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

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Abstract

Sustained glucose and glutamine transport are essential for activated T lymphocytes to support ATP and macromolecule biosynthesis. We now show that glutamine and glucose also fuel an indispensible dynamic regulation of intracellular protein O-GlcNAcylation at key stages of T cell development, transformation and differentiation. Glucose and glutamine are precursors of 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-GlcNAc glycosyltransferase as compared to naïve 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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Most cited references 35

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The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function.

Andrew N. Macintyre, Valerie Gerriets, Amanda G Nichols … (2014)

CD4 T cell activation leads to proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While each subset prefers distinct glycolytic or oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are uncertain. Despite expression of multiple glucose transporters, Glut1 deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1 deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased Teff survival and differentiation. Importantly, Glut1 deficiency decreased Teff expansion and the ability to induce inflammatory disease in vivo. Treg cells, in contrast, were enriched in vivo and appeared functionally unaffected and able to suppress Teff, irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival. Copyright © 2014 Elsevier Inc. All rights reserved.

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Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease.

Gerald Hart, Chad Slawson, Genaro Ramirez-Correa … (2011)

O-GlcNAcylation is the addition of β-D-N-acetylglucosamine to serine or threonine residues of nuclear and cytoplasmic proteins. O-linked N-acetylglucosamine (O-GlcNAc) was not discovered until the early 1980s and still remains difficult to detect and quantify. Nonetheless, O-GlcNAc is highly abundant and cycles on proteins with a timescale similar to protein phosphorylation. O-GlcNAc occurs in organisms ranging from some bacteria to protozoans and metazoans, including plants and nematodes up the evolutionary tree to man. O-GlcNAcylation is mostly on nuclear proteins, but it occurs in all intracellular compartments, including mitochondria. Recent glycomic analyses have shown that O-GlcNAcylation has surprisingly extensive cross talk with phosphorylation, where it serves as a nutrient/stress sensor to modulate signaling, transcription, and cytoskeletal functions. Abnormal amounts of O-GlcNAcylation underlie the etiology of insulin resistance and glucose toxicity in diabetes, and this type of modification plays a direct role in neurodegenerative disease. Many oncogenic proteins and tumor suppressor proteins are also regulated by O-GlcNAcylation. Current data justify extensive efforts toward a better understanding of this invisible, yet abundant, modification. As tools for the study of O-GlcNAc become more facile and available, exponential growth in this area of research will eventually take place.

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Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.

Erikka Carr, Alina Kelman, Glendon Wu … (2010)

Activation of a naive T cell is a highly energetic event, which requires a substantial increase in nutrient metabolism. Upon stimulation, T cells increase in size, rapidly proliferate, and differentiate, all of which lead to a high demand for energetic and biosynthetic precursors. Although amino acids are the basic building blocks of protein biosynthesis and contribute to many other metabolic processes, the role of amino acid metabolism in T cell activation has not been well characterized. We have found that glutamine in particular is required for T cell function. Depletion of glutamine blocks proliferation and cytokine production, and this cannot be rescued by supplying biosynthetic precursors of glutamine. Correlating with the absolute requirement for glutamine, T cell activation induces a large increase in glutamine import, but not glutamate import, and this increase is CD28-dependent. Activation coordinately enhances expression of glutamine transporters and activities of enzymes required to allow the use of glutamine as a Krebs cycle substrate in T cells. The induction of glutamine uptake and metabolism requires ERK function, providing a link to TCR signaling. Together, these data indicate that regulation of glutamine use is an important component of T cell activation. Thus, a better understanding of glutamine sensing and use in T cells may reveal novel targets for immunomodulation.

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Journal

Journal ID (nlm-journal-id): 100941354

Journal ID (pubmed-jr-id): 21750

Journal ID (nlm-ta): Nat Immunol

Journal ID (iso-abbrev): Nat. Immunol.

Title: Nature immunology

ISSN (Print): 1529-2908

ISSN (Electronic): 1529-2916

Publication date Nihms-submitted: 13 May 2016

Publication date (Electronic): 25 April 2016

Publication date (Print): June 2016

Publication date PMC-release: 01 December 2016

Volume: 17

Issue: 6

Pages: 712-720

Affiliations

[1 ]Division of Cell Signalling and Immunology, University of Dundee, United Kingdom

[2 ]Division of Biological Chemistry and Drug Discovery, University of Dundee, United Kingdom

[3 ]Medical Research Council Protein Phosphorylation and Ubiquitylation unit, University of Dundee, United Kingdom

Author notes

Correspondence should be addressed to D. A. Cantrell ( d.a.cantrell@ 123456dundee.ac.uk ).

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Manuscript ID: EMS68270

DOI: 10.1038/ni.3439

PMC ID: 4900450

PubMed ID: 27111141

SO-VID: 4ae8a5de-551f-446f-adb6-e674218b2564

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

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Gamma Delta T cells

Most cited references 35

The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function.

Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease.

Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.

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