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Biochem J. 2017 Apr 19;474(9):1481-1493. doi: 10.1042/BCJ20160910.

Manganese-induced turnover of TMEM165.

Author information

1
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").
2
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.
3
Centre de Biologie et Pathologies, UAM de glycopathologies, CHRU de Lille, University of Lille, 59000 France.
4
Center for Human Genetics, KU Leuven, Leuven, Belgium.
5
Institut des Sciences de la Vie, Université catholique de Louvain, Louvain-la-Neuve B-1348, Belgium.
6
Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A 1, Münster 48149, Germany.
7
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.

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.

KEYWORDS:

Golgi apparatus; TMEM165; congenital disorders of glycosylation; glycosylation; manganese

PMID:
28270545
PMCID:
PMC5595065
DOI:
10.1042/BCJ20160910
[Indexed for MEDLINE]
Free PMC Article

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