O-GlcNAcylation and its role in the immune system

Abstract

O-linked-N-acetylglucosaminylation (O-GlcNAcylation) is a type of glycosylation that occurs when a monosaccharide, O-GlcNAc, is added onto serine or threonine residues of nuclear or cytoplasmic proteins by O-GlcNAc transferase (OGT) and which can be reversibly removed by O-GlcNAcase (OGA). O-GlcNAcylation couples the processes of nutrient sensing, metabolism, signal transduction and transcription, and plays important roles in development, normal physiology and physiopathology. Cumulative studies have indicated that O-GlcNAcylation affects the functions of protein substrates in a number of ways, including protein cellular localization, protein stability and protein/protein interaction. Particularly, O-GlcNAcylation has been shown to have intricate crosstalk with phosphorylation as they both modify serine or threonine residues. Aberrant O-GlcNAcylation on various protein substrates has been implicated in many diseases, including neurodegenerative diseases, diabetes and cancers. However, the role of protein O-GlcNAcylation in immune cell lineages has been less explored. This review summarizes the current understanding of the fundamental biochemistry of O-GlcNAcylation, and discusses the molecular mechanisms by which O-GlcNAcylation regulates the development, maturation and functions of immune cells. In brief, O-GlcNAcylation promotes the development, proliferation, and activation of T and B cells. O-GlcNAcylation regulates inflammatory and antiviral responses of macrophages. O-GlcNAcylation promotes the function of activated neutrophils, but inhibits the activity of nature killer cells.

Post-Translational Regulations of Foxp3 in Treg Cells and Their Therapeutic Applications

“…Glycosylation is a form of co-translational and post-translational modifications that attaches glycans to proteins (153). As a rising field in biological studies, protein glycosylation has shown important effects on T cell development, activation, and differentiation (153).…”

Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism

“…O-GlcNAcylation enhances the development, as well as the activation and proliferation of neutrophils, T and B cells, with regulatory effects in macrophages, whilst inhibiting the development and cytotoxicity of NK cells [ 89 ]. O-GlcNAcylation significantly regulates many of the transcriptional and translational processes that underpin fast effector CD8+ T cell proliferation, as well as a more limited number of studied proteins in memory-like CD8+T cells [ 90 ].…”

“…In contrast to NK cells, heightened O-GlcNAcylation enhances the functional response of CD8+ T cells [ 89 , 90 ], which may be mediated via the inhibitory effects of O-GlcNAcylation on GSK3β function [ 171 ]. As GSK3β inhibition also increased NK cells cytotoxicity, this would indicate that the differential effects of O-GlcNAcylation in NK cells and CD8+ T cells are not mediated via the O-GlcNAcylation, and inhibition, of GSK3β [ 172 , 173 ].…”

Glucosamine and O-GlcNAcylation: a novel immunometabolic therapeutic target for OA and chronic, low-grade systemic inflammation?

“…O-GlcNAcylation plays a key role in the regulation of both cellular homeostasis, in response to nutritional or hormonal cues, but also in response to stress or damage, such as that induced by inflammation or immune activation. [24][25][26] In fact, protein O-GlcNAc has been proposed as a nutrient sensor that regulates crucial cell responses to very different pathophysiological processes, [24][25][26][27] ranging from cell transcription to protein folding or degradation.…”