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

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.
Nature (Impact Factor: 41.46). 04/2013; 496(7443):110-3. DOI: 10.1038/nature12038
Source: 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-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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Available from: Hening Lin, Mar 19, 2014
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    • "Apart from PARP1, SIRT6 has been reported to mediate mono-ADP ribosylation of the nuclear corepressor Kap1, thereby aiding in the packaging of L1 retrotransposons into transcriptionally repressive heterochromatin (Van Meter et al., 2014). Recently, hydrolysis of long-chain fatty acyl moieties from lysine residues has been described as the third enzymatic activity of SIRT6 (Jiang et al., 2013). Several independent studies have revealed and elucidated the roles of SIRT6 in a spectrum of biological processes, such as DNA damage repair, cellular metabolism, inflammation, cancer, and aging (Kugel and Mostoslavsky, 2014). "
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    ABSTRACT: The nuclear lamins are essential for various molecular events in the nucleus, such as chromatin organization, DNA replication, and provision of mechanical support. A specific point mutation in the LMNA gene creates a truncated prelamin A termed progerin, causing Hutchinson-Gilford progeria syndrome (HGPS). SIRT6 deficiency leads to defective genomic maintenance and accelerated aging similar to HGPS, suggesting a potential link between lamin A and SIRT6. Here, we report that lamin A is an endogenous activator of SIRT6 and facilitates chromatin localization of SIRT6 upon DNA damage. Lamin A promotes SIRT6-dependent DNA-PKcs (DNA-PK catalytic subunit) recruitment to chromatin, CtIP deacetylation, and PARP1 mono-ADP ribosylation in response to DNA damage. The presence of progerin jeopardizes SIRT6 activation and compromises SIRT6-mediated molecular events in response to DNA damage. These data reveal a critical role for lamin A in regulating SIRT6 activities, suggesting that defects in SIRT6 functions contribute to impaired DNA repair and accelerated aging in HGPS.
    Full-text · Article · Nov 2015 · Cell Reports
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    • "As for SIRT6, this deacetylase can locate at the endoplasmic reticulum and controls protein lysine fatty acylation [25]. Indeed, as revealed by crystal structure, SIRT6 possesses a large hydrophobic pocket able to accommodate long chain fatty acyl groups and efficiently remove them from lysine residues [25]. Beside the deacetylase activity, SIRT5 also shows demalonylase and desuccinylase activity [26] (Fig. 1). "
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    ABSTRACT: Silent information regulator-2 (Sir-2) proteins, or sirtuins, are a highly conserved protein family of histone deacetylases that promote longevity by mediating many of the beneficial effects of calorie restriction which extends life span and reduces the incidence of cancer, cardiovascular disease (CVD), and diabetes. Here, we review the role of sirtuins (SIRT1-7) in vascular homeostasis and diseases by providing an update on the latest knowledge about their roles in endothelial damage and vascular repair mechanisms. Among all sirtuins, in the light of the numerous functions reported on SIRT1 in the vascular system, herein we discuss its roles not only in the control of endothelial cells (EC) functionality but also in other cell types beyond EC, including endothelial progenitor cells (EPC), smooth muscle cells (SMC), and immune cells. Furthermore, we also provide an update on the growing field of compounds under clinical evaluation for the modulation of SIRT1 which, at the state of the art, represents the most promising target for the development of novel drugs against CVD, especially when concomitant with type 2 diabetes. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Mar 2015 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
    • "Initially recognized as protein deacetylases, they have lately been shown to catalyze further posttranslational modifications such as demyristoylation [26], demalonylation, desuccinylation [27] or ADP-ribosylation [28]. Through a multitude of protein substrates they are involved in key cellular processes including metabolic sensing, regulation of mitosis and aging. "
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    ABSTRACT: Sirtuins form a unique and highly conserved class of NAD(+)-dependent lysine deacylases. Among these the human subtypes Sirt1-3 has been implicated in the pathogenesis of numerous diseases such as cancer, metabolic syndromes, viral diseases and neurological disorders. Most of the sirtuin inhibitors that have been identified so far show limited potency and/or isoform selectivity. Here, we introduce a promising method to generate protein-inhibitor complexes of human Sirt1, Sirt2 and Sirt3 by means of ligand docking and molecular dynamics simulations. This method highly reduces the complexity of such applications and can be applied to other protein targets beside sirtuins. To the best of our knowledge, we present the first binding free energy method developed by using a validated data set of sirtuin inhibitors, where both a fair number of compounds (33 thieno[3,2-d]pyrimidine-6-carboxamide derivatives) was developed and tested in the same laboratory and also crystal structures in complex with the enzyme have been reported. A significant correlation between binding free energies derived from MM-GBSA calculations and in vitro data was found for all three sirtuin subtypes. The developed MM-GBSA protocol is computationally inexpensive and can be applied as a post-docking filter in virtual screening to find novel Sirt1-3 inhibitors as well as to prioritize compounds with similar chemical structures for further biological characterization. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    No preview · Article · Feb 2015 · European Journal of Medicinal Chemistry
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