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

Abstract

Chronic, low‑grade inflammation associated with obesity and diabetes result from the infiltration of adipose and vascular tissue by immune cells and contributes to cardiovascular complications. Despite an incomplete understanding of the mechanistic underpinnings of immune cell differentiation and inflammation, O‑GlcNAcylation, the addition of O‑linked N‑acetylglucosamine (O‑GlcNAc) to cytoplasmic, nuclear and mitochondrial proteins by the two cycling enzymes, the O‑linked N‑acetylglucosamine transferase (OGT) and the O‑GlcNAcase (OGA), may contribute to fine‑tune immunity and inflammation in both physiological and pathological conditions. Early studies have indicated that O‑GlcNAcylation of proteins play a pro‑inflammatory role in diabetes and insulin resistance, whereas subsequent studies have demonstrated that this post‑translational modification could also be protective against acute injuries. These studies suggest that diverse types of insults result in dynamic changes to O‑GlcNAcylation patterns, which fluctuate with cellular metabolism to promote or inhibit inflammation. In this review, the current understanding of O‑GlcNAcylation and its adaptive modulation in immune and inflammatory responses is summarized.

Figure 1

Nutrient flux through the HBP modulates protein O-GlcNAcylation. The majority of glucose is taken for glycolysis and glycogen synthesis, but a small percentage (~2-5%) is funneled directly into the HBP for UDP-GlcNAc synthesis. OGT catalyzes the addition of GlcNAc from UDP-GlcNAc to serine and threonine residues, while OGA catalyzes their removal. Together these two enzymes tune the dynamic addition and removal of O-GlcNAc for thousands of diverse proteins. O-GlcNAcylation sites are usually directly at, or close to, the same serine or threonine residues used by kinases. HBP, hexosamine biosynthetic pathway; OGT, O-linked N-acetylglucosamine transferase; OGA, O-GlcNAcase; GlcNAc, N-acetylglucosamine; UDP, uridine diphosphate; GFAT, glutamine-fructose-6-phosphate aminotransferase; OSMI-1, (αR)-α-[[(1,2-Dihydro-2-oxo-6-quinolinyl)sulfonyl]amino]-N-(2-furanylmethyl)-2-methoxy- N-(2-thienylmethyl)-benzeneacetamide.

Figure 2

Connection between helper T cell differentiation and HBP. After T cell antigen receptor engagement, naïve CD4⁺ T cells differentiate into effector T cells including Th1, Th2 and Th17 cells, as well as iTreg. Effector T cells utilize glucose through glycolysis and amino acids through glutaminolysis to meet their energy need for differentiation, whereas regulatory T cells use energy from fatty acid oxidation. Finally, HBP integrates glucose, amino acid and fatty acid metabolism to generate UDP-GlcNAc for O-GlcNAc modification. CD, cluster of differentiation; HBP, hexosamine biosynthetic pathway; iTregs, inducible regulatory T cells; MHC, major histo-compatibility complex; TCR, T cell receptor; IL, interleukin; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine; APC, antigen presenting cell.