Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy.
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.
Division of Cell Signalling and Immunology, University of Dundee, Dundee, UK.
Mahima
0000-0003-3977-3425
M
Swamy
Division of Cell Signalling and Immunology, University of Dundee, Dundee, UK.
Shalini
S
Pathak
Division of Cell Signalling and Immunology, University of Dundee, Dundee, UK.
Katarzyna M
KM
Grzes
Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, UK.
Sebastian
S
Damerow
Division of Cell Signalling and Immunology, University of Dundee, Dundee, UK.
Linda V
LV
Sinclair
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
Daan M F
0000-0002-1499-6908
DM
van Aalten
Division of Cell Signalling and Immunology, University of Dundee, Dundee, UK.
Doreen A
DA
Cantrell
D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D000066673:Cell Self Renewal / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002999:Clone Cells; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism*
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D011948:Receptors, Antigen, T-Cell; D051880:Receptors, Notch; D005973:Glutamine; D014537:Uridine Diphosphate N-Acetylglucosamine; D017351:N-Acetylglucosaminyltransferases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D005947:Glucose