title: Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation.
abstract: Rapidly proliferating cells switch from oxidative phosphorylation to aerobic glycolysis plus glutaminolysis, markedly increasing glucose and glutamine catabolism. Although Otto Warburg first described aerobic glycolysis in cancer cells >90 years ago, the primary purpose of this metabolic switch remains controversial. The hexosamine biosynthetic pathway requires glucose and glutamine for de novo synthesis of UDP-GlcNAc, a sugar-nucleotide that inhibits receptor endocytosis and signaling by promoting N-acetylglucosamine branching of Asn (N)-linked glycans. Here, we report that aerobic glycolysis and glutaminolysis co-operatively reduce UDP-GlcNAc biosynthesis and N-glycan branching in mouse T cell blasts by starving the hexosamine pathway of glucose and glutamine. This drives growth and pro-inflammatory TH17 over anti-inflammatory-induced T regulatory (iTreg) differentiation, the latter by promoting endocytic loss of IL-2 receptor-α (CD25). Thus, a primary function of aerobic glycolysis and glutaminolysis is to co-operatively limit metabolite supply to N-glycan biosynthesis, an activity with widespread implications for autoimmunity and cancer.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, United States.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Araujo
authors.affiliation: Department of Neurology and Institute for Immunology, University of California, Irvine, United States.
authors.forename: Phillip
authors.initials: P
authors.lastname: Khim
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Irvine, United States.
authors.forename: Haik
authors.initials: H
authors.lastname: Mkhikian
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, United States.
authors.forename: Christie-Lynn
authors.initials: CL
authors.lastname: Mortales
authors.affiliation: Department of Neurology and Institute for Immunology, University of California, Irvine, United States.
authors.forename: Michael
authors.identifier: 0000-0001-8547-5774
authors.initials: M
authors.lastname: Demetriou
mesh_terms: D000332:Aerobiosis; D000818:Animals; D002454:Cell Differentiation; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis; D006031:Glycosylation; D051379:Mice; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D005973:Glutamine
keywords: N-acetylglucosamine; N-glycosylation; T cell; Warburg effect; cell biology; glutaminolysis; glycolysis; immunology; mouse