New Roles of Magnesium as a Regulatory Ion in Immune Responses and Cell Behavior

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

The MAGT1 transporter is critically involved in the selective regulation of intracellular free Mg2+ levels in mammalian cells. The molecular functions of free Mg2+ in eukaryotic cells have not been fully established. We are developing a tool to reliably measure magnesium that is safe in cells, selective only for magnesium ions, and active in the physiological concentration range of magnesium. A smaller collaboration project looked at the role of MAGT1 in cancer. VEGF, a key regulator of vascular homeostasis, can be altered by enzyme ERO1-alpha through glycosylation. ERO1 deficiency increases utilization of its single N-glycosylation, and concomitantly slowed its secretion. Unbiased mass-spectrometric analysis revealed interactions between VEGF and N-glycosylation pathway proteins in ERO1-knockout (KO), but not wild-type cells. Notably, MAGT1, a thioredoxin-containing component of the post-translational oligosaccharyltransferase complex, was a major hit exclusive to ERO1-deficient cells. The increased trapping potential of MAGT1 may increase N-glycosylation of VEGF. Extending our investigation to tissues, we observed altered lectin staining of ERO1 KO breast tumor xenografts, implicating ERO1 as a physiologic regulator of protein N-glycosylation. Our study, highlighting the effect of ERO1 loss on N-glycosylation of proteins, is particularly relevant not only to angiogenesis but also to other mechanisms of cancer pathophysiology in light of recent findings suggesting a close causal link between alterations in protein glycosylation and cancer development.