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SIRT6 Regulates TNF-α Secretion Through Hydrolysis of Long-chain Fatty Acyl Lysine

11-04-2013

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.

The research was conducted at the SSRF beamline 17U1.

Structure basis for SIRT6 activity with long-chain fatty acyl groups