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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    • "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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