Lysine Deacetylases and Regulated Glycolysis in Macrophages

• Published in: Trends in immunology 2018-06, Vol.39 (6), p.473-488
• Main Authors: Shakespear, Melanie R., Iyer, Abishek, Cheng, Catherine Youting, Das Gupta, Kaustav, Singhal, Amit, Fairlie, David P., Sweet, Matthew J.
• Format: Article
• Language: English
• Subjects: Acetylation; Cancer; Cytoplasm; Deacetylation; Dehydrogenases; Enzymes; Gene expression; Gene regulation; Glucose; Glycolysis; HDACs; immunometabolism; Inflammation; Kinases; Localization; Lysine; lysine acetylation; macrophage; Macrophages; Metabolism; Metabolites; Mitochondria; NAD; post-translational modification; Protein families; Proteins; Respiration; Roles; Sirtuins; TCA cycle; Zinc
• ISSN: 1471-4906; 1471-4981
• DOI: 10.1016/j.it.2018.02.009

Regulated cellular metabolism has emerged as a fundamental process controlling macrophage functions, but there is still much to uncover about the precise signaling mechanisms involved. Lysine acetylation regulates the activity, stability, and/or localization of metabolic enzymes, as well as inflammatory responses, in macrophages. Two protein families, the classical zinc-dependent histone deacetylases (HDACs) and the NAD-dependent HDACs (sirtuins, SIRTs), mediate lysine deacetylation. We describe here mechanisms by which classical HDACs and SIRTs directly regulate specific glycolytic enzymes, as well as evidence that links these protein deacetylases to the regulation of glycolysis-related genes. In these contexts, we discuss HDACs and SIRTs as key control points for regulating immunometabolism and inflammatory outputs from macrophages. Metabolic and immune pathways are intimately linked in that key metabolic enzymes and energy metabolites have a direct influence on pro- and anti-inflammatory responses of macrophages. In response to danger signals, activated macrophages reprogram nutrient metabolic pathways, for example enhancing aerobic glycolysis, to meet heightened energy requirements and generate sufficient biomolecules to mount an effective innate immune response. Lysine deacetylases are dual regulators of both metabolic pathways and inflammatory responses of macrophages. The acetylation status of lysine residues on some key metabolic enzymes can control their enzymatic activity, protein stability, and/or subcellular localization. Understanding the precise molecular basis of metabolic control of macrophage inflammatory processes could lead to novel approaches to target immunometabolism and inflammation.