Nature 496, 110–113 (2013)

Sirtuin enzymes have been classified as protein deacetylases that use a common nicotinamide adenine dinucleotide (NAD)-dependent hydrolysis mechanism. Yet many human sirtuins have only weak activity on acetyl-lysine substrates, which has prompted the search for their primary physiological targets. Jiang et al. now show that SIRT6 preferentially hydrolyzes long-chain fatty acyl lysine post-translational modifications. Using acylated synthetic peptides, the authors found that SIRT6 removes long-chain fatty acyl groups more efficiently than acetyl groups and does so in a sequence-independent manner. Crystallographic studies revealed that the longer acyl group of a myristoylated (C14) peptide substrate is readily accommodated by a hydrophobic pocket in SIRT6. To explore the biological role of SIRT6, the authors hypothesized that a previous link between SIRT6 and tumor necrosis factor-α (TNF-α), a protein known to have two myristoylation sites, could be explained by SIRT6 deacylation activity. A bio-orthogonal fatty acid–labeling approach was used to show that SIRT6 enhances TNF-α delipidation. Further studies in an endogenous system showed that SIRT6 mediates demyristoylation of TNF-α and that this process directly enhances TNF-α secretion. In addition to clarifying SIRT6 activity and its functional role in TNF-α mobilization, the study highlights potential connections between protein post-translational modifications and metabolism.

Credit: HENING LIN