Members of the sirtuin family of enzymes are nicotinamide (NAD)–dependent deacetylases that are implicated in regulating gene expression through their deacetylation of modified histone proteins. Noting that some sirtuins, including SIRT5 and SIRT6, have weak deacetylase activity, Jiang et al. investigated whether SIRT6 had enzymatic activity toward other posttranslational modifications. In vitro analysis of the catalytic efficiency of SIRT6 on a histone H3K9-based peptide sequence that was modified with different acyl groups showed that the demyristoylation activity of SIRT6 was 300-fold more efficient than its deacetylation activity. Solving the structure of SIRT6 in complex with a myristoylated H3K9 peptide and adenosine diphosphate ribose revealed the presence of a hydrophobic pocket within SIRT6 that accommodated the long-chain fatty acyl modification of the peptide. Tumor necrosis factor–α (TNF-α) is a proinflammatory cytokine that undergoes myristoylation on two lysine residues, K19 and K20. Analyses of wild-type and SIRT6-deficient cells expressing tagged TNF-α showed that the extent of its myristoylation was greatest in the absence of SIRT6. Loss of SIRT6 also resulted in reduced secretion of TNF-α into the medium of cultured cells and intracellular accumulation of the acylated cytokine. Reconstitution of SIRT6-deficient cells with wild-type SIRT6, but not a catalytically inactive mutant SIRT6, restored the ability of cells to secrete TNF-α. In addition, knockdown of SIRT6 in mouse bone marrow–derived macrophages or a human macrophage cell line resulted in reduced secretion of TNF-α. Further analysis showed that SIRT6 was found in the endoplasmic reticulum fraction of cells, consistent with its potential role in promoting the secretion of TNF-α. As Bheda and Wolberger discuss in commentary, these data together with related recent findings suggest that sirtuins might be better considered lysine deacylases rather than deacetylases to reflect their broad enzymatic activities.
H. Jiang, S. Khan, Y. Wang, G. Charron, B. He, C. Sebastian, J. Du, R. Kim, E. Ge, R. Mostoslavsky, H. C. Hang, Q. Hao, H. Lin, SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496, 110–113 (2013). [PubMed]
P. Bheda, C. Wolberger, Sirtuin on a high-fat diet. Nature 496, 41–42 (2013). [PubMed]