Format

Send to

Choose Destination
J Biol Chem. 2019 Sep 13;294(37):13638-13656. doi: 10.1074/jbc.RA119.008903. Epub 2019 Jul 23.

Magnesium transporter 1 (MAGT1) deficiency causes selective defects in N-linked glycosylation and expression of immune-response genes.

Author information

1
Molecular Development of the Immune System Section, Laboratory of Immune System Biology, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
2
Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
3
Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
4
Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
5
Laboratory of Neurotoxicology, National Institute of Mental Health, Bethesda, Maryland 20892.
6
University of Queensland, School of Chemistry and Molecular Biology, Brisbane, St. Lucia, Queensland 4072, Australia.
7
Molecular Development of the Immune System Section, Laboratory of Immune System Biology, NIAID, National Institutes of Health, Bethesda, Maryland 20892 mlenardo@niaid.nih.gov.

Abstract

Magnesium transporter 1 (MAGT1) critically mediates magnesium homeostasis in eukaryotes and is highly-conserved across different evolutionary branches. In humans, loss-of-function mutations in the MAGT1 gene cause X-linked magnesium deficiency with Epstein-Barr virus (EBV) infection and neoplasia (XMEN), a disease that has a broad range of clinical and immunological consequences. We have previously shown that EBV susceptibility in XMEN is associated with defective expression of the antiviral natural-killer group 2 member D (NKG2D) protein and abnormal Mg2+ transport. New evidence suggests that MAGT1 is the human homolog of the yeast OST3/OST6 proteins that form an integral part of the N-linked glycosylation complex, although the exact contributions of these perturbations in the glycosylation pathway to disease pathogenesis are still unknown. Using MS-based glycoproteomics, along with CRISPR/Cas9-KO cell lines, natural killer cell-killing assays, and RNA-Seq experiments, we now demonstrate that humans lacking functional MAGT1 have a selective deficiency in both immune and nonimmune glycoproteins, and we identified several critical glycosylation defects in important immune-response proteins and in the expression of genes involved in immunity, particularly CD28. We show that MAGT1 function is partly interchangeable with that of the paralog protein tumor-suppressor candidate 3 (TUSC3) but that each protein has a different tissue distribution in humans. We observed that MAGT1-dependent glycosylation is sensitive to Mg2+ levels and that reduced Mg2+ impairs immune-cell function via the loss of specific glycoproteins. Our findings reveal that defects in protein glycosylation and gene expression underlie immune defects in an inherited disease due to MAGT1 deficiency.

KEYWORDS:

Epstein-Barr virus (EBV) infection; N-linked glycosylation (NLG) complex; X-linked magnesium deficiency with Epstein–Barr virus infection and neoplasia (XMEN); glycoprotein; glycosylation; immunodeficiency; immunology; infection; magnesium; magnesium transporter 1 (MAGT1); oligosaccharyltransferase (OST); transporter

PMID:
31337704
PMCID:
PMC6746436
[Available on 2020-09-13]
DOI:
10.1074/jbc.RA119.008903

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center