Lysine acetylation and regulation of gene expressionThe requirement for energy is central to all life forms. In order to maintain homeostasis, living organisms constantly regulate their metabolic networks and gene profiles in harmony with the surroundings. With limited numbers of genes and proteins, cells have developed different ways to generate signals and to propagate them in a very economical way, one of which is reversible chemical modification of proteins. Lysine acetylation is one of the important modifications that has direct implications for transcription regulation and hence in gene expression. [1] Identified in the early 1960s, [2] the significance of this modification in key cellular processes has been constantly increasing.The first identified acetylation-modulated physiological process was chromatin dynamics and transcription regulation. Chromatin is the complex nucleoprotein organization of DNA, histones, nonhistone proteins and small RNAs. The compact organization is a deterrent to cellular processes, but is overcome by the dynamicity exhibited by chromatin. The dynamic regulation is mediated to a large extent by the chemical modification lysine acetylation, which occurs both on histones and on nonhistone proteins.[3] Several mechanisms have been hypothesized and proven for the role of acetylation in altering chromatin organization, such as loosening of the DNA-histone contact due to the introduction of charge, recruitment of remodeling factors, because acetylation acts as a tag read by effector modules (bromo domain), etc. These events are followed by the ordered recruitment of transcription factors and finally by a transcriptional output. Several signals induce the activation of the transcription process.[4] These signals could be either intrinsic (metabolic flux) or extrinsic (heat shock). Acetylation is a reversible reaction catalyzed by acetyltransferases and deacetylases. The role of acetylation in transmitting phosphorylation-associated signaling events into read-outs as gene expression has been widely recognized. The focus of this highlight, however, is on the newly discovered role of lysine acetylation in metabolism.
Metabolic processes regulate lysine acetylationThe central metabolic processes are carbohydrate metabolism (glycolysis), lipid metabolism (b-fatty acid oxidation), protein metabolism and the TCA cycle. Each of these pathways has acetyl CoA as an intermediate (Figure 1). Hence, it is indeed obvious that metabolism and lysine acetylation should be linked, because acetyl CoA is the co-factor for the latter reaction. Amongst the deacetylases, the class III NAD + -dependent deacetylases known as sirtuins have an intricate link to cellular metabolism. These deacetylases, which target both histone and nonhistone proteins, are regulated by metabolic cues, [5][6][7][8][9] their deacetylase activities being dependent on NADH hydroly-