Publication Date:
2013-04-05
Description:
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-alpha (TNF-alpha) by removing the fatty acyl modification on K19 and K20 of TNF-alpha. 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635073/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635073/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Hong -- Khan, Saba -- Wang, Yi -- Charron, Guillaume -- He, Bin -- Sebastian, Carlos -- Du, Jintang -- Kim, Ray -- Ge, Eva -- Mostoslavsky, Raul -- Hang, Howard C -- Hao, Quan -- Lin, Hening -- R01 CA175727/CA/NCI NIH HHS/ -- R01 DK088190/DK/NIDDK NIH HHS/ -- R01 GM086703/GM/NIGMS NIH HHS/ -- R01 GM087544/GM/NIGMS NIH HHS/ -- R01 GM093072/GM/NIGMS NIH HHS/ -- R01GM086703/GM/NIGMS NIH HHS/ -- R01GM087544/GM/NIGMS NIH HHS/ -- R01GM093072/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Apr 4;496(7443):110-3. doi: 10.1038/nature12038.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23552949" target="_blank"〉PubMed〈/a〉
Keywords:
Acylation
;
Binding Sites
;
Crystallography, X-Ray
;
Fatty Acids/*chemistry/*metabolism
;
Humans
;
Hydrolysis
;
Hydrophobic and Hydrophilic Interactions
;
Lysine/*analogs & derivatives/chemistry/*metabolism
;
Protein Processing, Post-Translational
;
Sirtuins/chemistry/*metabolism
;
Tumor Necrosis Factor-alpha/chemistry/metabolism/*secretion
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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