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

Abstract

The sirtuin family of enzymes are known as NAD-dependent deacetylases, although some of them have very weak deacetylase activity; here human SIRT6, an enzyme important for DNA repair and transcription, is shown to remove long-chain fatty acyl groups from protein lysine residues, and to have a function in promoting tumour necrosis factor alpha secretion. Enzymes of the sirtuin family attract a lot of interest because of they regulate ageing, transcription, apoptosis and metabolism. They are often described as NAD-dependent deacetylases, but in fact some of them have only very weak deacetylase activity in vitro and two were shown previously to preferentially use alternative substrates. Here, human SIRT6, an enzyme important for DNA repair and transcription, is shown to remove long-chain fatty acyl groups, such as myristoyl, from lysine residues and to have a function in promoting TNF-α secretion. Its previously described histone deacetylase activity may account for only part of its function. The identification of SIRT6's new activity points to protein lysine fatty acylation as a potentially important area for study. The Sir2 family of enzymes or sirtuins are known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases1 and have been implicated in the regulation of transcription, genome stability, metabolism and lifespan2,3. 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.