Year: 2017
Type: article
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.
DOI: 10.1084/jem.20170453
Authors: Maria A. Rujano, Magda Cannata Serio, Ganna Panasyuk, Romain Péanne, Janine Reunert, Daisy Rymen, Virginie Hauser, Julien H. Park, Peter Freisinger, Erika Souche, Maria Clara Guida, Esther M. Maier, Yoshinao Wada, Stefanie Jäger, Nevan J. Krogan, Oliver Kretz, Susana Nobre, Paula Garcia, Dulce Quelhas, Thomas D. Bird, Wendy H. Raskind, Michael Schwake, Sandrine Duvet, Francois Foulquier, Gert Matthijs, Thorsten Marquardt, Matias Simons
Institutions: Sorbonne Paris Cité, Institut des Maladies Génétiques Imagine, Université Paris Descartes, Centre National de la Recherche Scientifique, Inserm, Institut Necker Enfants Malades, KU Leuven, University Hospital Münster, Kreiskliniken Reutlingen, Ludwig-Maximilians-Universität München, Osaka Women's and Children's Hospital, University of California, San Francisco, University of Freiburg, Unidade Local de Saúde de Coimbra, Universidade do Porto, Centro Hospitalar do Porto, Instituto de Ciências Biomédicas Albel Salazar, United States Department of Veterans Affairs, University of Washington, Veterans Health Administration, Bielefeld University, Université de Lille, Unité de Glycobiologie Structurale et Fonctionnelle
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: U.S. Department of Veterans Affairs, European Commission, Agence Nationale de la Recherche, Fonds Wetenschappelijk Onderzoek, Centre National de la Recherche Scientifique, Fondation Bettencourt Schueller, Vlaamse regering, National Institutes of Health, Horizon 2020 Framework Programme, Fundação para a Ciência e a Tecnologia, National Institute of Neurological Disorders and Stroke
Awards: G250961418, G3958026571, G4108394387, G434337789, Institut Hospitalo-Universitaire Imagine, G5083024019, G5485624415, G594818701, Unidade Multidisciplinar de Investigação Biomédica - UMIB, G6460715172, G7240651115, ERA-NET rare disease research implementing IRDiRC objectives, Using Drosophila melanogaster to study hereditary kidney diseases, Molecular determinants of hepatic nutrient homeostasis, G8883367568, G9000277095
OpenAlex ID: W2779197700