SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine
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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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Some sirtuin family members mediate non-acetyl lysine acylations, such as succinylation, malonylation and fatty acid acylation, whose cellular functions are poorly understood.
“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 [14]
Several NAD+-dependent deacetylases, SIRT1, SIRT2, SIRT3 and SIRT6, have been previously reported to possess lysine defatty-acylation activities.
“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 [15]
The majority of fatty-acylated proteins have N-glycine myristoylation or S-palmitoylation, while only a few proteins have lysine fatty acylation.
“The majority of these fatty-acylated proteins have been reported to have N-glycine myristoylation or S-palmitoylation, while only a few proteins are reported to have lysine fatty acylation.15,34”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [15]
SIRT1, 2, 3 and SIRT6 are capable of hydrolyzing long chain fatty acyl groups from lysine residues.
“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 [15]
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[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475 · see citing works
The CCP4 suite: programs for protein crystallography
Number Collaborative Computational Project (1994) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444994003112 · Cited by 17,299 · see citing works
The TNF and TNF Receptor Superfamilies
Locksley, R. M., Killeen, N., & Lenardo, M. J. (2001) · Cell · doi:10.1016/s0092-8674(01)00237-9 · Cited by 3,650 · see citing works
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
Imai, S.-I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000) · Nature · doi:10.1038/35001622 · Cited by 3,510 · see citing works
Sirtuins in mammals: insights into their biological function
Michán, S., & Sinclair, D. A. (2007) · Biochemical Journal · doi:10.1042/bj20070140 · Cited by 1,719 · see citing works
Genomic 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 · see citing works
Self-citationSirt5 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 · see citing works
Self-citationPhylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins
Frye, R. A. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.3000 · Cited by 1,409 · see citing works
SIRT6 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 · see citing works
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 · see citing works
The 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 · see citing works
Self-citationSauve, A. A., Wolberger, C., Schramm, V. L., & Boeke, J. D. (2006) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.082803.133500 · Cited by 763 · see citing works
Large-scale profiling of protein palmitoylation in mammalian cells
Martin, B. R., & Cravatt, B. F. (2009) · Nature Methods · doi:10.1038/nmeth.1293 · Cited by 511 · see citing works
Posttranslational Modification of Proteins: Expanding Nature's Inventory
Walsh, C. T. (2005) · Cited by 484 · see citing works
Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6
Michishita, E., McCord, R. A., Boxer, L. D., Barber, M. F., Hong, T., Gozani, O., & Chua, K. F. (2009) · Cell Cycle · doi:10.4161/cc.8.16.9367 · Cited by 384 · see citing works
Structure 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 311 · see citing works
Robust Fluorescent Detection of Protein Fatty-Acylation with Chemical Reporters
Charron, G., Zhang, M. M., Yount, J. S., Wilson, J. P., Raghavan, A. S., Shamir, E. R., & Hang, H. C. (2009) · Journal of the American Chemical Society · doi:10.1021/ja810122f · Cited by 301 · see citing works
Self-citationVan Gool, F., Gallí, M., Gueydan, C., Kruys, V., Prevot, P.-P., Bedalov, A., Mostoslavsky, R., Alt, F. W., De Smedt, T., & Leo, O. (2009) · Nature Medicine · doi:10.1038/nm.1906 · Cited by 285 · see citing works
Self-citationThe 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 · see citing works
(2010) · doi:10.1074/jbc.m110.168039 · Cited by 207 · see citing works
Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity
Schwer, B., Schumacher, B., Lombard, D. B., Xiao, C., Kurtev, M. V., Gao, J., Schneider, J. I., Chai, H., Bronson, R. T., Tsai, L., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016306107 · Cited by 176 · see citing works
Bruzzone, S., Fruscione, F., Morando, S., Ferrando, T., Poggi, A. D., Garuti, A., D’Urso, A., Selmo, M., Benvenuto, F., Cea, M., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007897 · Cited by 171 · see citing works
Self-citationStevenson, F. T., Bursten, S. L., Fanton, C. P., Locksley, R. M., & Lovett, D. H. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.15.7245 · Cited by 147 · see citing works
Insights into the Sirtuin Mechanism from Ternary Complexes Containing NAD+ and Acetylated Peptide
Hoff, K. G., Avalos, J. L., Sens, K. L., & Wolberger, C. (2006) · Structure · doi:10.1016/j.str.2006.06.006 · Cited by 141 · see citing works
Wilson, J. P., Raghavan, A. S., Yang, Y., Charron, G., & Hang, H. C. (2010) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m110.001198 · Cited by 137 · see citing works
Self-citationMyristyl 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 · see citing works
Plasmodium 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 · see citing works
Self-citationSebastián, C., Serra, M., Yeramian, A., Serrat, N., Lloberas, J., & Celada, A. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.9.5898 · Cited by 54 · see citing works
Stephens, S. B., Dodd, R. D., Lerner, R. S., Pyhtila, B. M., & Nicchitta, C. V. (2008) · Methods in molecular biology · doi:10.1007/978-1-59745-033-1_14 · Cited by 47 · see citing works
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- [29]Sebastian C Deacetylase activity is required for STAT5-dependent GM-CSF functional activity in macrophages and differentiation to dendritic cells J Immunol 180 5898 5906 2008 18424709
Cited by
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Cantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648 · see citing works
NAD+ 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 · see citing works
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 · see citing works
Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype
Wiley, C. D., Velarde, M. C., Lecot, P., Liu, S., Sarnoski, E. A., Freund, A., Shirakawa, K., Lim, H. W., Davis, S. S., Ramanathan, A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.11.011 · Cited by 1,275 · see citing works
Functions and mechanisms of non-histone protein acetylation
Narita, T., Weinert, B. T., & Choudhary, C. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0081-3 · Cited by 1,232 · see citing works
Modulation of cellular processes by histone and non-histone protein acetylation
Shvedunova, M., & Akhtar, A. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00441-y · Cited by 975 · see citing works
Acetyl-CoA and the regulation of metabolism: mechanisms and consequences
Shi, L., & Tu, B. P. (2015) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2015.02.003 · Cited by 903 · see citing works
The sirtuin family in health and disease
Wu, Q., Zhang, T., Chen, H., Yu, X., Lv, J.-L., Liu, Y., Liu, Y., Zheng, G., Zhao, J.-Q., Wei, Y., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01257-8 · Cited by 891 · see citing works
Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence
Rajman, L., Chwalek, K., & Sinclair, D. A. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.02.011 · Cited by 865 · see citing works
Class I histone deacetylases (HDAC1–3) are histone lysine delactylases
Moreno-Yruela, C., Zhang, D., Wei, W., Bæk, M., Liu, W., Gao, J., Danková, D., Nielsen, A. L., Bolding, J. E., Yang, L., et al. (2022) · Science Advances · doi:10.1126/sciadv.abi6696 · Cited by 841 · see citing works
Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development
Baenke, F., Peck, B., Miess, H., & Schulze, A. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.011338 · Cited by 772 · see citing works
Feldman, J. L., Baeza, J., & Denu, J. M. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.c113.511261 · Cited by 637 · see citing works
“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.”
BackgroundSmall molecule SIRT1 activators for the treatment of aging and age-related diseases
Hubbard, B. P., & Sinclair, D. A. (2014) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.12.004 · Cited by 572 · see citing works
Interplay between Metabolism and Epigenetics: A Nuclear Adaptation to Environmental Changes
Etchegaray, J., & Mostoslavsky, R. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.05.029 · Cited by 521 · see citing works
Self-citationThe multifaceted functions of sirtuins in cancer
Chalkiadaki, A., & Guarente, L. (2015) · Nature reviews. Cancer · doi:10.1038/nrc3985 · Cited by 501 · see citing works
Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies
Jiang, H., Zhang, X., Chen, X., Aramsangtienchai, P., Tong, Z., & Lin, H. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00750 · Cited by 501 · see citing works
Self-citationSIRT1 in Neurodevelopment and Brain Senescence
Herskovits, A. Z., & Guarente, L. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.028 · Cited by 493 · see citing works
Sirtuins, a promising target in slowing down the ageing process
Grabowska, W., Sikora, E., & Bielak-Zmijewska, A. (2017) · Biogerontology · doi:10.1007/s10522-017-9685-9 · Cited by 470 · see citing works
Sirtuin activators and inhibitors: Promises, achievements, and challenges
Dai, H., Sinclair, D. A., Ellis, J. L., & Steegborn, C. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.03.004 · Cited by 463 · see citing works
“In addition exploiting their differing acyl selectivities (Feldman et al., 2013; Jiang et al., 2013; Roessler et al., 2014; Rajabi et al., 2017) yielded potent and/or isoform-specific inhibitors.”
BackgroundInfluentialSirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity
Mathias, R. A., Greco, T. M., Oberstein, A., Budayeva, H. G., Chakrabarti, R., Rowland, E. A., Kang, Y., Shenk, T., & Cristea, I. M. (2014) · Cell · doi:10.1016/j.cell.2014.11.046 · Cited by 430 · see citing works
Li, L., Shi, L., Yang, S., Yan, R., Zhang, D., Yang, J., He, L., Li, W., Yi, X., Sun, L., et al. (2016) · Nature Communications · doi:10.1038/ncomms12235 · Cited by 392 · see citing works
Evolution and functional cross‐talk of protein post‐translational modifications
Beltrão, P., Bork, P., Krogan, N. J., & van Noort, V. (2013) · Molecular Systems Biology · doi:10.1002/msb.201304521 · Cited by 379 · see citing works
The role of sirtuins in cardiac disease
Matsushima, S., & Sadoshima, J. (2015) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00053.2015 · Cited by 378 · see citing works
Sadhukhan, S., Liu, X., Ryu, D., Nelson, O. D., Stupinski, J. A., Li, Z., Chen, W., Zhang, S., Weiss, R. S., Locasale, J. W., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1519858113 · Cited by 376 · see citing works
Self-citationChromatin and beyond: the multitasking roles for SIRT6
Kugel, S., & Mostoslavsky, R. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2013.12.002 · Cited by 367 · see citing works
Self-citationThe Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy
Guo, L., Tian, Y., & Zhu, W. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.576946 · Cited by 358 · see citing works
Advances and Challenges of HDAC Inhibitors in Cancer Therapeutics
McClure, J. J., Li, X., & Chou, C. J. (2018) · Advances in cancer research · doi:10.1016/bs.acr.2018.02.006 · Cited by 356 · see citing works
Chemical reporters for biological discovery
Grammel, M., & Hang, H. C. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1296 · Cited by 345 · see citing works
Self-citationProtein acetylation in metabolism – metabolites and cofactors
Menzies, K. J., Zhang, H., Katsyuba, E., & Auwerx, J. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.181 · Cited by 331 · see citing works
SIRT4 is a lysine deacylase that controls leucine metabolism and insulin secretion
Anderson, K. A., Huynh, F. K., Fisher-Wellman, K., Stuart, J. D., Peterson, B. S., Douros, J. D., Wagner, G. R., Thompson, J. W., Madsen, A. S., Green, M. F., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.003 · Cited by 326 · see citing works
Bao, X., Wang, Y., Li, X., Li, X.-M., Liu, Z., Yang, T., Wong, C. F., Zhang, J., Hao, Q., & Li, X. D. (2014) · eLife · doi:10.7554/elife.02999 · Cited by 324 · see citing works
Self-citationNonenzymatic Protein Acylation as a Carbon Stress Regulated by Sirtuin Deacylases
Wagner, G. R., & Hirschey, M. D. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.03.027 · Cited by 319 · see citing works
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Baeza, J., Smallegan, M. J., & Denu, J. M. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.12.006 · Cited by 312 · see citing works
Selective Sirt2 inhibition by ligand-induced rearrangement of the active site
Rumpf, T., Schiedel, M., Karaman, B., Roessler, C., North, B. J., Lehotzky, A., Oláh, J., Ladwein, K. I., Schmidtkunz, K., Gajer, M., et al. (2015) · Nature Communications · doi:10.1038/ncomms7263 · Cited by 302 · see citing works
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Walsh, C. T., Tu, B. P., & Tang, Y. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00510 · Cited by 302 · see citing works
The Beneficial Roles of SIRT1 in Neuroinflammation-Related Diseases
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Sirtuins: guardians of mammalian healthspan
Giblin, W., Skinner, M. E., & Lombard, D. B. (2014) · Trends in Genetics · doi:10.1016/j.tig.2014.04.007 · Cited by 280 · see citing works
Fatty acylation of proteins: The long and the short of it
Resh, M. D. (2016) · Progress in Lipid Research · doi:10.1016/j.plipres.2016.05.002 · Cited by 277 · see citing works
Identification of a cellularly active SIRT6 allosteric activator
Huang, Z., Zhao, J., Deng, W., Chen, Y., Shang, J., Song, K., Zhang, L., Wang, C., Lu, S., Yang, X., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0150-0 · Cited by 277 · see citing works
Self-citationSchiedel, M., Herp, D., Hammelmann, S., Swyter, S., Lehotzky, A., Robaa, D., Oláh, J., Ovádi, J., Sippl, W., & Jung, M. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01872 · Cited by 275 · see citing works
Chen, B., Sun, Y., Niu, J., Jarugumilli, G. K., & Wu, X. (2018) · Cell chemical biology · doi:10.1016/j.chembiol.2018.05.003 · Cited by 274 · see citing works
Sirtuins in Epigenetic Regulation
Jing, H., & Lin, H. (2015) · Chemical Reviews · doi:10.1021/cr500457h · Cited by 271 · see citing works
Self-citationSIRT6: Novel Mechanisms and Links to Aging and Disease
Tasselli, L., Zheng, W., & Chua, K. F. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.10.002 · Cited by 267 · see citing works
A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation
Wagner, G. R., Bhatt, D. P., O’Connell, T. M., Thompson, J. W., Dubois, L. G., Backos, D. S., Yang, H., Mitchell, G. A., Ilkayeva, O. R., Stevens, R. D., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.006 · Cited by 258 · see citing works
The Substrate Specificity of Sirtuins
Bheda, P., Jing, H., Wolberger, C., & Lin, H. (2016) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060815-014537 · Cited by 247 · see citing works
Self-citationProtein acylation: mechanisms, biological functions and therapeutic targets
Shang, S., Liu, J., & Hua, F. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01245-y · Cited by 247 · see citing works
Sirtuin regulation in aging and injury
Poulose, N., & Raju, R. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.08.017 · Cited by 236 · see citing works
SIRT6, a Mammalian Deacylase with Multitasking Abilities
Chang, A. R., Ferrer, C. M., & Mostoslavsky, R. (2019) · Physiological Reviews · doi:10.1152/physrev.00030.2018 · Cited by 236 · see citing works
Self-citationJing, H., Hu, J., He, B., Abril, Y. L. N., Stupinski, J., Weiser, K., Carbonaro, M., Chiang, Y., Southard, T. L., Giannakakou, P., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.02.007 · Cited by 234 · see citing works
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Sinclair, D. A., & Guarente, L. (2011) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010611-134657 · Cited by 223 · see citing works
Flynn, E. M., Huang, O. W., Poy, F., Oppikofer, M., Bellon, S. F., Tang, Y., & Cochran, A. G. (2015) · Structure · doi:10.1016/j.str.2015.08.004 · Cited by 222 · see citing works
Alrob, O. A., Sankaralingam, S., Ma, C., Wagg, C. S., Fillmore, N., Jaswal, J. S., Sack, M. N., Lehner, R. S., Gupta, M. P., Michelakis, E. D., et al. (2014) · Cardiovascular Research · doi:10.1093/cvr/cvu156 · Cited by 221 · see citing works
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Tasselli, L., Xi, Y., Zheng, W., Tennen, R. I., Odrowaz, Z., Simeoni, F., Li, W., & Chua, K. F. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3202 · Cited by 213 · see citing works
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Jing, H., Hu, J., He, B., Abril, Y. L. N., Stupinski, J., Weiser, K., Carbonaro, M., Chiang, Y., Southard, T. L., Giannakakou, P., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.04.005 · Cited by 190 · see citing works
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Cao, J., Sun, L., Aramsangtienchai, P., Spiegelman, N. A., Zhang, X., Huang, W., Seto, E., & Lin, H. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1815365116 · Cited by 189 · see citing works
Self-citationFeldman, J. L., Dittenhafer‐Reed, K. E., Kudo, N., Thelen, J. N., Ito, A., Yoshida, M., & Denu, J. M. (2015) · Biochemistry · doi:10.1021/acs.biochem.5b00150 · Cited by 189 · see citing works
Sirtuins at the crossroads of stemness, aging, and cancer
O'Callaghan, C., & Vassilopoulos, A. (2017) · Aging Cell · doi:10.1111/acel.12685 · Cited by 187 · see citing works
The role of sirtuins in aging and age-related diseases
Wątroba, M., & Szukiewicz, D. (2015) · Advances in Medical Sciences · doi:10.1016/j.advms.2015.09.003 · Cited by 185 · see citing works
Efficient Demyristoylase Activity of SIRT2 Revealed by Kinetic and Structural Studies
Teng, Y.-B., Jing, H., Aramsangtienchai, P., He, B., Khan, S., Hu, J., Lin, H., & Hao, Q. (2015) · Scientific Reports · doi:10.1038/srep08529 · Cited by 184 · see citing works
Self-citationMetabolites Regulate Cell Signaling and Growth via Covalent Modification of Proteins
Figlia, G., Willnow, P., & Teleman, A. A. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.06.036 · Cited by 184 · see citing works
Dual Tumor Suppressor and Tumor Promoter Action of Sirtuins in Determining Malignant Phenotype
Carafa, V., Altucci, L., & Nebbioso, A. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00038 · Cited by 183 · see citing works
Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6
Tao, R., Xiong, X., DePinho, R. A., Deng, C., & Dong, X. C. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m039339 · Cited by 179 · see citing works
The role of mitochondrial sirtuins in health and disease
Osborne, B., Bentley, N. L., Montgomery, M. K., & Turner, N. A. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.197 · Cited by 179 · see citing works
NAD+ biosynthesis, aging, and disease
Johnson, S., & Imai, S. (2018) · F1000Research · doi:10.12688/f1000research.12120.1 · Cited by 178 · see citing works
Rider, P., Voronov, E., Dinarello, C. A., Apte, R. N., & Cohen, I. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601342 · Cited by 178 · see citing works
Emerging roles of SIRT6 in human diseases and its modulators
Liu, G., Chen, H., Liu, H., Zhang, W., & Zhou, J. (2020) · Medicinal Research Reviews · doi:10.1002/med.21753 · Cited by 177 · see citing works
Histone deacetylase 11 is a fatty-acid deacylase
Kutil, Z., Novakova, Z., Meleshin, M., Mikesova, J., Schutkowski, M., & Barinka, C. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.7b00942 · Cited by 174 · see citing works
Structure of p300 in complex with acyl-CoA variants
Kaczmarska, Z., Ortega, E. M., Goudarzi, A., Huang, H., KIM, S. ‐., Márquez, J. A., Zhao, Y., Khochbin, S., & Panne, D. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2217 · Cited by 174 · see citing works
Fan, Y., Yang, Q., Yang, Y., Gao, Z., Ma, Y., Zhang, L., Liang, W., & Ding, G. (2019) · International Journal of Biological Sciences · doi:10.7150/ijbs.29323 · Cited by 174 · see citing works
Sirtuins and their Biological Relevance in Aging and Age-Related Diseases
Zhao, L., Cao, J., Hu, K., He, X., Dou, Y., Tong, T., & Han, L. (2020) · Aging and Disease · doi:10.14336/ad.2019.0820 · Cited by 174 · see citing works
Understanding the Function of Mammalian Sirtuins and Protein Lysine Acylation
Wang, M., & Lin, H. (2021) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-082520-125411 · Cited by 171 · see citing works
Self-citationStructural Basis of Sirtuin 6 Activation by Synthetic Small Molecules
You, W., Rotili, D., Li, T., Kambach, C., Meleshin, M., Schutkowski, M., Chua, K. F., Mai, A., & Steegborn, C. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201610082 · Cited by 170 · see citing works
Sirtuin Inhibitors as Anticancer Agents
Hu, J., Jing, H., & Lin, H. (2014) · Future Medicinal Chemistry · doi:10.4155/fmc.14.44 · Cited by 168 · see citing works
Self-citationHistone Deacetylases in Bone Development and Skeletal Disorders
Bradley, E. W., Shull, L. C., van Wijnen, A. J., McGee‐Lawrence, M. E., & Westendorf, J. J. (2015) · Physiological Reviews · doi:10.1152/physrev.00004.2015 · Cited by 163 · see citing works
SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases
Guo, Z., Li, P., Ge, J., & Li, H. (2022) · Aging and Disease · doi:10.14336/ad.2022.0413 · Cited by 160 · see citing works
Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer
Kumar, S., & Lombard, D. B. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6213 · Cited by 158 · see citing works
Histone lysine crotonylation during acute kidney injury in mice
Ruiz‐Andrés, O., Sánchez-Niño, M. D., Cannata‐Ortiz, P., Ruiz‐Ortega, M., Egido, J., Ortíz, A., & Sanz, A. B. (2016) · Disease Models & Mechanisms · doi:10.1242/dmm.024455 · Cited by 158 · see citing works
Zhang, G., Deng, Y.-J., Xie, Q.-Q., Ren, E., Ma, Z., He, X., Gao, Y., & Kang, X. (2020) · Clinica Chimica Acta · doi:10.1016/j.cca.2020.04.016 · Cited by 157 · see citing works
Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway
Huang, H., Luo, Z., Qi, S., Huang, J. L., Xu, P., Wang, X., Gao, L. P., Li, F., Wang, J., Zhao, W., et al. (2017) · Cell Research · doi:10.1038/cr.2017.149 · Cited by 150 · see citing works
Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase
Moreno-Yruela, C., Galleano, I., Madsen, A. S., & Olsen, C. A. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2018.04.007 · Cited by 149 · see citing works
Natural polyphenols as sirtuin 6 modulators
Rahnasto‐Rilla, M., Tyni, J., Huovinen, M., Jarho, E. M., Kulikowicz, T., Ravichandran, S., Bohr, V. A., Ferrucci, L., Lahtela-Kakkonen, M. K., & Moaddel, R. (2018) · Scientific Reports · doi:10.1038/s41598-018-22388-5 · Cited by 149 · see citing works
Dynamic Protein Acylation: New Substrates, Mechanisms, and Drug Targets
Lanyon‐Hogg, T., Faronato, M., Serwa, R. A., & Tate, E. W. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.04.004 · Cited by 146 · see citing works
SIRT6 is a DNA double-strand break sensor
Onn, L., Portillo, M., Ilic, S., Cleitman, G., Stein, D., Kaluski, S., Shirat, I., Slobodnik, Z., Einav, M., Erdel, F., et al. (2020) · eLife · doi:10.7554/elife.51636 · Cited by 145 · see citing works
Sirtuins Are Evolutionarily Conserved Viral Restriction Factors
Koyuncu, E., Budayeva, H. G., Miteva, Y., Ricci, D. P., Silhavy, T. J., Shenk, T. E., & Cristea, I. M. (2014) · mBio · doi:10.1128/mbio.02249-14 · Cited by 144 · see citing works
Cold-Inducible SIRT6 Regulates Thermogenesis of Brown and Beige Fat
Yao, L., Cui, X., Chen, Q., Yang, X., Fang, F., Zhang, J., Liu, G., Jin, W., & Chang, Y. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.06.069 · Cited by 144 · see citing works
Sirtuins and Insulin Resistance
Zhou, S., Tang, X., & Chen, H. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00748 · Cited by 143 · see citing works
The chemical biology of sirtuins
Chen, B., Zang, W., Wang, J., Huang, Y., He, Y., Yan, L., Liu, J., & Zheng, W. (2015) · Chemical Society Reviews · doi:10.1039/c4cs00373j · Cited by 142 · see citing works
CPT 1A‐mediated succinylation of S100A10 increases human gastric cancer invasion
Wang, C., Zhang, C., Li, X., Shen, J., Xu, Y., Shi, H. M., Mu, X., Pan, J., Zhao, T., Li, M., et al. (2018) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13920 · Cited by 141 · see citing works
Ni, D., Wei, J., He, X., Rehman, A. U., Li, X., Qiu, Y., Pu, J., Lu, S., & Zhang, J. (2020) · Chemical Science · doi:10.1039/d0sc05131d · Cited by 137 · see citing works
A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis
He, T., Shang, J., Gao, C., Guan, X., Chen, Y., Zhu, L., Zhang, L., Zhang, C., Zhang, J., & Pang, T. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.11.002 · Cited by 137 · see citing works
Kuang, J., Zhang, Y., Liu, Q., Shen, J., Pu, S., Cheng, S., Chen, L., Li, H., Wu, T., Li, R., et al. (2017) · Diabetes · doi:10.2337/db16-1225 · Cited by 134 · see citing works
SIRT6 exhibits nucleosome-dependent deacetylase activity
Gil, R., Barth, S., Kanfi, Y., & Cohen, H. Y. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt642 · Cited by 133 · see citing works
Sirtuin‐dependent epigenetic regulation in the maintenance of genome integrity
Bosch‐Presegué, L., & Vaquero, A. (2015) · The FEBS Journal · doi:10.1111/febs.13053 · Cited by 132 · see citing works
The Natural History of ADP-Ribosyltransferases and the ADP-Ribosylation System
Aravind, L., Zhang, D., de Souza, R. F., Anand, S., & Iyer, L. M. (2014) · Current topics in microbiology and immunology · doi:10.1007/82_2014_414 · Cited by 132 · see citing works
Sirtuins, metabolism, and DNA repair
Choi, J.-E., & Mostoslavsky, R. (2014) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2014.05.005 · Cited by 132 · see citing works
Self-citationMetabolic Characterization of a Sirt5 deficient mouse model
Yu, J., Sadhukhan, S., Noriega, L. G., Moullan, N., He, B., Weiss, R. S., Lin, H., Schoonjans, K., & Auwerx, J. H. (2013) · Scientific Reports · doi:10.1038/srep02806 · Cited by 130 · see citing works
Self-citation
- Authors
- Jiang, H., Khan, S., Wang, Y., Charron, G., He, B., Sebastian, C., Du, J., Kim, R., Ge, E., Mostoslavsky, R., Hang, H. C., Hao, Q., & Lin, H.
- Affiliations
- Cornell University (US)
- University of Hong Kong (HK)
- Rockefeller University (US)
- Corresponding author
- Hao, Quan
- Lin, Hening
- ORCID
- Venue
- Nature
- Published
- 2013-04
- Volume
- 496
- Issue
- 7443
- Pages
- 110-113
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3635073
- OpenAlex
- W1972924731
- Cited by
- 697
- References
- 29
- Citations by year
- 2026: 29 · 2025: 36 · 2024: 43 · 2023: 44 · 2022: 60 · 2021: 54 · 2020: 58 · 2019: 49 · 2018: 56 · 2017: 61 · 2016: 72 · 2015: 63 · 2014: 47 · 2013: 24
- FWCI
- 32.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- National Cancer Institute (R01CA175727)
- National Institute of General Medical Sciences (R01GM093072, R01GM086703, R01GM087544)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088190)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- SIRT6, sirtuins, TNF-alpha secretion, myristoylation, protein secretion regulation, post-translational modification, NAD+-dependent deacetylase, crystal structure
- MeSH terms
- Acylation, Binding Sites, Fatty Acids, Humans, Hydrolysis, Lysine, Protein Processing, Post-Translational, Tumor Necrosis Factor-alpha, Crystallography, X-Ray, Sirtuins, Hydrophobic and Hydrophilic Interactions
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