Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 12 2022
01 12 2022
Historique:
received:
30
04
2022
accepted:
14
11
2022
entrez:
1
12
2022
pubmed:
2
12
2022
medline:
6
12
2022
Statut:
epublish
Résumé
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
Identifiants
pubmed: 36456551
doi: 10.1038/s41467-022-35014-w
pii: 10.1038/s41467-022-35014-w
pmc: PMC9715696
doi:
Substances chimiques
Hexosamines
0
Glucosamine
N08U5BOQ1K
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
Receptors, Antigen, T-Cell, gamma-delta
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
7404Subventions
Organisme : NCI NIH HHS
ID : R01 CA236936
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM137493
Pays : United States
Organisme : NIGMS NIH HHS
ID : R24 GM137782
Pays : United States
Informations de copyright
© 2022. The Author(s).
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