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

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 D(3), including genetic variants in interleukin-7 receptor-α (IL7RAC), interleukin-2 receptor-α (IL2RAT), MGAT1 (IV(A)V(T-T)) and CTLA-4 (Thr17Ala). Downregulation of Mgat1 by IL7RAC and IL2RAT is opposed by MGAT1 (IV(A)V(T-T)) and vitamin D(3), 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.
Authors	Haik Mkhikian, Ani Grigorian, Carey F Li, Hung-Lin Chen, Barbara Newton, Raymond W Zhou, Christine Beeton, Sevan Torossian, Gevork Grikor Tatarian, Sung-Uk Lee, Ken Lau, Erin Walker, Katherine A Siminovitch, K George Chandy, Zhaoxia Yu, James W Dennis, Michael Demetriou
Journal	Nature communications (Nat Commun) Vol. 2 Pg. 334 ( 2011) ISSN: 2041-1723 [Electronic] England
PMID	21629267 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Antigens, CD CTLA-4 Antigen CTLA4 protein, human Ctla4 protein, mouse Receptors, Interleukin-2 Receptors, Interleukin-7 Cholecalciferol MGAT1 protein, human N-Acetylglucosaminyltransferases
Topics	Animals Antigens, CD (genetics) CTLA-4 Antigen Case-Control Studies Cholecalciferol (metabolism) Cohort Studies Down-Regulation Female Genetic Variation Glycosylation Haplotypes Humans Male Mice Mice, Inbred Strains Multiple Sclerosis (genetics, metabolism) N-Acetylglucosaminyltransferases (genetics, metabolism) Receptors, Interleukin-2 (genetics) Receptors, Interleukin-7 (genetics) Risk Factors Signal Transduction Sunlight

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