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Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects
Maria A Rujano1,2, Magda Cannata Serio1,2, Ganna Panasyuk3,4
1Laboratory of Epithelial Biology and Disease, Imagine Institute, Paris, France.
Abstract:
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.
Insights
Two mutations in the ATP6AP2 gene cause a rare disorder affecting protein glycosylation and autophagy. These ATP6AP2 mutations disrupt vacuolar-type H+-ATPase assembly, leading to liver disease and developmental issues.
Area of Science:
- Cell Biology
- Biochemistry
- Genetics
Background:
- Vacuolar-type H+-ATPase (V-ATPase) biogenesis begins in the endoplasmic reticulum, involving the V0 proton pore and assembly factors.
- ATP6AP2, also known as the [pro]renin receptor, is an accessory subunit of the V-ATPase.
Purpose of the Study:
- To investigate the role of ATP6AP2 mutations in a human disorder characterized by glycosylation defects, liver disease, immunodeficiency, cutis laxa, and psychomotor impairment.
- To elucidate the molecular mechanisms underlying the identified ATP6AP2 mutations in V-ATPase assembly, glycosylation, and autophagy.
Main Methods:
- Identification of hemizygous missense mutations in the extracellular domain of ATP6AP2.
- Analysis of ATP6AP2 deficiency and mutations in mouse liver and Drosophila models.
- Assessment of serum protein glycosylation, autophagy, lysosomal acidification, and mTOR signaling.
Main Results:
- ATP6AP2 deficiency in mouse liver resulted in hypoglycosylation of serum proteins and impaired autophagy.
- A missense mutation in Drosophila led to reduced survival and altered lipid metabolism.
- Autophagic dysregulation in Drosophila fat bodies was linked to defective lysosomal acidification and mTOR signaling.
- Both ATP6AP2 mutations decreased protein stability and impaired interaction with ATP6AP1, a V0 complex component.
Conclusions:
- Missense mutations in ATP6AP2 disrupt V-ATPase assembly, leading to impaired protein glycosylation and autophagy.
- These findings link ATP6AP2 function to critical cellular processes and human disease pathogenesis.
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