title: 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 (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.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697-4025, USA.
authors.forename: Haik
authors.initials: H
authors.lastname: Mkhikian
authors.forename: Ani
authors.initials: A
authors.lastname: Grigorian
authors.forename: Carey F
authors.initials: CF
authors.lastname: Li
authors.forename: Hung-Lin
authors.initials: HL
authors.lastname: Chen
authors.forename: Barbara
authors.initials: B
authors.lastname: Newton
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Zhou
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
authors.forename: Sevan
authors.initials: S
authors.lastname: Torossian
authors.forename: Gevork Grikor
authors.initials: GG
authors.lastname: Tatarian
authors.forename: Sung-Uk
authors.initials: SU
authors.lastname: Lee
authors.forename: Ken
authors.initials: K
authors.lastname: Lau
authors.forename: Erin
authors.initials: E
authors.lastname: Walker
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
authors.forename: K George
authors.initials: KG
authors.lastname: Chandy
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Yu
authors.forename: James W
authors.initials: JW
authors.lastname: Dennis
authors.forename: Michael
authors.initials: M
authors.lastname: Demetriou
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D002762:Cholecalciferol / Q000378:metabolism; D015331:Cohort Studies; D015536:Down-Regulation; D005260:Female; D014644:Genetic Variation; D006031:Glycosylation; D006239:Haplotypes; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction; D013472:Sunlight
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D015375:Receptors, Interleukin-2; D020395:Receptors, Interleukin-7; D002762:Cholecalciferol; C561128:MGAT1 protein, human; D017351:N-Acetylglucosaminyltransferases