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Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects

2017-12-04Journal article Open access
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dc.contributor.authorRujano, M.
dc.contributor.authorCannata Serio, M.
dc.contributor.authorPanasyuk, G.
dc.contributor.authorPéanne, R.
dc.contributor.authorReunert, J.
dc.contributor.authorRymen, D.
dc.contributor.authorHauser, V.
dc.contributor.authorPark, J.
dc.contributor.authorFreisinger, P.
dc.contributor.authorSouche, E.
dc.contributor.authorGuida, M.
dc.contributor.authorMaier, E.
dc.contributor.authorWada, Y.
dc.contributor.authorJäger, S.
dc.contributor.authorKrogan, N.
dc.contributor.authorKretz, O.
dc.contributor.authorNobre, S.
dc.contributor.authorGarcia, P.
dc.contributor.authorQuelhas, D.
dc.contributor.authorBird, T.
dc.contributor.authorRaskind, W.
dc.contributor.authorSchwake, M.
dc.contributor.authorDuvet, S.
dc.contributor.authorFoulquier, F.
dc.contributor.authorMatthijs, G.
dc.contributor.authorMarquardt, T.
dc.contributor.authorSimons, M.
dc.date.accessioned2018-08-27T13:07:47Z
dc.date.available2018-08-27T13:07:47Z
dc.date.issued2017-12-04
dc.description.abstractThe 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.pt_PT
dc.description.sponsorshipThis work has been supported by the ATIP-Avenir program, the Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology), state funding by the Agence Nationale de la Recherche under the Investissements d’avenir program (grant no. ANR-10-IAHU-01), and a NEPHROFLY grant (no. ANR-14-ACHN-0013) to M. Simons. This research was also supported by an Agence Nationale de la Recherche grant (no. SOLV-CDG) to F. Foulquier and a NUTRISENSPIK grant (no. ANR-16-CE14-0029) to G. Panasyuk. G. Matthijs received support from the European Union’s Horizon 2020 research and innovation program under the ERA-NET Cofund action (grant no. 643578); the research was funded by the Research Foundation (FWO, Flanders; EURO-CDG-2 project). F. Folquier, G. Matthijs, and R. Péanne belong to LIA GLYCOLAB4CDG (International Associated Laboratory), funded by CNRS (France) and FWO. R. Péanne is a postdoctoral researcher (Pegasus Marie Curie Fellow) of the FWO. T.D. Bird and W.H. Raskind receive support from the National Institutes of Health (grant no. R01NS069719) and the Department of Veterans Affairs. This work is supported by National Funds through the Fundação para a Ciência e a Tecnologia (Portuguese national funding agency for science, research and technology) in the frameworks of the UID/Multi/00215/2013 project–Unit for Multidisciplinary Research in Biomedicine–UMIB/ICBAS/UP.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationJ Exp Med. 2017 Dec 4;214(12):3707-3729pt_PT
dc.identifier.doi10.1084/jem.20170453pt_PT
dc.identifier.issn0022-1007
dc.identifier.issn1540-9538
dc.identifier.urihttp://hdl.handle.net/10400.16/2228
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherRockefeller University Presspt_PT
dc.relation.publisherversionhttp://jem.rupress.org/content/214/12/3707.longpt_PT
dc.titleMutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defectspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F00215%2F2013/PT
oaire.citation.conferencePlaceUnited States of Americapt_PT
oaire.citation.endPage3729pt_PT
oaire.citation.issue12pt_PT
oaire.citation.startPage3707pt_PT
oaire.citation.titleJournal of Experimental Medicinept_PT
oaire.citation.volume214pt_PT
oaire.fundingStream5876
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicationfe3b8b21-3ef5-41b2-a767-0b77f6873482
relation.isProjectOfPublication.latestForDiscoveryfe3b8b21-3ef5-41b2-a767-0b77f6873482

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