title: Manganese-induced turnover of TMEM165.
abstract: TMEM165 deficiencies lead to one of the congenital disorders of glycosylation (CDG), a group of inherited diseases where the glycosylation process is altered. We recently demonstrated that the Golgi glycosylation defect due to TMEM165 deficiency resulted from a Golgi manganese homeostasis defect and that Mn2+supplementation was sufficient to rescue normal glycosylation. In the present paper, we highlight TMEM165 as a novel Golgi protein sensitive to manganese. When cells were exposed to high Mn2+concentrations, TMEM165 was degraded in lysosomes. Remarkably, while the variant R126H was sensitive upon manganese exposure, the variant E108G, recently identified in a novel TMEM165-CDG patient, was found to be insensitive. We also showed that the E108G mutation did not abolish the function of TMEM165 in Golgi glycosylation. Altogether, the present study identified the Golgi protein TMEM165 as a novel Mn2+-sensitive protein in mammalian cells and pointed to the crucial importance of the glutamic acid (E108) in the cytosolic ELGDK motif in Mn2+-induced degradation of TMEM165.
authors.affiliation: CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille F-59000, France and the LIA GLYCOLAB4CDG France/ Belgium (International Associated Laboratory "Laboratory for the Research on Congenital Disorders of Glycosylation - from cellular mechanisms to cure").
authors.forename: Sven
authors.initials: S
authors.lastname: Potelle
authors.affiliation: CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille F-59000, France and the LIA GLYCOLAB4CDG France/ Belgium (International Associated Laboratory "Laboratory for the Research on Congenital Disorders of Glycosylation - from cellular mechanisms to cure").
authors.forename: Eudoxie
authors.initials: E
authors.lastname: Dulary
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of Arkansas for Medical Sciences, Biomed 261-2, Slot 505, 200 South Cedar St., Little Rock, AR 72205, U.S.A.
authors.forename: Leslie
authors.initials: L
authors.lastname: Climer
authors.affiliation: CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille F-59000, France and the LIA GLYCOLAB4CDG France/ Belgium (International Associated Laboratory "Laboratory for the Research on Congenital Disorders of Glycosylation - from cellular mechanisms to cure").
authors.forename: Sandrine
authors.initials: S
authors.lastname: Duvet
authors.affiliation: CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille F-59000, France and the LIA GLYCOLAB4CDG France/ Belgium (International Associated Laboratory "Laboratory for the Research on Congenital Disorders of Glycosylation - from cellular mechanisms to cure").
authors.forename: Willy
authors.initials: W
authors.lastname: Morelle
authors.affiliation: CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille F-59000, France and the LIA GLYCOLAB4CDG France/ Belgium (International Associated Laboratory "Laboratory for the Research on Congenital Disorders of Glycosylation - from cellular mechanisms to cure").
authors.forename: Dorothée
authors.initials: D
authors.lastname: Vicogne
authors.affiliation: CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille F-59000, France and the LIA GLYCOLAB4CDG France/ Belgium (International Associated Laboratory "Laboratory for the Research on Congenital Disorders of Glycosylation - from cellular mechanisms to cure").|Centre de Biologie et Pathologies, UAM de glycopathologies, CHRU de Lille, University of Lille, 59000 France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Lebredonchel
authors.affiliation: CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille F-59000, France and the LIA GLYCOLAB4CDG France/ Belgium (International Associated Laboratory "Laboratory for the Research on Congenital Disorders of Glycosylation - from cellular mechanisms to cure").
authors.forename: Marine
authors.initials: M
authors.lastname: Houdou
authors.affiliation: CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille F-59000, France and the LIA GLYCOLAB4CDG France/ Belgium (International Associated Laboratory "Laboratory for the Research on Congenital Disorders of Glycosylation - from cellular mechanisms to cure").
authors.forename: Corentin
authors.initials: C
authors.lastname: Spriet
authors.affiliation: CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille F-59000, France and the LIA GLYCOLAB4CDG France/ Belgium (International Associated Laboratory "Laboratory for the Research on Congenital Disorders of Glycosylation - from cellular mechanisms to cure").
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Krzewinski-Recchi
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Romain
authors.initials: R
authors.lastname: Peanne
authors.affiliation: CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille F-59000, France and the LIA GLYCOLAB4CDG France/ Belgium (International Associated Laboratory "Laboratory for the Research on Congenital Disorders of Glycosylation - from cellular mechanisms to cure").|Centre de Biologie et Pathologies, UAM de glycopathologies, CHRU de Lille, University of Lille, 59000 France.
authors.forename: André
authors.initials: A
authors.lastname: Klein
authors.affiliation: CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille F-59000, France and the LIA GLYCOLAB4CDG France/ Belgium (International Associated Laboratory "Laboratory for the Research on Congenital Disorders of Glycosylation - from cellular mechanisms to cure").
authors.forename: Geoffroy
authors.initials: G
authors.lastname: de Bettignies
authors.affiliation: Institut des Sciences de la Vie, Université catholique de Louvain, Louvain-la-Neuve B-1348, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Morsomme
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.affiliation: Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A 1, Münster 48149, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of Arkansas for Medical Sciences, Biomed 261-2, Slot 505, 200 South Cedar St., Little Rock, AR 72205, U.S.A.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lupashin
authors.affiliation: CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Lille F-59000, France and the LIA GLYCOLAB4CDG France/ Belgium (International Associated Laboratory "Laboratory for the Research on Congenital Disorders of Glycosylation - from cellular mechanisms to cure") francois.foulquier@univ-lille1.fr.
authors.forename: François
authors.initials: F
authors.lastname: Foulquier
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D017920:Antiporters; D015153:Blotting, Western; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins; D004305:Dose-Response Relationship, Drug; D055785:Gene Knockdown Techniques; D005971:Glutamates / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008345:Manganese / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D009154:Mutation; D059748:Proteolysis / Q000187:drug effects
chemical_list: D017920:Antiporters; D027682:Cation Transport Proteins; D005971:Glutamates; D008565:Membrane Proteins; C575014:TMEM165 protein, human; D008345:Manganese; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases
keywords: Golgi apparatus; TMEM165; congenital disorders of glycosylation; glycosylation; manganese