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Nat Immunol. 2016 Jun;17(6):712-20. doi: 10.1038/ni.3439. Epub 2016 Apr 25.

Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy.

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Division of Cell Signalling and Immunology, University of Dundee, Dundee, UK.
Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, UK.
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.


Sustained glucose and glutamine transport are essential for activated T lymphocytes to support ATP and macromolecule biosynthesis. We found that glutamine and glucose also fuel an indispensable dynamic regulation of intracellular protein O-GlcNAcylation at key stages of T cell development, transformation and differentiation. Glucose and glutamine are precursors of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a substrate for cellular glycosyltransferases. Immune-activated T cells contained higher concentrations of UDP-GlcNAc and increased intracellular protein O-GlcNAcylation controlled by the enzyme O-linked-β-N-acetylglucosamine (O-GlcNAc) glycosyltransferase as compared with naive cells. We identified Notch, the T cell antigen receptor and c-Myc as key controllers of T cell protein O-GlcNAcylation via regulation of glucose and glutamine transport. Loss of O-GlcNAc transferase blocked T cell progenitor renewal, malignant transformation and peripheral T cell clonal expansion. Nutrient-dependent signaling pathways regulated by O-GlcNAc glycosyltransferase are thus fundamental for T cell biology.

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Conflict of interest statement

statement The authors have no competing interests, or other interests that might be perceived to influence the results and discussion reported in this paper.

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