Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation

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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 T_H17 over anti-inflammatory induced T regulatory (iTreg) differentiation, the latter by promoting endocytic loss of IL-2 receptor-Î± (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.

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Lindsey Araujo

Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, United States

Competing interests
The authors declare that no competing interests exist.
Phillip Khim

Department of Neurology and Institute for Immunology, University of California, Irvine, Irvine, United States

Competing interests
The authors declare that no competing interests exist.
Haik Mkhikian

Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, United States

Competing interests
The authors declare that no competing interests exist.
Christie-Lynn Mortales

Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, United States

Competing interests
The authors declare that no competing interests exist.
Michael Demetriou

Department of Neurology and Institute for Immunology, University of California, Irvine, Irvine, United States

For correspondence
mdemetri@uci.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8547-5774

Funding

National Institute of Allergy and Infectious Diseases (R01 AI053331)

Michael Demetriou

National Center for Complementary and Integrative Health (R01 AT007452)

Michael Demetriou

National Institute of Allergy and Infectious Diseases (R01 AI108917)

Michael Demetriou

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2001-2305) of the University of California, Irvine.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.