Acetylation goes global: the emergence of acetylation biology

Abstract

For the first 30 years since its discovery, reversible protein acetylation has been studied and understood almost exclusively in the context of histone modification and gene transcription. With the discovery of non-histone acetylated proteins and acetylation-modifying enzymes in cellular compartments outside the nucleus, the regulatory potential of reversible acetylation has slowly been recognized in the last decade. However, the scope of protein acetylation involvement in complex biological processes remains uncertain. The recent development of new technology has enabled, for the first time, the identification and quantification of the acetylome, acetylation events at the whole-proteome level. These efforts have uncovered a stunning complexity of the acetylome that potentially rivals that of the phosphoproteome. The remarkably ubiquitous and conserved nature of protein acetylation revealed by these new studies suggests the regulatory power of this dynamic modification. The establishment of comprehensive acetylomes will change the landscape of protein acetylation, where an exciting research frontier awaits.

Fig. 1

The acetylome (K-AC) undergoes dynamic and specific changes in response to cell signaling, stress, metabolic demands, and HDAC inhibitor (HDACI) treatment, all of which can modulate activity of deacetylases (HDAC) or lysine acetyltransferases (KAT). These changes contribute to unique acetylomic signatures, represented by different shades of K-Ac–containing circles, and are integral parts of physiological and pathological responses important for homeostasis, disease development, metabolic adaptation, and therapy. For example, the mitochondrial acetylome likely plays a critical role in metabolic adaptation and longevity. The regulatory power of the acetylome is further amplified through its crosstalk with other modifications, including phosphorylation of serine or threonine residues (S/T-P) and other lysine-based modifications (K-X), where X can be ubiquitination, methylation, neddylation, or sumoylation.