Glycosylation abnormalities in Gdt1p/TMEM165 deficient cells result from a defect in Golgi manganese homeostasis.
(2016) Human Molecular Genetics — Vol. 25, n° 8, p. 1489-1500 (2016)
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- 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. AsGDT1is the ortholog ofTMEM165in yeast, bothgdt1Δ null mutant yeasts andTMEM165depleted 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 inTMEM165depleted 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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Potelle, S., Morelle, W., Dulary, E., Duvet, S., Vicogne, D., Spriet, C., Krzewinski-Recchi, M.-A., Morsomme, P., Jaeken, J., Matthijs, G., De Bettignies, G., & Foulquier, F. (2016). Glycosylation abnormalities in Gdt1p/TMEM165 deficient cells result from a defect in Golgi manganese homeostasis. Human Molecular Genetics, 25(8), 1489-1500. https://doi.org/10.1093/hmg/ddw026 (Original work published 2016)