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...
Autores principales: | , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782207936420904960 |
---|---|
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. |
format | Online Article Text |
id | pubmed-3133923 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT mkhikianhaik geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT grigorianani geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT licareyf geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT chenhunglin geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT newtonbarbara geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT zhouraymondw geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT beetonchristine geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT torossiansevan geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT tatariangevorkgrikor geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT leesunguk geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT lauken geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT walkererin geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT siminovitchkatherinea geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT chandykgeorge geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT yuzhaoxia geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT dennisjamesw geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis AT demetrioumichael geneticsandtheenvironmentconvergetodysregulatenglycosylationinmultiplesclerosis |