The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.
SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine
Open accessAbstract
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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“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]
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 [15]
In the citing paper
“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]
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 [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
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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
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
Sirtuins in mammals: insights into their biological function
Michán, S., & Sinclair, D. A. (2007) · Biochemical Journal · doi:10.1042/bj20070140 · Cited by 1,750
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
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
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
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
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
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Items 701–717 of 717
BindingDB (2016) · UC San Diego · doi:10.7270/q2k35wgv
BindingDB Entry 50012971: Structural Basis for Activation of Human Sirtuin 6 by Fluvastatin.
BindingDB (2022) · UC San Diego · doi:10.7270/q208691t
BindingDB (2017) · UC San Diego · doi:10.7270/q2cj8cc2
BindingDB Entry 50044446: Discovery of novel and selective SIRT6 inhibitors.
BindingDB (2015) · UC San Diego · doi:10.7270/q2377b8b
BindingDB Entry 50018259: Emerging Therapeutic Potential of SIRT6 Modulators.
BindingDB (2024) · UC San Diego · doi:10.7270/q2mw2nb8
Doo, J. G., Kim, H. O., Choi, M., Park, M., Lee, J. M., Cha, Y. J., Kim, J. M., Kang, I. U., Kim, S. S., Park, D. C., et al. (2026) · Biomedicines · doi:10.3390/biomedicines14112528
Acetylation in the Control of Mitochondrial Metabolism and Integrity
Sack, M. N. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1227-8_8
Metadata
- 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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