SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine Academic Article uri icon

Overview

MeSH Major

  • Fatty Acids
  • Lysine
  • Sirtuins
  • Tumor Necrosis Factor-alpha

abstract

  • 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.

publication date

  • April 4, 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3635073

Digital Object Identifier (DOI)

  • 10.1038/nature12038

PubMed ID

  • 23552949

Additional Document Info

start page

  • 110

end page

  • 3

volume

  • 496

number

  • 7443