis Cell High 19379691
2013 VMA21 is confirmed as the diverged human ortholog of yeast Vma21p and functions as an essential V-ATPase assembly chaperone. VMA21 deficiency causes autophagic vacuolar myopathy through lysosomal pH increase, reduced lysosomal degradation, blocked autophagy, reduced free amino acids, downregulation of mTORC1, and consequent macroautophagic overcompensation. Analysis of XMEA patient muscle biopsies and cells with hypomorphic VMA21 alleles; lysosomal pH measurement, autophagy assays, mTORC1 pathway analysis Acta neuropathologica High 23315026
2020 Pathogenic VMA21 variants cause V-ATPase misassembly and dysfunction, impairing lysosomal acidification and degradation of phagocytosed materials, leading to lipid droplet accumulation in autolysosomes, ER stress, sequestration of unesterified cholesterol in lysosomes, and activation of SREBP-mediated cholesterol synthesis pathways — establishing a liver-specific CDG phenotype. Patient-derived cells with VMA21 variants; V-ATPase assembly assays, lysosomal acidification assays, lipidomics, ER stress markers, cholesterol trafficking experiments Hepatology High 32145091
2022 Follicular lymphoma-associated VMA21 hotspot mutation p.93X removes a C-terminal non-canonical ER retrieval signal, causing VMA21 mislocalization to lysosomes, impairing V-ATPase activity, preventing full lysosomal acidification and pH-dependent protein degradation (shown by lysosomal metabolomics), depleting cytoplasmic amino acids, and driving compensatory autophagy activation that creates a survival dependency on ULK1. Identification of FL patient mutations, cellular mislocalization studies, lysosomal metabolomics, V-ATPase activity assays, autophagy assays in human and yeast cells, ULK1 inhibitor sensitivity assays Autophagy High 35287545
2022 In yeast, the FL-associated Vma21[Δ66-77] mutation (corresponding to human p.93X) reduces V-ATPase assembly, shown by decreased vacuolar levels of V0 subunits and a Vph1 stability assay, and significantly reduces vacuolar levels of histidine, lysine, and arginine, explaining autophagy activation. Yeast genetic model with Vma21[Δ66-77]; V0 subunit vacuolar fractionation, 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 differentiation of mouse and human muscle precursors, and accumulates during muscle development, regeneration, and denervation. Both isoforms localize to the sarcoplasmic reticulum of muscle cells and interact with the V-ATPase. XMEA-associated mutations cause loss of both VMA21-101 and VMA21-120. Isoform identification by molecular cloning; immunofluorescence/fractionation for localization to sarcoplasmic reticulum; co-immunoprecipitation with V-ATPase; expression analysis in mouse/human muscle differentiation models; XMEA patient samples Human molecular genetics High 37756622
2023 Aerobic exercise upregulates VMA21 levels via ADRB2/β2-adrenergic receptor activation and the AMPK-MTOR signaling pathway, thereby restoring V-ATPase function and reversing autophagy-lysosomal deficits in APP-PSEN1 Alzheimer disease mice. Inhibition of ADRB2 by propranolol blocked this VMA21 upregulation and the associated reduction in amyloid-β pathology. In vivo aerobic exercise intervention in APP-PSEN1 mice; propranolol pharmacological inhibition of ADRB2; VMA21 protein level measurement; V-ATPase activity assays; autophagy flux assays; Aβ pathology assessment Autophagy Medium 37964627
2000 X-linked myopathy with excessive autophagy (XMEA) maps to chromosome Xq28 by genetic linkage analysis using polymorphic markers across the X chromosome in multiple affected families. Two-point and multipoint linkage analysis with 32 polymorphic X-chromosome markers in four XMEA families; maximum lod score 2.74 at DXS1183 European journal of human genetics Medium 10757644
2024 VMA21 stabilizes TCIRG1 protein expression in triple-negative breast cancer cells by binding to TCIRG1 and inhibiting its ubiquitination-mediated degradation, thereby promoting TNBC cell proliferation, invasion, and immune evasion. Co-immunoprecipitation of VMA21 and TCIRG1; ubiquitination assay after VMA21 knockdown; functional assays (clone formation, scratch, Transwell) in TNBC cells; in vivo xenograft with CD8+ T cell immune infiltration analysis American journal of cancer research Medium 39267677

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 244 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.) 44 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 27 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 19 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.) 11 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
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 1 39973400
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

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