Dataset Information

H⁺ and Pi Byproducts of Glycosylation Affect Ca²⁺ Homeostasis and Are Retrieved from the Golgi Complex by Homologs of TMEM165 and XPR1.

ABSTRACT: Glycosylation reactions in the Golgi complex and the endoplasmic reticulum utilize nucleotide sugars as donors and produce inorganic phosphate (Pi) and acid (H⁺) as byproducts. Here we show that homologs of mammalian XPR1 and TMEM165 (termed Erd1 and Gdt1) recycle luminal Pi and exchange luminal H⁺ for cytoplasmic Ca²⁺, respectively, thereby promoting growth of yeast cells in low Pi and low Ca²⁺ environments. As expected for reversible H⁺/Ca²⁺ exchangers, Gdt1 also promoted growth in high Ca²⁺ environments when the Golgi-localized V-ATPase was operational but had the opposite effect when the V-ATPase was eliminated. Gdt1 activities were negatively regulated by calcineurin signaling and by Erd1, which recycled the Pi byproduct of glycosylation reactions and prevented the loss of this nutrient to the environment via exocytosis. Thus, Erd1 transports Pi in the opposite direction from XPR1 and other EXS family proteins and facilitates byproduct removal from the Golgi complex together with Gdt1.

SUBMITTER: Snyder NA

PROVIDER: S-EPMC5714488 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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H+ and Pi Byproducts of Glycosylation Affect Ca2+ Homeostasis and Are Retrieved from the Golgi Complex by Homologs of TMEM165 and XPR1.

Snyder Nathan A NA Stefan Christopher P CP Soroudi Camille T CT Kim Adam A Evangelista Carlos C Cunningham Kyle W KW

G3 (Bethesda, Md.) 20171204 12

Glycosylation reactions in the Golgi complex and the endoplasmic reticulum utilize nucleotide sugars as donors and produce inorganic phosphate (Pi) and acid (H+) as byproducts. Here we show that homologs of mammalian XPR1 and TMEM165 (termed Erd1 and Gdt1) recycle luminal Pi and exchange luminal H+ for cytoplasmic Ca2+, respectively, thereby promoting growth of yeast cells in low Pi and low Ca2+ environments. As expected for reversible H+/Ca ...[more]

PMID: 29042410

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Project description:ContextTMEM165 deficiency is a severe multisystem disease that manifests with metabolic, endocrine, and skeletal involvement. It leads to one type of congenital disorders of glycosylation (CDG), a rapidly growing group of inherited diseases in which the glycosylation process is altered. Patients have decreased galactosylation by serum glycan analysis. There are >100 CDGs, but only specific types are treatable.ObjectiveGalactose has been shown to be beneficial in other CDG types with abnormal galactosylation. The aim of this study was to characterize the effects of galactose supplementation on Golgi glycosylation in TMEM165-depleted HEK293 cells, as well as in 2 patients with TMEM165-CDG and in their cultured skin fibroblast cells.Design and settingGlycosylation was assessed by mass spectrometry, western blot analysis, and transferrin isoelectrofocusing.Patients and interventionsBoth unrelated patients with TMEM165-CDG with the same deep intronic homozygous mutation (c.792+182G>A) were allocated to receive d-galactose in a daily dose of 1 g/kg.ResultsWe analyzed N-linked glycans and glycolipids in knockout TMEM165 HEK293 cells, revealing severe hypogalactosylation and GalNAc transfer defects. Although these defects were completely corrected by the addition of Mn2+, we demonstrated that the observed N-glycosylation defect could also be overcome by galactose supplementation. We then demonstrated that oral galactose supplementation in patients with TMEM165-deficient CDG improved biochemical and clinical parameters, including a substantial increase in the negatively charged transferrin isoforms, and a decrease in hypogalactosylated total N-glycan structures, endocrine function, and coagulation parameters.ConclusionTo our knowledge, this is the first description of abnormal glycosylation of lipids in the TMEM165 defect and the first report of successful dietary treatment in TMEM165 deficiency. We recommend the use of oral d-galactose therapy in TMEM165-CDG.

Dataset Information

H⁺ and Pi Byproducts of Glycosylation Affect Ca²⁺ Homeostasis and Are Retrieved from the Golgi Complex by Homologs of TMEM165 and XPR1.

Publications

H<sup>+</sup> and Pi Byproducts of Glycosylation Affect Ca<sup>2+</sup> Homeostasis and Are Retrieved from the Golgi Complex by Homologs of TMEM165 and XPR1.

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