| Structural highlights
Function
[SIR6_HUMAN] NAD-dependent protein deacetylase. Has deacetylase activity towards histone H3K9Ac and H3K56Ac. Modulates acetylation of histone H3 in telomeric chromatin during the S-phase of the cell cycle. Deacetylates histone H3K9Ac at NF-kappa-B target promoters and may down-regulate the expression of a subset of NF-kappa-B target genes. Acts as a corepressor of the transcription factor HIF1A to control the expression of multiple glycolytic genes to regulate glucose homeostasis. Required for genomic stability. Regulates the production of TNF protein. Has a role in the regulation of life span (By similarity). Deacetylation of nucleosomes interferes with RELA binding to target DNA. May be required for the association of WRN with telomeres during S-phase and for normal telomere maintenance. Required for genomic stability. Required for normal IGF1 serum levels and normal glucose homeostasis. Modulates cellular senescence and apoptosis. On DNA damage, promotes DNA end resection via deacetylation of RBBP8. Has very weak deacetylase activity and can bind NAD(+) in the absence of acetylated substrate.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
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.
SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty acyl lysine.,Jiang H, Khan S, Wang Y, Charron G, He B, Sebastian C, Du J, Kim R, Ge E, Mostoslavsky R, Hang HC, Hao Q, Lin H Nature. 2013 Apr 4;496(7443):110-3. doi: 10.1038/nature12038. PMID:23552949[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M, Cheung P, Kusumoto R, Kawahara TL, Barrett JC, Chang HY, Bohr VA, Ried T, Gozani O, Chua KF. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature. 2008 Mar 27;452(7186):492-6. doi: 10.1038/nature06736. Epub 2008 Mar 12. PMID:18337721 doi:10.1038/nature06736
- ↑ Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Ongaigui KC, Boxer LD, Chang HY, Chua KF. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell. 2009 Jan 9;136(1):62-74. doi: 10.1016/j.cell.2008.10.052. PMID:19135889 doi:10.1016/j.cell.2008.10.052
- ↑ Michishita E, McCord RA, Boxer LD, Barber MF, Hong T, Gozani O, Chua KF. Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle. 2009 Aug 15;8(16):2664-6. Epub 2009 Aug 26. PMID:19625767
- ↑ Kaidi A, Weinert BT, Choudhary C, Jackson SP. Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science. 2010 Sep 10;329(5997):1348-53. doi: 10.1126/science.1192049. PMID:20829486 doi:10.1126/science.1192049
- ↑ Pan PW, Feldman JL, Devries MK, Dong A, Edwards AM, Denu JM. Structure and biochemical functions of SIRT6. J Biol Chem. 2011 Apr 22;286(16):14575-87. Epub 2011 Mar 1. PMID:21362626 doi:10.1074/jbc.M111.218990
- ↑ Jiang H, Khan S, Wang Y, Charron G, He B, Sebastian C, Du J, Kim R, Ge E, Mostoslavsky R, Hang HC, Hao Q, Lin H. SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty acyl lysine. Nature. 2013 Apr 4;496(7443):110-3. doi: 10.1038/nature12038. PMID:23552949 doi:http://dx.doi.org/10.1038/nature12038
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