In the past decade, Lys acetylation has been found in a variety of proteins, ranging from many nuclear regulators to cytosolic proteins, mitochondrial enzymes, and plasma membrane-associated receptors. As emphasized herein (–), acetylation of some non-histone proteins occurs at multiple sites and crosstalks with phosphorylation, methylation, sumoylation, ubiquitination and other PTMs to form dynamic regulatory programs. Many acetyl-proteins are key components of different signaling pathways ( & ). Instead of relying solely on phosphorylation, signaling pathways likely are controlled by the coordinated actions of phosphorylation, acetylation, and other PTMs. Thus, acetylation diversifies cellular signaling networks. Owing to biased candidate approaches and/or the fact that there are more acetyl-proteins present in higher organisms, most known acetylated non-histone proteins are mammalian. Although Lys acetylation occurs in bacteria, many non-histone acetylation events may have been acquired during evolution. In support of this idea, α-tubulin Lys 40 is not conersved in yeast, and most p53 acetylation sites are absent in fly and worm homologs ().
At least six research trends will enhance our understanding of Lys acetylation. First, proteomic survey by mass spectrometry will continue to identify new acetyl-proteins. Second, systematic mapping of acetylation sites in known acetylated proteins by mass spectrometry will reveal additional sites, as recently shown for RIP140 () (Huq and Wei, 2005
). This approach has also yielded surprises concerning histone modifications (Hyland et al., 2005
) and surely will lead to unexpected discoveries about non-histone acetylation. Third, the mouse knock-in strategy will be more frequently used to examine the biological consequences of individual modification sites, as exemplified by the studies of p53 acetylation (Toledo and Wahl, 2006
). Fourth, gene inactivation has been used to analyze nearly all known HDACs and some HATs in mouse development. Together with mass spectrometry, these mutant mice will be invaluable for identifying new substrates for HATs and HDACs, as shown for Sirt3−/−
mice (Lombard et al., 2007
). A similar approach should also be applicable to other model organisms. Fifth, it will be important to map out signaling pathways that regulate reversible acetylation. One relevant question is how this modification interacts with other PTMs (e.g., sequence of occurrence and kinetics of duration) and forms dynamic programs for regulating cellular function under diverse conditions. Finally, studies of non-histone protein acetylation will shed light on the pathogenesis—and thus diagnosis, therapy and prevention—of different diseases. It will be interesting to examine how single nucleotide polymorphisms (SNPs) and different genetic variations affect acetylation and other PTM patterns among individuals. Small-molecule HDAC inhibitors and activators have emerged as promising therapeutic agents for cancer, heart diseases, diabetes, and neurodegenerative disorders, so studies of Lys acetylation would identify non-histone targets for KAT- and KDAC-modulating compounds and illuminate new avenues to improve the efficacy of related therapeutic agents.
In summary, Lys acetylation has emerged as a major PTM for over one hundred proteins. Within the acetyl-proteome, functional impact of this PTM is context-dependent and varies from protein to protein. As in histones (Strahl and Allis, 2000
; Margueron et al., 2005
; Berger, 2007
; Latham and Dent, 2007
) and in the representative examples illustrated here (–), Lys acetylation interplays actively with other PTMs—agonistically or antagonistically—to form codified ‘intramolecular signaling’ programs that are crucial for governing functions of various nuclear and cytoplasmic proteins.