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

doi:10.1038/ncomms1333

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 language	English
Pages (from-to)	1-13
Number of pages	13
Journal	Nature Communications
Volume	2
Issue number	334
DOIs	https://doi.org/10.1038/ncomms1333
Publication status	Published - 2011
Externally published	Yes

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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, 2(334), 1-13. https://doi.org/10.1038/ncomms1333

@article{dbccce72780a42cca4e0a10b496a1501,

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 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",

year = "2011",

doi = "10.1038/ncomms1333",

language = "English",

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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

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

SN - 2041-1723

VL - 2

SP - 1

EP - 13

JO - Nature Communications

JF - Nature Communications

IS - 334

ER -

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

Abstract

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