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



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.

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Figure 1: SIRT6 preferentially hydrolyses long-chain fatty acyl lysine in vitro.
Figure 2: Structure basis for SIRT6 activity with long-chain fatty acyl groups.
Figure 3: SIRT6 regulates TNF-α fatty acylation and secretion.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

The crystal structure of SIRT6 in complex with a H3K9 myristoyl peptide and ADP-ribose is deposited in the Protein Data Bank as accession number 3ZG6.


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This work was supported in part by NIH R01GM086703 (H.L.), R01GM093072 (R.M.), Hong Kong GRF766510 (Q.H.) and NIH R01GM087544 (H.C.H.). We thank C. Zhang for help with the cloning of SIRT6 WT and H133Y to generate lentiviral particles and the staff at the Shanghai Synchrotron Radiation Facility for assistance during the data collection.

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Authors and Affiliations



H.J. designed and carried out all biochemical experiments involving TNF-α and synthesized Rh-N3. S.K. synthesized acyl peptides and carried out all enzymology experiments of SIRT6. Y.W. carried out all crystallography experiments. G.C. and B.H. synthesized Alk14. G.C. and H.C.H. provided expertise on the labelling experiments using Alk14. C.S. and R.M. generated the MEF cells and bone marrow-derived macrophages from SIRT6 WT and KO mice. J.D., R.K. and E.G. contributed to the cloning, expression and purification of SIRT6. Q.H. directed the structural studies and wrote the structural part of the manuscript. H.L. directed the biochemical studies, coordinated the collaborations among different labs, and wrote the manuscript with help from H.J., S.K., Y.W., R.M., H.C.H. and Q.H.

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Correspondence to Quan Hao or Hening Lin.

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Competing interests

R.M. is on the scientific advisory board for Sirtris, a GSK company.

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Jiang, H., Khan, S., Wang, Y. et al. SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496, 110–113 (2013).

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