Abstract
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) serves as an energy sensor and master regulator of metabolism. In general, AMPK inhibits anabolism to minimize energy consumption and activates catabolism to increase ATP production. One of the mechanisms employed by AMPK to regulate metabolism is protein acetylation. AMPK regulates protein acetylation by at least five distinct mechanisms. First, AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC) and thus regulates acetyl-CoA homeostasis. Since acetyl-CoA is a substrate for all lysine acetyltransferases (KATs), AMPK affects the activity of KATs by regulating the cellular level of acetyl-CoA. Second, AMPK activates histone deacetylases (HDACs) sirtuins by increasing the cellular concentration of NAD+, a cofactor of sirtuins. Third, AMPK inhibits class I and II HDACs by upregulating hepatic synthesis of α-hydroxybutyrate, a natural inhibitor of HDACs. Fourth, AMPK induces translocation of HDACs 4 and 5 from the nucleus to the cytoplasm and thus increases histone acetylation in the nucleus. Fifth, AMPK directly phosphorylates and downregulates p300 KAT. On the other hand, protein acetylation regulates AMPK activity. Sirtuin SIRT1-mediated deacetylation of liver kinase B1 (LKB1), an upstream kinase of AMPK, activates LKB1 and AMPK. AMPK phosphorylates and inactivates ACC, thus increasing acetyl-CoA level and promoting LKB1 acetylation and inhibition. In yeast cells, acetylation of Sip2p, one of the regulatory β-subunits of the SNF1 complex, results in inhibition of SNF1. This results in activation of ACC and reduced cellular level of acetyl-CoA, which promotes deacetylation of Sip2p and activation of SNF1. Thus, in both yeast and mammalian cells, AMPK/SNF1 regulate protein acetylation and are themselves regulated by protein acetylation.
Highlights
Protein AcetylationProtein acetylation is a posttranslational protein modification in which the acetyl group from acetyl-CoA is transferred onto ε-amino group of lysine residues
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) serves as an energy sensor and master regulator of metabolism
Acetyl-CoA is the donor of acetyl groups for protein acetylation and KATs depend on intermediary metabolism for supplying acetyl-CoA in the nucleocytosolic compartment (Figure 1)
Summary
Protein acetylation is a posttranslational protein modification in which the acetyl group from acetyl-CoA is transferred onto ε-amino group of lysine residues. Similar analyses of human and mouse proteins identified ~2200 phosphoproteins [35,36] It appears that protein acetylation is as widespread as phosphorylation [37]. Acetylation of histones affects the chromatin structure and transcriptional regulation by two mechanisms. It neutralizes positive charges of lysines and diminishes interaction of histone tails with DNA. By forming acetyllysines, histone acetylation creates sites that are recognized and bound by proteins and protein complexes that contain bromodomains. Many of these bromodomain-containing protein complexes covalently or noncovalently modify chromatin structure and regulate transcription [40,41]
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