1. Manganese-induced turnover of TMEM165.
- Author
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Potelle S, Dulary E, Climer L, Duvet S, Morelle W, Vicogne D, Lebredonchel E, Houdou M, Spriet C, Krzewinski-Recchi MA, Peanne R, Klein A, de Bettignies G, Morsomme P, Matthijs G, Marquardt T, Lupashin V, and Foulquier F
- Subjects
- Amino Acid Motifs genetics, Amino Acid Sequence, Antiporters, Blotting, Western, Calcium-Transporting ATPases genetics, Calcium-Transporting ATPases metabolism, Cation Transport Proteins, Dose-Response Relationship, Drug, Gene Knockdown Techniques, Glutamates genetics, Glutamates metabolism, Glycosylation drug effects, Golgi Apparatus metabolism, HEK293 Cells, HeLa Cells, Humans, Lysosomes metabolism, Membrane Proteins genetics, Microscopy, Confocal, Mutation, Proteolysis drug effects, Golgi Apparatus drug effects, Lysosomes drug effects, Manganese pharmacology, Membrane Proteins metabolism
- 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 Mn
2+ 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., (© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.)- Published
- 2017
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