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

• Published in: The Journal of biological chemistry 2019-09, Vol.294 (37), p.13638-13656
• Main Authors: Matsuda-Lennikov, Mami, Biancalana, Matthew, Zou, Juan, Ravell, Juan C., Zheng, Lixin, Kanellopoulou, Chrysi, Jiang, Ping, Notarangelo, Giulia, Jing, Huie, Masutani, Evan, Oler, Andrew J., Olano, Lisa Renee, Schulz, Benjamin L., Lenardo, Michael J.
• Format: Article
• Language: English
• Subjects: Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cell Biology; Epstein-Barr virus (EBV) infection; Epstein-Barr Virus Infections - genetics; glycoprotein; Glycoproteins - metabolism; Glycosylation; HEK293 Cells; Homeostasis; Humans; immunodeficiency; immunology; infection; Killer Cells, Natural - metabolism; magnesium; Magnesium - metabolism; Magnesium Deficiency - genetics; magnesium transporter 1 (MAGT1); Membrane Proteins - genetics; Membrane Proteins - metabolism; Mutation; N-linked glycosylation (NLG) complex; Neoplasms - genetics; oligosaccharyltransferase (OST); transporter; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; X-linked magnesium deficiency with Epstein–Barr virus infection and neoplasia (XMEN)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.008903

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.