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]
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“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]
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“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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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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