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Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis
T cell development requires the coordinated rearrangement of T cell receptor (TCR) gene segments and the expression of either αβ or γδ TCR. However, whether and how de novo synthesis of nutrients contributes to thymocyte commitment to either lineage remains unclear. Here, we find that T cell-specifi...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9715696/ https://www.ncbi.nlm.nih.gov/pubmed/36456551 http://dx.doi.org/10.1038/s41467-022-35014-w |
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author | Werlen, Guy Li, Mei-Ling Tottone, Luca da Silva-Diz, Victoria Su, Xiaoyang Herranz, Daniel Jacinto, Estela |
author_facet | Werlen, Guy Li, Mei-Ling Tottone, Luca da Silva-Diz, Victoria Su, Xiaoyang Herranz, Daniel Jacinto, Estela |
author_sort | Werlen, Guy |
collection | PubMed |
description | T cell development requires the coordinated rearrangement of T cell receptor (TCR) gene segments and the expression of either αβ or γδ TCR. However, whether and how de novo synthesis of nutrients contributes to thymocyte commitment to either lineage remains unclear. Here, we find that T cell-specific deficiency in glutamine:fructose-6-phosphate aminotransferase 1 (GFAT1), the rate-limiting enzyme of the de novo hexosamine biosynthesis pathway (dn-HBP), attenuates hexosamine levels, blunts N-glycosylation of TCRβ chains, reduces surface expression of key developmental receptors, thus impairing αβ-T cell ontogeny. GFAT1 deficiency triggers defects in N-glycans, increases the unfolded protein response, and elevates γδ-T cell numbers despite reducing γδ-TCR diversity. Enhancing TCR expression or PI3K/Akt signaling does not reverse developmental defects. Instead, dietary supplementation with the salvage metabolite, glucosamine, and an α-ketoglutarate analogue partially restores αβ-T cell development in GFAT1(T-/-) mice, while fully rescuing it in ex vivo fetal thymic organ cultures. Thus, dn-HBP fulfils, while salvage nutrients partially satisfy, the elevated demand for hexosamines during early T cell development. |
format | Online Article Text |
id | pubmed-9715696 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-97156962022-12-03 Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis Werlen, Guy Li, Mei-Ling Tottone, Luca da Silva-Diz, Victoria Su, Xiaoyang Herranz, Daniel Jacinto, Estela Nat Commun Article T cell development requires the coordinated rearrangement of T cell receptor (TCR) gene segments and the expression of either αβ or γδ TCR. However, whether and how de novo synthesis of nutrients contributes to thymocyte commitment to either lineage remains unclear. Here, we find that T cell-specific deficiency in glutamine:fructose-6-phosphate aminotransferase 1 (GFAT1), the rate-limiting enzyme of the de novo hexosamine biosynthesis pathway (dn-HBP), attenuates hexosamine levels, blunts N-glycosylation of TCRβ chains, reduces surface expression of key developmental receptors, thus impairing αβ-T cell ontogeny. GFAT1 deficiency triggers defects in N-glycans, increases the unfolded protein response, and elevates γδ-T cell numbers despite reducing γδ-TCR diversity. Enhancing TCR expression or PI3K/Akt signaling does not reverse developmental defects. Instead, dietary supplementation with the salvage metabolite, glucosamine, and an α-ketoglutarate analogue partially restores αβ-T cell development in GFAT1(T-/-) mice, while fully rescuing it in ex vivo fetal thymic organ cultures. Thus, dn-HBP fulfils, while salvage nutrients partially satisfy, the elevated demand for hexosamines during early T cell development. Nature Publishing Group UK 2022-12-01 /pmc/articles/PMC9715696/ /pubmed/36456551 http://dx.doi.org/10.1038/s41467-022-35014-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Werlen, Guy Li, Mei-Ling Tottone, Luca da Silva-Diz, Victoria Su, Xiaoyang Herranz, Daniel Jacinto, Estela Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis |
title | Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis |
title_full | Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis |
title_fullStr | Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis |
title_full_unstemmed | Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis |
title_short | Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis |
title_sort | dietary glucosamine overcomes the defects in αβ-t cell ontogeny caused by the loss of de novo hexosamine biosynthesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9715696/ https://www.ncbi.nlm.nih.gov/pubmed/36456551 http://dx.doi.org/10.1038/s41467-022-35014-w |
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