ATP6AP2 functions as a V-ATPase assembly factor in the endoplasmic reticulum

Guida, Maria Clara; Hermle, Tobias; Graham, Laurie A.; Hauser, Virginie; Ryan, M. Dominic; Stevens, Tom H.; Simons, Matias

doi:10.1091/mbc.e18-04-0234

Cited by 28 publications

(23 citation statements)

References 38 publications

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“…Recent studies in yeast and flies suggest that ATP6AP2 contributes to the assembly of the V-ATPase proton pore in the endoplasmic reticulum (11). unknown.…”

Section: Atp6ap2 Variant Impairs Cns Development and Neuronal Survivamentioning

confidence: 99%

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration

Hirose¹,

Cabrera-Socorro²,

Chitayat³

et al. 2019

Journal of Clinical Investigation

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“…Recent studies in yeast and flies suggest that ATP6AP2 contributes to the assembly of the V-ATPase proton pore in the endoplasmic reticulum (11). unknown.…”

Section: Atp6ap2 Variant Impairs Cns Development and Neuronal Survivamentioning

confidence: 99%

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration

Hirose¹,

Cabrera-Socorro²,

Chitayat³

et al. 2019

Journal of Clinical Investigation

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“…Its role in Drosophila and Xenopus development is also established (25)(26)(27). Atp6ap2 colocalizes with V-ATPase subunits (28,29), and overexpression studies showed its coprecipitation with V 0 subunits (27) in association with V-ATPase dysfunction (30). Atp6ap2 has been proposed to chaperone V-ATPase assembly as its deletion causes reduced levels of V-ATPase subunits (18,19).…”

Section: Significancementioning

confidence: 99%

Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells

Binger

Neukam

Tattikota

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic β cells store insulin within secretory granules which undergo exocytosis upon elevation of blood glucose levels. Crinophagy and autophagy are instead responsible to deliver damaged or old granules to acidic lysosomes for intracellular degradation. However, excessive consumption of insulin granules can impair β cell function and cause diabetes. Atp6ap2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy. Here, we show that Cre recombinase-mediated conditional deletion of Atp6ap2 in mouse β cells causes a dramatic accumulation of large, multigranular vacuoles in the cytoplasm, with reduction of insulin content and compromised glucose homeostasis. Loss of insulin stores and gigantic vacuoles were also observed in cultured insulinoma INS-1 cells upon CRISPR/Cas9-mediated removal of Atp6ap2. Remarkably, these phenotypic alterations could not be attributed to a deficiency in autophagy or acidification of lysosomes. Together, these data indicate that Atp6ap2 is critical for regulating the stored insulin pool and that a balanced regulation of granule turnover is key to maintaining β cell function and diabetes prevention.

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“…(3) Vma12p, Vma21p, and Vma22p correspond to transmembrane protein 199 (TMEM199), vacuolar ATPase assembly integral membrane protein (VMA21), and coiledcoil domain containing protein 115 (CCDC115), respectively, in mammals. Voa1p has been replaced by ATPase H+ Transporting Accessory Protein 1 and 2 (ATP6AP1 and ATP6AP2), (8,9) whereas Pkr1p does not have a mammalian ortholog. Whether the assembly of the mammalian V 0 is mechanistically similar to yeast V 0 assembly is currently unclear.…”

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confidence: 99%

Mutations in the V‐ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease

et al. 2020

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BaCKgRoUND aND aIMS: Vacuolar H+-ATP complex (V-ATPase) is a multisubunit protein complex required for acidification of intracellular compartments. At least five different factors are known to be essential for its assembly in the endoplasmic reticulum (ER). Genetic defects in four of these V-ATPase assembly factors show overlapping clinical features, including steatotic liver disease and mild hypercholesterolemia. An exception is the assembly factor vacuolar ATPase assembly integral membrane protein (VMA21), whose X-linked mutations lead to autophagic myopathy. appRoaCH aND ReSUltS: Here, we report pathogenic variants in VMA21 in male patients with abnormal protein glycosylation that result in mild cholestasis, chronic elevation of aminotransferases, elevation of (low-density lipoprotein) cholesterol and steatosis in hepatocytes. We also show that the VMA21 variants lead to V-ATPase misassembly and dysfunction. As a consequence, lysosomal acidification and degradation of phagocytosed materials are impaired, causing lipid droplet (LD) accumulation in autolysosomes. Moreover, VMA21 deficiency triggers ER stress and sequestration of unesterified cholesterol in lysosomes, thereby activating the sterol response element-binding protein-mediated cholesterol synthesis pathways. CoNClUSIoNS: Together, our data suggest that impaired lipophagy, ER stress, and increased cholesterol synthesis lead to LD accumulation and hepatic steatosis. V-ATPase assembly defects are thus a form of hereditary liver disease with implications for the pathogenesis of nonalcoholic fatty liver disease.

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ATP6AP2 functions as a V-ATPase assembly factor in the endoplasmic reticulum

Cited by 28 publications

References 38 publications

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration

Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells

Mutations in the V‐ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease

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