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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CTLA-4 Antigen
Glycosylation
lymphocytes
antigens
Multiple Sclerosis
interleukins
vitamins
Cholecalciferol
1,4-alpha-Glucan Branching Enzyme
Interleukin-7 Receptors
T-cells
Interleukin-2 Receptors
pathology
Demyelinating Diseases
Pathology
metabolism
Endocytosis
Metabolism
Modulators
Polysaccharides

Cite this

Mkhikian, H., Grigorian, A., Li, C., Hung-Lin, C., Newton, B., Zhou, R., ... 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
Mkhikian, Haik ; Grigorian, Ani ; Li, Carey ; Hung-Lin, Chen ; Newton, Barbara ; Zhou, Raymond ; Beeton, Christine ; Torossian, Sevan ; Tatarian, Grikor ; Lee, Sung-Uk ; Lau, Ken ; Walker, Erin ; Siminovitch, Katherine ; Chandy, K ; Yu, Zhaoxia ; Dennis, James ; Demetriou, Michael. / Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis. In: Nature Communications. 2011 ; Vol. 2, No. 334. pp. 1-13.
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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.",
author = "Haik Mkhikian and Ani Grigorian and Carey Li and Chen Hung-Lin and Barbara Newton and Raymond Zhou and Christine Beeton and Sevan Torossian and Grikor Tatarian and Sung-Uk Lee and Ken Lau and Erin Walker and Katherine Siminovitch and K Chandy and Zhaoxia Yu and James Dennis and Michael Demetriou",
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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, vol. 2, no. 334, pp. 1-13. https://doi.org/10.1038/ncomms1333

Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis. / Mkhikian, Haik; Grigorian, Ani; Li, Carey; Hung-Lin, Chen; Newton, Barbara; Zhou, Raymond; Beeton, Christine; Torossian, Sevan; Tatarian, Grikor; Lee, Sung-Uk; Lau, Ken; Walker, Erin; Siminovitch, Katherine; Chandy, K; Yu, Zhaoxia; Dennis, James; Demetriou, Michael.

In: Nature Communications, Vol. 2, No. 334, 2011, p. 1-13.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis

AU - Mkhikian, Haik

AU - Grigorian, Ani

AU - Li, Carey

AU - Hung-Lin, Chen

AU - Newton, Barbara

AU - Zhou, Raymond

AU - Beeton, Christine

AU - Torossian, Sevan

AU - Tatarian, Grikor

AU - Lee, Sung-Uk

AU - Lau, Ken

AU - Walker, Erin

AU - Siminovitch, Katherine

AU - Chandy, K

AU - Yu, Zhaoxia

AU - Dennis, James

AU - Demetriou, Michael

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms1333

DO - 10.1038/ncomms1333

M3 - Article

VL - 2

SP - 1

EP - 13

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 334

ER -