PubMed ID:
21629267
Public Release Type:
Journal
Publication Year: 2011
Affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697-4025, USA.
DOI:
https://doi.org/10.1038/ncomms1333
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
Request IDs:
10264
,
10294
,
10336
Studies:
The Genetics of Kidneys in Diabetes
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.