Dendritic cells (DCs) orchestrate immune responses to infectious and metabolic diseases. Known as the central regulators of immune system, DCs are dedicated to detecting pathogens or environmental alterations and subsequently initiate specific immune responses. Besides the phenotypic changes in DCs upon encountering danger signals, there is also recent focus on changes in intracellular milieu, especially metabolism. O-GlcNAc glycosylation, a modification as yet unaddressed in DC’s, acts as a metabolic and stress sensor which, by engaging in an extensive crosstalk with phosphorylation, regulates various intracellular processes. The enzymes O-GlcNAc transferase (OGT) and O-GlcNAse (OGA) catalyse the addition and removal of monosaccharide O-GlcNAc, respectively on either Serine/Threonine residues of proteins. Since O-GlcNAc recycling on intracellular proteins is initiated by cells responding to environmental and metabolic changes, we hypothesised that O-GlcNAc glycosylation could play a functional role in DCs.
Our data showed that genetic ablation of OGT affected DC development and functions as well as their metabolic fitness. Loss of DC function also affected immune homeostasis in OGT deficient mice. Using biochemical and mass spectrometric methods, we then sought to identify the repertoire of OGlcNAc proteins that influences DC functions. We discovered that O-GlcNAc proteome changed upon DC activation, which included key factors that mediate cellular signalling, transcription and metabolism. Notably, we identified an epigenetic mechanism by which OGT controlled gene expression during DC activation. Overall, our study for the first time reveals that OGlcNAcylation influences DC maturation and function via a metabolic-epigenetic axis.