Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis

Haik Mkhikian, Ani Grigorian, Carey Li, Chen Hung-Lin, Barbara Newton, Raymond Zhou, Christine Beeton, Sevan Torossian, Grikor Tatarian, Sung-Uk Lee, Ken Lau, Erin Walker, Katherine Siminovitch, K Chandy, Zhaoxia Yu, James Dennis, Michael Demetriou

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Abstract

How environmental factors combine with genetic risk at the molecular level to promote complex trait diseases such as multiple sclerosis (MS) is largely unknown. In mice, N-glycan branching by the Golgi enzymes Mgat1 and/or Mgat5 prevents T cell hyperactivity, cytotoxic T-lymphocyte antigen 4 (CTLA-4) endocytosis, spontaneous inflammatory demyelination and neurodegeneration, the latter pathologies characteristic of MS. Here we show that MS risk modulators converge to alter N-glycosylation and/or CTLA-4 surface retention conditional on metabolism and vitamin D3, including genetic variants in interleukin-7 receptor-α (IL7RA*C), interleukin-2 receptor-α (IL2RA*T), MGAT1 (IVAVT−T) and CTLA-4 (Thr17Ala). Downregulation of Mgat1 by IL7RA*C and IL2RA*T is opposed by MGAT1 (IVAVT−T) and vitamin D3, optimizing branching and mitigating MS risk when combined with enhanced CTLA-4 N-glycosylation by CTLA-4 Thr17. Our data suggest a molecular mechanism in MS whereby multiple environmental and genetic inputs lead to dysregulation of a final common pathway, namely N-glycosylation.
Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalNature Communications
Volume2
Issue number334
DOIs
Publication statusPublished - 2011
Externally publishedYes

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    Mkhikian, H., Grigorian, A., Li, C., Hung-Lin, C., Newton, B., Zhou, R., Beeton, C., Torossian, S., Tatarian, G., Lee, S-U., Lau, K., Walker, E., Siminovitch, K., Chandy, K., Yu, Z., Dennis, J., & Demetriou, M. (2011). Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis. Nature Communications, 2(334), 1-13. https://doi.org/10.1038/ncomms1333