Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• The Journal of biological chemistry, 2019-09, Vol.294 (37), p.13638-13656

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.