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

Mahima Swamy, Shalini Pathak, Katarzyna M. Grzes, Sebastian Damerow, Linda V. Sinclair, Daan M F van Aalten, Doreen A. Cantrell (Lead / Corresponding author)

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Abstract

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.

Original languageEnglish
Pages (from-to)712-720
Number of pages9
JournalNature Immunology
Volume17
Issue number6
Early online date25 Apr 2016
DOIs
Publication statusPublished - Jun 2016

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Keywords

  • Glycobiology
  • T cells

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