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. 2016 Apr 15;25(8):1489-500.
doi: 10.1093/hmg/ddw026. Epub 2016 Feb 1.

Glycosylation abnormalities in Gdt1p/TMEM165 deficient cells result from a defect in Golgi manganese homeostasis

Sven Potelle  1 , Willy Morelle  1 , Eudoxie Dulary  1 , Sandrine Duvet  1 , Dorothée Vicogne  1 , Corentin Spriet  1 , Marie-Ange Krzewinski-Recchi  1 , Pierre Morsomme  2 , Jaak Jaeken  3 , Gert Matthijs  4 , Geoffroy De Bettignies  1 , François Foulquier  5
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Free article

Glycosylation abnormalities in Gdt1p/TMEM165 deficient cells result from a defect in Golgi manganese homeostasis

Sven Potelle et al. Hum Mol Genet. .
Free article

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.

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