Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects
Résumé
The biogenesis of the multi-subunit vacuolar-type H+-ATPase (V-ATPase) is initiated in the endoplasmic reticulum with the assembly of the proton pore V0, which is controlled by a group of assembly factors. Here, we identify two hemizygous missense mutations in the extracellular domain of the accessory V-ATPase subunit ATP6AP2 (also known as the [pro]renin receptor) responsible for a glycosylation disorder with liver disease, immunodeficiency, cutis laxa, and psychomotor impairment. We show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. The introduction of one of the missense mutations into Drosophila led to reduced survival and altered lipid metabolism. We further demonstrate that in the liver-like fat body, the autophagic dysregulation was associated with defects in lysosomal acidification and mammalian target of rapamycin (mTOR) signaling. Finally, both ATP6AP2 mutations impaired protein stability and the interaction with ATP6AP1, a member of the V0 assembly complex. Collectively, our data suggest that the missense mutations in ATP6AP2 lead to impaired V-ATPase assembly and subsequent defects in glycosylation and autophagy.
Mots clés
Young Adult
Genes
X-Linked
Base Sequence
Fibroblasts
Vacuolar Proton-Translocating ATPases
Amino Acid Sequence
Drosophila Proteins
Glycosylation
Neural Stem Cells
Animals
Blood Proteins
Proton-Translocating ATPases
Adolescent
Protein Binding
Mice
Membrane Protein
Protein Processing
Post-Translational
Mutation
Liver Diseases
Drosophila melanogaster
Psychomotor Disorders
Endoplasmic Reticulum-Associated Degradation
Brain
Humans
Liver
Cutis Laxa
Male
Lipids
Infant
Receptors
Cell Surface
Autophagy
Domaines
Chimie théorique et/ou physique| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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