SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.
Nature (Impact Factor: 41.46). 04/2013; 496(7443):110-3. DOI: 10.1038/nature12038
Source: PubMed


The Sir2 family of enzymes or sirtuins are known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases and have been implicated in the regulation of transcription, genome stability, metabolism and lifespan. However, four of the seven mammalian sirtuins have very weak deacetylase activity in vitro. Here we show that human SIRT6 efficiently removes long-chain fatty acyl groups, such as myristoyl, from lysine residues. The crystal structure of SIRT6 reveals a large hydrophobic pocket that can accommodate long-chain fatty acyl groups. We demonstrate further that SIRT6 promotes the secretion of tumour necrosis factor-α (TNF-α) by removing the fatty acyl modification on K19 and K20 of TNF-α. Protein lysine fatty acylation has been known to occur in mammalian cells, but the function and regulatory mechanisms of this modification were unknown. Our data indicate that protein lysine fatty acylation is a novel mechanism that regulates protein secretion. The discovery of SIRT6 as an enzyme that controls protein lysine fatty acylation provides new opportunities to investigate the physiological function of a protein post-translational modification that has been little studied until now.

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Available from: Hening Lin, Mar 19, 2014
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    • "As for SIRT6, this deacetylase can locate at the endoplasmic reticulum and controls protein lysine fatty acylation [25]. Indeed, as revealed by crystal structure, SIRT6 possesses a large hydrophobic pocket able to accommodate long chain fatty acyl groups and efficiently remove them from lysine residues [25]. Beside the deacetylase activity, SIRT5 also shows demalonylase and desuccinylase activity [26] (Fig. 1). "
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    ABSTRACT: Silent information regulator-2 (Sir-2) proteins, or sirtuins, are a highly conserved protein family of histone deacetylases that promote longevity by mediating many of the beneficial effects of calorie restriction which extends life span and reduces the incidence of cancer, cardiovascular disease (CVD), and diabetes. Here, we review the role of sirtuins (SIRT1-7) in vascular homeostasis and diseases by providing an update on the latest knowledge about their roles in endothelial damage and vascular repair mechanisms. Among all sirtuins, in the light of the numerous functions reported on SIRT1 in the vascular system, herein we discuss its roles not only in the control of endothelial cells (EC) functionality but also in other cell types beyond EC, including endothelial progenitor cells (EPC), smooth muscle cells (SMC), and immune cells. Furthermore, we also provide an update on the growing field of compounds under clinical evaluation for the modulation of SIRT1 which, at the state of the art, represents the most promising target for the development of novel drugs against CVD, especially when concomitant with type 2 diabetes. Copyright © 2015. Published by Elsevier B.V.
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    • "Two mammalian sirtuins, SIRT4 and SIRT6, have been shown to possess biologically relevant mono-ADP-ribosyltransferase activity (Ahuja et al., 2007; Frye, 1999; Haigis et al., 2006; Liszt et al., 2005). Some sirtuins remove non-canonical lysine post-translational modifications such as succinyl, malonyl, glutaryl and acyl groups (Du et al., 2011; Feldman et al., 2013; Jiang et al., 2013; Peng et al., 2011; Tan et al., 2014). Through these activities, mammalian sirtuins modulate a diverse array of biological processes, such as transcriptional regulation, metabolism, genomic stability, cell cycle control and inflammation (Morris, 2013). "
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    • "Importantly, these modifications can be removed by HDACs and sirtuins in vitro (Feldman et al., 2013; Madsen and Olsen, 2012). Additionally, longer-chain acyl lysine modifications occur in cells and are targeted for removal by SIRT6 in vivo (Jiang et al., 2013). Although no dedicated lysine propionyltransferase or butyryltransferase has been identified, some acetyltransferases can catalyze propionylation and butyrylation of histones at substantially lower efficiency than acetylation (Albaugh et al., 2011). "
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    ABSTRACT: Cellular proteins are decorated with a wide range of acetyl and other acyl modifications. Many studies have demonstrated regulation of site-specific acetylation by acetyltransferases and deacetylases. Acylation is emerging as a new type of lysine modification, but less is known about its overall regulatory role. Furthermore, the mechanisms of lysine acylation, its overlap with protein acetylation, and how it influences cellular function are major unanswered questions in the field. In this review, we discuss the known roles of acetyltransferases and deacetylases and the sirtuins as a conserved family of a nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacylases that are important for response to cellular stress and homeostasis. We also consider the evidence for an emerging idea of nonenzymatic protein acylation. Finally, we put forward the hypothesis that protein acylation is a form of protein "carbon stress" that the deacylases evolved to remove as a part of a global protein quality-control network.
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