Reciprocal Regulation of AMPK/SNF1 and Protein Acetylation

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.

Connections between Metabolism and Epigenetic Modification in MDSCs

“…Since acetyl-CoA is a substrate for lysine acetyltransferase (KATS), AMPK can affect the activity of KATS by regulating the cell level of acetyl-CoA. In addition, AMPK can activate HDACs by increasing the cell concentration of NAD + , a cofactor of HDACs [ 97 ]. AMPK also regulates DNA methylation and histone acetylation by phosphorylating epigenetic factors such as DNMT1, retinoblastoma binding protein 7 (RBBP7), and HAT1, thereby promoting mitochondrial biosynthesization and function.…”

Archaeal Histone Contributions to the Origin of Eukaryotes

“…AMPK senses the ratio of ATP to ADP and AMP and thereby acts as a fuel gauge for the cell [90], conveying to TOR signals required for informed decisions as to whether to sustain growth (continue the cell cycle) or to exit the cell cycle and enter G0 or quiescence. Starvation sensing via AMPK and the TOR family can also send signals that lead to autophagy [88,104], a self-digestion process in which cytoplasmic organelles, including mitochondria, are enzymatically degraded in vacuoles to provide basic nutrients for survival [93]. The signals sent by AMPK and TOR (GCN2 via TOR) elicit changes in histone modification [88,89], forging links between histone-dependent regulation of genes and the cell cycle on the one hand, with the most basic, vital needs of the cell (nutrition) on the other.…”

“…Starvation sensing via AMPK and the TOR family can also send signals that lead to autophagy [88,104], a self-digestion process in which cytoplasmic organelles, including mitochondria, are enzymatically degraded in vacuoles to provide basic nutrients for survival [93]. The signals sent by AMPK and TOR (GCN2 via TOR) elicit changes in histone modification [88,89], forging links between histone-dependent regulation of genes and the cell cycle on the one hand, with the most basic, vital needs of the cell (nutrition) on the other. In humans, nutrition limitation in early life can elicit epigenetic effects [105].…”

“…Today, histone modification is highly regulated and tightly linked to (i) the energetic status of the cell [84], (ii) chromatin condensation [85], and (iii) decisions about the eukaryotic cell cycle [86]. Eukaryotes sense the energetic state of the cell with the help of the sensor proteins AMPactivated protein kinase (AMPK) and target of rapamycin (TOR) [87][88][89], and they sense the nutritional status of the cell (carbon, energy, and amino acid availability) via TOR and GCN2 [90]. By dry weight, nonphotosynthetic cells are about 50% protein and 10% nitrogen [91].…”

“…The three main energy and nutrient signaling pathways of eukaryotes -AMPK, TOR, and GCN2are conserved across eukaryotic groups [90]. All three master regulators transmit signals to chromatin via histone modification [88,89] (Box 1). By sensing the nutrient state of the cell they connect mitochondrial energy supplyand mitochondrial quality-control via autophagy [92,93] with the eukaryotic cell cycle.…”