Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases

Abstract

Silent Information Regulator 2 (Sir2) enzymes (or sirtuins) are NAD ؉ -dependent deacetylases that modulate gene silencing, aging and energy metabolism. Previous work has implicated several transcription factors as sirtuin targets. Here, we investigated whether mammalian sirtuins could directly control the activity of metabolic enzymes. We demonstrate that mammalian Acetyl-CoA synthetases (AceCSs) are regulated by reversible acetylation and that sirtuins activate AceCSs by deacetylation. Site-specific acetylation of mouse AceCS1 on Lys-661 was identified by using mass spectrometry and a specific anti-acetyl-AceCS antibody. SIRT1 was the only member of seven human Sir2 homologues capable of deacetylating AceCS1 in cellular coexpression experiments. SIRT1 expression also led to a pronounced increase in AceCS1-dependent fatty-acid synthesis from acetate. Using purified enzymes, only SIRT1 and SIRT3 exhibited high catalytic efficiency against acetylated AceCS1. In mammals, two AceCSs have been identified: cytoplasmic AceCS1 and mitochondrial AceCS2. Because SIRT3 is localized to the mitochondria, we investigated whether AceCS2 also might be regulated by acetylation, and specifically deacetylated by mitochondrial SIRT3. AceCS2 was completely inactivated upon acetylation and was rapidly reactivated by SIRT3 deacetylation. Lys-635 of mouse AceCS2 was identified as the targeted residue. Using reversible acetylation to modulate enzyme activity, we propose a model for the control of AceCS1 by SIRT1 and of AceCS2 by SIRT3.acetate ͉ deacetylation ͉ Sir2 ͉ acetyltransferase ͉ metabolism

Deacetylation of cortactin by SIRT1 promotes cell migration

“…Several lines of evidence showed that localization of SIRT1 in the cytoplasm is induced during apoptosis (Ohsawa and Miura, 2006;Jin et al, 2007). In addition, Hallows et al demonstrated that SIRT1 catalyses the deacetylation of Acetyl-CoA synthetases (AceCSs) in the cytoplasm (Hallows et al, 2006). In this study, we found that SIRT1 is localized in both the nucleus and cytoplasm in OV2008 and C13 ovarian cancer surface epithelial cells (Supplementary Figures S1 and S2).…”

Sirtuins: critical regulators at the crossroads between cancer and aging

“…SIRT3 functions as a protein deacetylase (Onyango et al, 2002;Schwer et al, 2002), and specifically targets K642 of the mitochondrial protein acetyl-CoA synthetase 2. Deacetylation of acetyl-CoA synthetase 2 activates the enzyme and promotes the production of acetyl-CoA (Hallows et al, 2006;Schwer et al, 2006). Several genetic studies have linked SIRT3 to aging, including in humans (Rose et al, 2003;Glatt et al, 2007).…”

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

“…Rapid progress in the discovery and functional analysis of an increasing number of nuclear enzymes involved in protein lysine acetylation and deacetylation, histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively, have demonstrated that these enzymes, independently of transcription, can control some of the basic cellular processes such as protein stability (reviewed in Caron et al, 2005). Moreover, it is now clear that acetylation is not an exclusive modification of nuclear proteins, since many cytoplasmic proteins, including a significant subset of mitochondrial proteins, have recently been shown to bear lysine acetylation (Cohen et al, 2004;Dihazi et al, 2005;Iwabata et al, 2005;Kovacs et al, 2005;Hallows et al, 2006;Kim et al, 2006;Schwer et al, 2006). The regulation of these acetylations and the determination of their functional significance now constitute a real challenge for biologists.…”