Cited by 717Sirtuins and Resveratrol in MedicineSphingolipid Metabolism and SignalingHistone Deacetylase Inhibitors Research

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

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Jiang, Hong, Khan, Saba, Wang, Yi, Charron, Guillaume, He, Bin, Sebastian, Carlos, Du, Jintang, Kim, Ray, Ge, Eva, Mostoslavsky, Raul, Hang, Howard C., Hao, Quan, Lin, Hening·2013·Nature

DOI 10.1038/nature12038PMC PMC3635073

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Abstract

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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Additional file 5 of Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant
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Additional file 3 of Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant
Fröhlich, J., Liorni, N., Mangoni, M., Lochmanová, G., Pírek, P., Kaštánková, N., Pata, P., Kucera, J., Chaldakov, G. N., Tonchev, A. B., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26752201
Additional file 1 of Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant
Fröhlich, J., Liorni, N., Mangoni, M., Lochmanová, G., Pírek, P., Kaštánková, N., Pata, P., Kučera, J., Chaldakov, G. N., Tonchev, A. B., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26752195
Additional file 1 of Sirt6 inhibition delays the onset of experimental autoimmune encephalomyelitis by reducing dendritic cell migration
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Additional file 8 of Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant
Fröhlich, J., Liorni, N., Mangoni, M., Lochmanová, G., Pírek, P., Kaštánková, N., Pata, P., Kučera, J., Chaldakov, G. N., Tonchev, A. B., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26752216
Additional file 10 of Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant
Fröhlich, J., Liorni, N., Mangoni, M., Lochmanová, G., Pírek, P., Kaštánková, N., Pata, P., Kucera, J., Chaldakov, G. N., Tonchev, A. B., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26752222
Additional file 7 of Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant
Fröhlich, J., Liorni, N., Mangoni, M., Lochmanová, G., Pírek, P., Kaštánková, N., Pata, P., Kucera, J., Chaldakov, G. N., Tonchev, A. B., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26752213
Additional file 6 of Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant
Fröhlich, J., Liorni, N., Mangoni, M., Lochmanová, G., Pírek, P., Kaštánková, N., Pata, P., Kučera, J., Chaldakov, G. N., Tonchev, A. B., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26752210
Additional file 2 of Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant
Fröhlich, J., Liorni, N., Mangoni, M., Lochmanová, G., Pírek, P., Kaštánková, N., Pata, P., Kucera, J., Chaldakov, G. N., Tonchev, A. B., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26752198
Additional file 4 of Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant
Fröhlich, J., Liorni, N., Mangoni, M., Lochmanová, G., Pírek, P., Kaštánková, N., Pata, P., Kucera, J., Chaldakov, G. N., Tonchev, A. B., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26752204
Additional file 11 of Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant
Fröhlich, J., Liorni, N., Mangoni, M., Lochmanová, G., Pírek, P., Kaštánková, N., Pata, P., Kucera, J., Chaldakov, G. N., Tonchev, A. B., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26752225
Additional file 9 of Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant
Fröhlich, J., Liorni, N., Mangoni, M., Lochmanová, G., Pírek, P., Kaštánková, N., Pata, P., Kucera, J., Chaldakov, G. N., Tonchev, A. B., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26752219
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BindingDB Entry 50001308: The mimics of N
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BindingDB Entry 50011830: Sensitive fluorogenic substrates for sirtuin deacylase inhibitor discovery.
BindingDB (2022) · UC San Diego · doi:10.7270/q26d5xmr
BindingDB Entry 50004507: Development of Peptide-Based Sirtuin Defatty-Acylase Inhibitors Identified by the Fluorescence Probe, SFP3, That Can Efficiently Measure Defatty-Acylase Activity of Sirtuin.
BindingDB (2021) · UC San Diego · doi:10.7270/q2hh6p91
BindingDB Entry 50045761: A FRET-based assay for screening SIRT6 modulators.
BindingDB (2016) · UC San Diego · doi:10.7270/q2ft8nrp
BindingDB Entry 50044838: Methyl effect in azumamides provides insight into histone deacetylase inhibition by macrocycles.
BindingDB (2016) · UC San Diego · doi:10.7270/q2fj2jcg
BindingDB Entry 50022773: Structure-Guided Discovery of Subtype Selective SIRT6 Inhibitors with a β-Carboline Skeleton for the Treatment of Breast Cancer.
BindingDB (2026) · UC San Diego · doi:10.7270/q2vh5tqs
BindingDB Entry 50045543: A FRET-based assay for screening SIRT5 specific modulators.
BindingDB (2016) · UC San Diego · doi:10.7270/q2mk6fkb
BindingDB Entry 50010551: An overview of Sirtuins as potential therapeutic target: Structure, function and modulators.
BindingDB (2021) · UC San Diego · doi:10.7270/q2w380vz
BindingDB Entry 50014255: Discovery of new human Sirtuin 5 inhibitors by mimicking glutaryl-lysine substrates.
BindingDB (2022) · UC San Diego · doi:10.7270/q2xg9vz4

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: Jiang, Hong
Khan, Saba
Wang, Yi
Charron, Guillaume
He, Bin
Ge, Eva
Hang, Howard C.
Hao, Quan
Lin, Hening
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2013-04
Volume: 496
Issue: 7443
Pages: 110-113
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature12038
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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SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine

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