O-GlcNAc: a novel regulator of immunometabolism

Abstract

The rapidly expanding field of immunometabolism focuses on how metabolism controls the function of immune cells. CD4 T cells are essential for the adaptive immune response leading to the eradication of specific pathogens. However, when T cells are inappropriately over-active, they can drive autoimmunity, allergic disease, and chronic inflammation. The mechanisms by which metabolic changes influence function in CD4 T cells are not fully understood. The post-translational protein modification, O-GlcNAc (O-linked β-N-acetylglucosamine), dynamically cycles on and off of intracellular proteins as cells respond to their environment and flux through metabolic pathways changes. As the rate of O-GlcNAc cycling fluctuates, protein function, stability, and/or localization can be affected. Thus, O-GlcNAc is critically poised at the nexus of cellular metabolism and function. This review highlights the intra- and extracellular metabolic factors that influence CD4 T cell activation and differentiation and how O-GlcNAc regulates these processes. We also propose areas of future research that may illuminate O-GlcNAc's role in the plasticity and pathogenicity of CD4 T cells and uncover new potential therapeutic targets.

Proteomic Profiling of Astrocytic O-GlcNAc Transferase-Related Proteins in the Medial Prefrontal Cortex

“…More than 4,000 proteins have been identified as containing O-GlcNAcylation sites, and are present widely in the cytoplasm, nucleus, plasma membrane, and mitochondria ( Jayaprakash and Surolia, 2017 ). Disruption of O-GlcNAcylation is closely related to diabetes, cancer, and neurodegeneration ( Ma and Hart, 2013 ; Dassanayaka and Jones, 2014 ; Singh et al, 2015 ; Peterson and Hart, 2016 ; Machacek et al, 2018 ). O-GlcNAcylation is mediated by the enzymes OGT and OGA, which, respectively, catalyze the covalent attachment of N-acetyl-D-glucosamine to serine or threonine residues of proteins and their removal.…”

O-GlcNAcylation in immunity and inflammation: An intricate system (Review)

“…Moreover, the conversion of glutamine to acetyl CoA boosts fatty acid synthesis during T cell activation (36,37). Taken together, glucose, glutamine and acetyl CoA are all substrates that participate in the HBP, driving an increase in UDP-GlcNAc synthesis and thus protein O-GlcNAcylation by OGT (37,38) (Fig. 2).…”

Functional glycomics: Application to medical science and hepatology

“…O ‐GlcNAc, which is a modification involved in the pathophysiology of many diseases, involves the attachment of GlcNAc to Ser/Thr residues of cellular or nuclear proteins, and this modification can be coordinated with or outcompeted by Ser/Thr phosphorylation. Additionally, O ‐GlcNAc modification is associated with numerous cell signaling pathways . Although these details are still emerging, it is obvious that the complex modification of glycans on proteins and lipids, as well as the free unconjugated forms, cannot be ignored as we strive to understand disease pathogenesis and develop targeted therapies.…”

“…Additionally, O-GlcNAc modification is associated with numerous cell signaling pathways. 83,84 Although these details are still emerging, it is obvious that the complex modification of glycans on proteins and lipids, as well as the free unconjugated forms, cannot be ignored as we strive to 77 or certain cancer cell lines. 79 These FNGs are assumed to be degradation intermediates, mostly Gn1-type, bearing a single Nacetylglucosamine at their reducing termini.…”