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

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...

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Autores principales: Mkhikian, Haik, Grigorian, Ani, Li, Carey F., Chen, Hung-Lin, Newton, Barbara, Zhou, Raymond W., Beeton, Christine, Torossian, Sevan, Tatarian, Gevork Grikor, Lee, Sung-Uk, Lau, Ken, Walker, Erin, Siminovitch, Katherine A., Chandy, K. George, Yu, Zhaoxia, Dennis, James W., Demetriou, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3133923/
https://www.ncbi.nlm.nih.gov/pubmed/21629267
http://dx.doi.org/10.1038/ncomms1333
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author Mkhikian, Haik
Grigorian, Ani
Li, Carey F.
Chen, Hung-Lin
Newton, Barbara
Zhou, Raymond W.
Beeton, Christine
Torossian, Sevan
Tatarian, Gevork Grikor
Lee, Sung-Uk
Lau, Ken
Walker, Erin
Siminovitch, Katherine A.
Chandy, K. George
Yu, Zhaoxia
Dennis, James W.
Demetriou, Michael
author_facet Mkhikian, Haik
Grigorian, Ani
Li, Carey F.
Chen, Hung-Lin
Newton, Barbara
Zhou, Raymond W.
Beeton, Christine
Torossian, Sevan
Tatarian, Gevork Grikor
Lee, Sung-Uk
Lau, Ken
Walker, Erin
Siminovitch, Katherine A.
Chandy, K. George
Yu, Zhaoxia
Dennis, James W.
Demetriou, Michael
author_sort Mkhikian, Haik
collection PubMed
description 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.
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spelling pubmed-31339232011-07-25 Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis Mkhikian, Haik Grigorian, Ani Li, Carey F. Chen, Hung-Lin Newton, Barbara Zhou, Raymond W. Beeton, Christine Torossian, Sevan Tatarian, Gevork Grikor Lee, Sung-Uk Lau, Ken Walker, Erin Siminovitch, Katherine A. Chandy, K. George Yu, Zhaoxia Dennis, James W. Demetriou, Michael Nat Commun Article 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. Nature Publishing Group 2011-05 2011-05-31 /pmc/articles/PMC3133923/ /pubmed/21629267 http://dx.doi.org/10.1038/ncomms1333 Text en Copyright © 2011, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Article
Mkhikian, Haik
Grigorian, Ani
Li, Carey F.
Chen, Hung-Lin
Newton, Barbara
Zhou, Raymond W.
Beeton, Christine
Torossian, Sevan
Tatarian, Gevork Grikor
Lee, Sung-Uk
Lau, Ken
Walker, Erin
Siminovitch, Katherine A.
Chandy, K. George
Yu, Zhaoxia
Dennis, James W.
Demetriou, Michael
Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis
title Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis
title_full Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis
title_fullStr Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis
title_full_unstemmed Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis
title_short Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis
title_sort genetics and the environment converge to dysregulate n-glycosylation in multiple sclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3133923/
https://www.ncbi.nlm.nih.gov/pubmed/21629267
http://dx.doi.org/10.1038/ncomms1333
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