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Activation of the Protein Deacetylase SIRT6 by Long-chain Fatty Acids and Widespread Deacylation by Mammalian Sirtuins
Open accessAbstract
Mammalian sirtuins (SIRT1 through SIRT7) are members of a highly conserved family of NAD + -dependent protein deacetylases that function in metabolism, genome maintenance, and stress responses. Emerging evidence suggests that some sirtuins display substrate specificity toward other acyl groups attached to the lysine ϵ-amine. SIRT6 was recently reported to preferentially hydrolyze long-chain fatty acyl groups over acetyl groups. Here we investigated the catalytic ability of all sirtuins to hydrolyze 13 different acyl groups from histone H3 peptides, ranging in carbon length, saturation, and chemical diversity. We find that long-chain deacylation is a general feature of mammalian sirtuins, that SIRT1 and SIRT2 act as efficient decrotonylases, and that SIRT1, SIRT2, SIRT3, and SIRT4 can remove lipoic acid. These results provide new insight into sirtuin function and a means for cellular removal of an expanding list of endogenous lysine modifications. Given that SIRT6 is a poor deacetylase in vitro , but binds and prefers to hydrolyze long-chain acylated peptides, we hypothesize that binding of certain free fatty acids (FFAs) could stimulate deacetylation activity. Indeed, we demonstrate that several biologically relevant FFAs (including myristic, oleic, and linoleic acids) at physiological concentrations induce up to a 35-fold increase in catalytic efficiency of SIRT6 but not SIRT1. The activation mechanism is consistent with fatty acid inducing a conformation that binds acetylated H3 with greater affinity. Binding of long-chain FFA and myristoylated H3 peptide is mutually exclusive. We discuss the implications of discovering endogenous, small-molecule activators of SIRT6. Background: Sirtuins regulate metabolism, genome maintenance, and stress responses. Results: Long-chain free fatty acids stimulate SIRT6 deacetylase, and sirtuins display distinct but overlapping specificity for diverse acylated peptides. Conclusion: SIRT6 is activated by biologically relevant fatty acids, and long-chain deacylation is a general feature of sirtuins. Significance: Discovery of endogenous, small-molecule activators of SIRT6 demonstrates the therapeutic potential of compounds that promote SIRT6 function.
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“Additionally, some members of the sirtuin family mediate non-acetyl lysine acylations (for example, succinylation, malonylation and fatty acid acylation)13–15, the cellular functions of which are so far poorly understood16.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [13]
In the citing paper
“Unsurprisingly, given the range of their potential substrates, sirtuins 1, 216 and 317 were shown to be decrotonylases in vitro.”
From Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo (2018) · cites this paper as [16]
In the citing paper
“To date, decrotonylase activity has been described for HDAC1-3 and Sirtuins 1-316–18,21,22.”
From Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo (2018) · cites this paper as [16]
In the citing paper
“While some of the sirtuins, the NAD+-dependent HDACs, have been recognized as protein defatty-acylases,12,16,17 this is the first report of a zinc-dependent HDAC possessing this enzymatic activity.”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [16]
In the citing paper
“Several NAD+-dependent deacetylase, SIRT1, SIRT2, SIRT3 and SIRT6, have been previously reported to possess lysine defatty-acylation activities.15-17”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [16]
In the citing paper
“and SIRT1, 2, 3 and SIRT6 are capable of hydrolyzing long chain fatty acyl groups from lysine residues.15-17”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [16]
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Citations
Cites
1 retracted
RETRACTED: Human SIRT6 Promotes DNA End Resection Through CtIP Deacetylation
Kaidi, A., Weinert, B. T., Choudhary, C., & Jackson, S. P. (2010) · Science · doi:10.1126/science.1192049 · Cited by 366 · cited 1×
“In cells, the ability of SIRT6 to promote deacetylation of histones and non-histone proteins (18) seemed at odds with the low in vitro deacetylation rates (13, 19) and with the recently described demyristoylation activity (13).”
BackgroundRetractedTan, M., Luo, H., Lee, S., Jin, F., Yang, J. S., Montellier, E., Buchou, T., Cheng, Z., Rousseaux, S., Rajagopal, N., et al. (2011) · Cell · doi:10.1016/j.cell.2011.08.008 · Cited by 1,902 · cited 1×
“Crotonyllysine was identified as a histone modification in several eukaryotic cells types and is associated with active promoters or enhancers (11).”
BackgroundSirtuins in mammals: insights into their biological function
Michán, S., & Sinclair, D. A. (2007) · Biochemical Journal · doi:10.1042/bj20070140 · Cited by 1,750 · cited 1×
“SIRT6 is one of seven members of the mammalian NAD dependent protein deacetylases that are evolutionarily ancient (1).”
BackgroundGenomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6
Mostoslavsky, R., Chua, K. F., Lombard, D. B., Pang, W. W., Fischer, M. R., Gellon, L., Liu, P., Mostoslavsky, G., Franco, S., Murphy, M. M., et al. (2006) · Cell · doi:10.1016/j.cell.2005.11.044 · Cited by 1,637 · cited 2×
“Recent studies indicate that SIRT6 plays critical roles in intermediary metabolism and genomic stability (2).”
BackgroundSirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase
Du, J., Zhou, Y., Su, X., Yu, J. J., Khan, S., Jiang, H., Kim, J., Woo, J., Kim, J. H., Choi, B. H., et al. (2011) · Science · doi:10.1126/science.1207861 · Cited by 1,429 · cited 1×
“The recent observation that SIRT5 prefers succinylated/malonylated substrates helps explain the observed low activity on acetylated substrates (8).”
BackgroundOmega-3 Fatty Acids and Inflammatory Processes
Calder, P. C. (2010) · Nutrients · doi:10.3390/nu2030355 · Cited by 1,116 · cited 1×
“For instance, omega-3 fatty acids, including eicosapentaenoic acid (20:5,n-3) and docosahexaenoic acid (22:6,n-3), are reported to exert beneficial effects against cardiovascular disease and inflammation (29, 30).”
BackgroundSIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin
Michishita, E., McCord, R. A., Berber, E., Kioi, M., Padilla-Nash, H., Damian, M., Cheung, P., Kusumoto, R., Kawahara, T. L. A., Barrett, J. C., et al. (2008) · Nature · doi:10.1038/nature06736 · Cited by 1,111 · cited 1×
“However, several prior studies indicated that SIRT6 acted through deacetylation of histonemarksH3K9Ac (14) and H3K56Ac (15), which modulated HIF1- -dependent (16), NF- B-dependent (17), and c-Myc-dependent (3) pathways.”
BackgroundKawahara, T. L. A., Michishita, E., Adler, A. S., Damian, M., Berber, E., Lin, M., McCord, R. A., Ongaigui, K. C. L., Boxer, L. D., Chang, H. Y., et al. (2009) · Cell · doi:10.1016/j.cell.2008.10.052 · Cited by 1,090
The sirtuin SIRT6 regulates lifespan in male mice
Kanfi, Y., Naiman, S., Amir, G., Peshti, V., Zinman, G., Nahum, L., Bar-Joseph, Z., & Cohen, H. Y. (2012) · Nature · doi:10.1038/nature10815 · Cited by 1,059 · cited 1×
“SIRT6 overexpression lowers LDL and triglyceride levels, improves glucose tolerance (4), and increases lifespan of male mice (5).”
BackgroundThe Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α
Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R. E., Vadysirisack, D. D., Guimaraes, A., Marinelli, B., Wikstrom, J. D., Nir, T., et al. (2010) · Cell · doi:10.1016/j.cell.2009.12.041 · Cited by 1,001 · cited 2×
“However, several prior studies indicated that SIRT6 acted through deacetylation of histonemarksH3K9Ac (14) and H3K56Ac (15), which modulated HIF1- -dependent (16), NF- B-dependent (17), and c-Myc-dependent (3) pathways.”
BackgroundSirtuins deacetylate and activate mammalian acetyl-CoA synthetases
Hallows, W. C., Lee, S., & Denu, J. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604392103 · Cited by 792 · cited 1×
“Expression and Purification of Recombinant SIRT1-SIRT7— His-tagged SIRT1–7 were overexpressed in BL21(DE3) or BL21(DE3) CobB Escherichia coli strains and purified as described (19, 20).”
MethodSelf-citationLysine propionylation and butyrylation are novel post-translational modifications in histones
Chen, Y., Sprung, R., Tang, Y., Ball, H., Sangras, B., Kim, S. C., Falck, J. R., Peng, J., Gu, W., & Zhao, Y. (2007) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m700021-mcp200 · Cited by 764
SIRT6 regulates TNF-α 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., et al. (2013) · Nature · doi:10.1038/nature12038 · Cited by 697 · cited 1×
“Consistent with this idea, Jiang et al. (13) demonstrated recently that SIRT6 preferentially hydrolyzes long-chain fatty acyl groups, including myristoyl and palmitoyl groups, from lysine residues.”
BackgroundThe histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism
Sebastián, C., Zwaans, B. M. M., Silberman, D. M., Gymrek, M., Goren, A., Zhong, L., Ram, O., Truelove, J., Guimaraes, A. R., Toiber, D., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.047 · Cited by 660 · cited 2×
“However, several prior studies indicated that SIRT6 acted through deacetylation of histonemarksH3K9Ac (14) and H3K56Ac (15), which modulated HIF1- -dependent (16), NF- B-dependent (17), and c-Myc-dependent (3) pathways.”
BackgroundMechanisms underlying the cardioprotective effects of omega-3 polyunsaturated fatty acids
Adkins, Y. C., & Kelley, D. S. (2010) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2009.12.004 · Cited by 577 · cited 2×
“Omega-3 fatty acids, including eicosapentaenoic acid, elicit an anti-inflammatory response in part by preventing translocation of NF- B to the nucleus, thereby decreasing TNF- expression (30).”
Background(2010) · doi:10.1016/j.cmet.2010.06.009 · Cited by 512 · cited 1×
“SIRT6 was shown to negatively control the mRNA expression of glycolytic and lipogenic genes (16, 32).”
BackgroundThe sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun
Sundaresan, N. R., Vasudevan, P., Zhong, L., Kim, G. H., Samant, S. A., Parekh, V., Pillai, V. B., Veeranna, R. P., Gupta, M., Jeevanandam, V., et al. (2012) · Nature Medicine · doi:10.1038/nm.2961 · Cited by 484
Dietary polyunsaturated fatty acids and regulation of gene transcription
Jump, D. Β. (2002) · Current Opinion in Lipidology · doi:10.1097/00041433-200204000-00007 · Cited by 441 · cited 1×
“Together with transcription factors peroxisome proliferator-activated receptor (PPAR , - , and - ), hepatic nuclear factor-4 (HNF-4), MAX-like factor X (MLX), and sterol regulatory element-binding proteins (SREBPs) 1 and 2 (28), these mechanisms permit tight control of carbohydrate and lipid metabolism pathways.”
BackgroundStructure and Biochemical Functions of SIRT6
Pan, P. W., Feldman, J. L., Devries, M., Dong, A., Edwards, A. M., & Denu, J. M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.218990 · Cited by 312 · cited 5×
“Given this unique conformation, we proposed that SIRT6 could be activated if the two domains could be induced to the canonical active-site conformation (19).”
BackgroundMethodInfluentialSelf-citationSIRT6 protects against pathological damage caused by diet‐induced obesity
Kanfi, Y., Peshti, V., Gil, R., Naiman, S., Nahum, L., Levin, E., Kronfeld‐Schor, N., & Cohen, H. Y. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2009.00544.x · Cited by 311 · cited 1×
“SIRT6 overexpression lowers LDL and triglyceride levels, improves glucose tolerance (4), and increases lifespan of male mice (5).”
BackgroundCoordinate regulation of glycolytic and lipogenic gene expression by polyunsaturated fatty acids.
Jump, D. Β., Clarke, S. D., Thelen, A. P., & Liimatta, M. B. (1994) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)40103-8 · Cited by 305
Nakagawa, T., & Guarente, L. (2011) · Journal of Cell Science · doi:10.1242/jcs.081067 · Cited by 292 · cited 1×
“SIRT1–3 display robust protein deacetylase activity, and numerous studies have identified in vivo substrates (35, 36).”
BackgroundThe sirtuin SIRT6 deacetylates H3 K56Ac in vivo to promote genomic stability
Yang, B., Zwaans, B. M. M., Eckersdorff, M., & Lombard, D. B. (2009) · Cell Cycle · doi:10.4161/cc.8.16.9329 · Cited by 254 · cited 1×
“However, several prior studies indicated that SIRT6 acted through deacetylation of histonemarksH3K9Ac (14) and H3K56Ac (15), which modulated HIF1- -dependent (16), NF- B-dependent (17), and c-Myc-dependent (3) pathways.”
BackgroundSirtuin catalysis and regulation
Feldman, J. L., Dittenhafer-Reed, K. E., & Denu, J. M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.r112.378877 · Cited by 248 · cited 1×
“SIRT1–3 display robust protein deacetylase activity, and numerous studies have identified in vivo substrates (35, 36).”
BackgroundSelf-citationProtein Lysine Acylation and Cysteine Succination by Intermediates of Energy Metabolism
Lin, H., Su, X., & He, B. (2012) · ACS Chemical Biology · doi:10.1021/cb3001793 · Cited by 238 · cited 3×
“Acyl-CoA donors are intermediates in different central metabolic pathways, including glycolysis, the TCA cycle, -oxidation, and FA synthesis (7).”
BackgroundLipoic Acid Metabolism in Microbial Pathogens
Spalding, M. D., & Prigge, S. T. (2010) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00008-10 · Cited by 193
Sirt6 Regulates Tnf-Alpha Secretion Through Hydrolysis of Long-Chain Fatty Acyl Lysine
Jiang, H. X., Khan, S., Wang, Y., Charron, G., He, B., Sebastián, C., Du, J., Kim, R., Ge, E. J., Mostoslavsky, R., et al. (2013) · Nature · doi:10.2210/pdb3zg6/pdb · Cited by 169 · cited 7×
“On the other hand, SIRT6 enhances a pro-inflammatory response by promoting the secretion of TNF- through lysine demyristoylation (13).”
BackgroundResultInfluentialSirtuin deacylases: a molecular link between metabolism and immunity
Preyat, N., & Léo, O. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.1112557 · Cited by 134 · cited 1×
“However, other studies suggest a pro-inflammatory effect on intracellular signaling (6).”
BackgroundYuan, C., Sidhu, R. S., Kuklev, D. V., Kado, Y., Wada, M., Song, I., & Smith, W. L. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808634200 · Cited by 131 · cited 12×
“Together, these results suggest that FFAs stimulate the deacetylase activity of SIRT6 by increasing the affinity of SIRT6 for an acetylated substrate by 35 times in the case of myristic acid.”
BackgroundMethodInfluentialTholstrup, T., Sandström, B., Bysted, A., & Hølmer, G. (2001) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/73.2.198 · Cited by 120 · cited 1×
“The EC50 values arewithin the range of postprandial levels of nonesterified FAs in mice (25) and humans (26).”
BackgroundMyristyl acylation of the tumor necrosis factor alpha precursor on specific lysine residues.
Stevenson, F. T., Bursten, S. L., Locksley, R. M., & Lovett, D. H. (1992) · The Journal of experimental medicine · doi:10.1084/jem.176.4.1053 · Cited by 117
Assays for mechanistic investigations of protein/histone acetyltransferases
Berndsen, C., & Denu, J. M. (2005) · Methods · doi:10.1016/j.ymeth.2005.03.002 · Cited by 76
Self-citationXu, J., Christian, B., & Jump, D. Β. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601277200 · Cited by 76 · cited 1×
“Importantly, a decrease in L-PK gene expression correlated with a reduction in H3 and H4 acetylation (34), indicating that FFAs have the ability to alter the histone acetylation status at specific genomic loci.”
BackgroundPlasmodium falciparum Sir2A Preferentially Hydrolyzes Medium and Long Chain Fatty Acyl Lysine
Zhu, A. Y., Zhou, Y., Khan, S., Deitsch, K., Hao, Q., & Lin, H. (2011) · ACS Chemical Biology · doi:10.1021/cb200230x · Cited by 67 · cited 3×
“TLC plates were analyzed by ImageQuant TL (GE Healthcare).”
BackgroundMethodFitting enzyme-kinetic data to
Northrop, D. B. (1983) · Analytical Biochemistry · doi:10.1016/0003-2697(83)90034-9 · Cited by 50
Quantitative Assays for Characterization of the Sir2 Family of NAD+-Dependent Deacetylases
Borra, M. T., & Denu, J. M. (2003) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(03)76011-x · Cited by 42 · cited 1×
“6- m, Phenomenex) by monitoring the formation of deacylated product at 214 nm, as described (21).”
MethodSelf-citationIntracellular targeting and functional analysis of single-chain Fv fragments in mammalian cells
Cardinale, A. (2004) · Methods · doi:10.1016/j.ymeth.2004.04.006 · Cited by 33
Gonçalves-de-Albuquerque, C. F., Burth, P., Younes-Ibrahim, M., Garcia, D. G., Bozza, P. T., Neto, H. C. C. F., & Faria, M. V. C. (2012) · Mediators of Inflammation · doi:10.1155/2012/601032 · Cited by 26 · cited 1×
“The EC50 values arewithin the range of postprandial levels of nonesterified FAs in mice (25) and humans (26).”
Background
Cited by
Sorted by citations
Cantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648
“For example, SIRT1, SIRT2, and SIRT3 can also act as effective decrotonylases (Bao et al., 2014; Feldman et al., 2013).”
BackgroundNAD+ metabolism and its roles in cellular processes during ageing
Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00313-x · Cited by 1,617
The growing landscape of lysine acetylation links metabolism and cell signalling
Choudhary, C., Weinert, B. T., Nishida, Y., Verdin, E., & Mann, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3841 · Cited by 1,324
NAD + in aging, metabolism, and neurodegeneration
Verdin, E. (2015) · Science · doi:10.1126/science.aac4854 · Cited by 1,319
Metabolic regulation of gene expression through histone acylations
Sabari, B. R., Zhang, D., Allis, C. D., & Zhao, Y. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.140 · Cited by 1,168
Metadata
- Authors
- Feldman, J. L., Baeza, J., & Denu, J. M.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Denu, John M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 288
- Issue
- 43
- Pages
- 31350-31356
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3829447
- OpenAlex
- W2061576857
- Cited by
- 637
- References
- 38
- Citations by year
- 2026: 23 · 2025: 34 · 2024: 36 · 2023: 44 · 2022: 50 · 2021: 61 · 2020: 55 · 2019: 53 · 2018: 66 · 2017: 47 · 2016: 73 · 2015: 53 · 2014: 37 · 2013: 5
- FWCI
- 26.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P30CA014520)
- National Institute of General Medical Sciences (GM-065386, R01GM065386, T32GM007215, R37GM059785)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- SIRT6, sirtuins, long-chain fatty acids, lysine acylation, histone H3, free fatty acids, enzyme activation, substrate specificity, myristoylation, NAD+-dependent deacetylase
- MeSH terms
- Acylation, Enzyme Activation, Fatty Acids, Histones, Humans, Hydrolysis, Sirtuins, Lipoylation, Sirtuin 1, Sirtuin 2, Sirtuin 3
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