An official website of the United States government
Publication Information
Affiliation
Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697-4025, USA.
Authors
Beeton C, Chandy KG, Chen HL, Demetriou M, Dennis JW, Grigorian A, Lau K, Lee SU, Li CF, Mkhikian H, Newton B, Siminovitch KA, Tatarian GG, Torossian S, Walker E, Yu Z, Zhou RW
Studies
Citation
Mkhikian H, Grigorian A, Li CF, Chen HL, Newton B, Zhou RW, Beeton C, Torossian S, Tatarian GG, Lee SU, Lau K, Walker E, Siminovitch KA, Chandy KG, Yu Z, Dennis JW, Demetriou M. Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis. Nat Commun 2011;2:334.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 (IL7RA*C), interleukin-2 receptor-α (IL2RA*T), MGAT1 (IV(A)V(T-T)) and CTLA-4 (Thr17Ala). Downregulation of Mgat1 by IL7RA*C and IL2RA*T 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.