title: Glycosylation abnormalities in Gdt1p/TMEM165 deficient cells result from a defect in Golgi manganese homeostasis.
abstract: Congenital disorders of glycosylation (CDG) are severe inherited diseases in which aberrant protein glycosylation is a hallmark. From this genetically and clinically heterogenous group, a significant subgroup due to Golgi homeostasis defects is emerging. We previously identified TMEM165 as a Golgi protein involved in CDG. Extremely conserved in the eukaryotic reign, the molecular mechanism by which TMEM165 deficiencies lead to Golgi glycosylation abnormalities is enigmatic. AsGDT1 is the ortholog of TMEM165 in yeast, both gdt1Δ null mutant yeasts and TMEM165 depleted cells were used. We highlighted that the observed Golgi glycosylation defects due to Gdt1p/TMEM165 deficiency result from Golgi manganese homeostasis defect. We discovered that in both yeasts and mammalian Gdt1p/TMEM165-deficient cells, Mn(2+) supplementation could restore a normal glycosylation. We also showed that the GPP130 Mn(2+) sensitivity was altered in TMEM165 depleted cells. This study not only provides novel insights into the molecular causes of glycosylation defects observed in TMEM165-deficient cells but also suggest that TMEM165 is a key determinant for the regulation of Golgi Mn(2+) homeostasis.
authors.affiliation: Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.
authors.forename: Sven
authors.initials: S
authors.lastname: Potelle
authors.affiliation: Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.
authors.forename: Willy
authors.initials: W
authors.lastname: Morelle
authors.affiliation: Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.
authors.forename: Eudoxie
authors.initials: E
authors.lastname: Dulary
authors.affiliation: Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Duvet
authors.affiliation: Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Vicogne
authors.affiliation: Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.
authors.forename: Corentin
authors.initials: C
authors.lastname: Spriet
authors.affiliation: Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Krzewinski-Recchi
authors.affiliation: Institut des Sciences de la Vie, Université Catholique de Louvain, B-1348, Louvain-la-Neuve, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Morsomme
authors.affiliation: Center for Metabolic Diseases, University Hospital Gasthuisberg, KU Leuven, Belgium and.
authors.forename: Jaak
authors.initials: J
authors.lastname: Jaeken
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.affiliation: Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.
authors.forename: Geoffroy
authors.initials: G
authors.lastname: De Bettignies
authors.affiliation: Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France, francois.foulquier@univ-lille1.fr.
authors.forename: François
authors.initials: F
authors.lastname: Foulquier
mesh_terms: D017920:Antiporters; D027682:Cation Transport Proteins; D018981:Congenital Disorders of Glycosylation / Q000235:genetics; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D006031:Glycosylation / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D008345:Manganese / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D017920:Antiporters; D027682:Cation Transport Proteins; D005656:Fungal Proteins; C107340:GOLIM4 protein, human; D008565:Membrane Proteins; C575014:TMEM165 protein, human; D033921:Vesicular Transport Proteins; D008345:Manganese