The role of O‐GlcNAcylation in immunity against infections

Abstract

Mounting an effective immune response is crucial for the host to protect itself against invading pathogens. It is now well appreciated that reprogramming of core metabolic pathways in immune cells is a key requirement for their activation and function during infections. The role of several ancillary metabolic pathways in shaping immune cell function is less well understood. One such pathway, for which interest has recently been growing, is the hexosamine biosynthesis pathway (HBP) that generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the donor substrate for a specific form of glycosylation termed O-GlcNAcylation. O-GlcNAc is an intracellular post-translational modification that alters the functional properties of the modified proteins, in particular transcription factors and epigenetic regulators. An increasing number of studies suggest a central role for the HBP and O-GlcNAcylation in dictating immune cell function, including the response to different pathogens. We here discuss the most recent insights regarding O-GlcNAcylation and immunity, and explore whether targeting of O-GlcNAcylation could hold promise as a therapeutic approach to modulate immune responses to infections.

Advances in chemical probing of protein O-GlcNAc glycosylation: structural role and molecular mechanisms

“…This further research might contribute to elucidate the structural role of O-GlcNAc in protein conformation and how this influences the interaction with its corresponding binding partners, yielding critical information on the molecular mechanisms of recognition that may be at the basis of fundamental O-GlcNAc mediated cellular processes. Notably, given the emerging, important links between O-GlcNAc and the immune system, [262][263][264] immunology is another discipline where current progress in the O-GlcNAc field is expected to provide key insights into the functional consequences of O-GlcNAc modification. Thus, chemical immunology emerges as a fertile area in which novel chemical strategies can be developed and exploited to uncover new roles of O-GlcNAc in immunity.…”

Demystifying the O-GlcNAc Code: A Systems View

“…Emerging evidence demonstrates that O-GlcNAcylation plays a key role in immune responses to bacterial infection. 117 For example, it has been shown that O-GlcNAcylation-induced by bacterial infection regulates neutrophil chemotaxis, 161,162 necroptosis, and inflammatory cytokine secretion in macrophage 163 as well as the adaptive immune response by T cells. 164 Very intriguingly, besides the host OGT-mediated O-GlcNAcylation of proteins upon infection, it appears that some host proteins can even be modified by the bacterial OGT homologues.…”

The Beginner’s Guide to O-GlcNAc: From Nutrient Sensitive Pathway Regulation to Its Impact on the Immune System

“…As described above, O-GlcNAc is extensively involved in a multitude of cellular processes, and the immune system is no exception. Many reviews have been written detailing O-GlcNAc's role in various immune system aspects, such as: T-cell development (65), inflammation (101), infection (102), autoimmunity (103), lymphocytic cancers (104), immunometabolism (105), and broad overviews (106). In this section a brief overview of several aspects will be discussed highlighting O-GlcNAc's function in the immune system, particularly as it relates to sensing nutritional cues that govern protein activities.…”