SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine.
SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine.
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Sir2 酶家族或 Sirtuins 被称为烟酰胺腺嘌呤二核苷酸 (NAD) 依赖性脱乙酰酶，与转录、基因组稳定性、代谢和寿命的调节有关。然而，七种哺乳动物去乙酰化酶中有四种在体外具有非常弱的脱乙酰酶活性。在这里，我们证明人类 Sirt6 可以有效地去除赖氨酸残基中的长链脂肪酰基，例如肉豆蔻酰基。 Sirt6 的晶体结构揭示了一个大的疏水口袋，可以容纳长链脂肪酰基。我们进一步证明Sirt6通过去除TNFα的K19和K20上的脂肪酰基修饰来促进肿瘤坏死因子α（TNFα）的分泌。已知蛋白质赖氨酸脂肪酰化发生在哺乳动物细胞中，但这种修饰的功能和调节机制尚不清楚。我们的数据表明蛋白质赖氨酸脂肪酰化是调节蛋白质分泌的新机制。 Sirt6 作为控制蛋白质赖氨酸脂肪酰化的酶的发现为研究以前被忽视的蛋白质翻译后修饰的生理功能提供了新的机会。
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 tumor necrosis factor α (TNFα) by removing the fatty acyl modification on K19 and K20 of TNFα. 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 suggest 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 the previously ignored protein posttranslational modification.
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影响因子：
4
作者：
Zhu, Anita Y.;Zhou, Yeyun;Khan, Saba;Deitsch, Kirk W.;Hao, Quan;Lin, Hening
通讯作者：
Lin, Hening
DOI：
10.1006/bbrc.2000.3000
发表时间：
2000-07-05
影响因子：
3.1
作者：
Frye, RA
通讯作者：
Frye, RA
神经沉默调节蛋白 6 (Sirt6) 消融会减弱体细胞生长并导致肥胖
DOI：
10.1073/pnas.1016306107
发表时间：
2010-12-14
影响因子：
11.1
作者：
Schwer, Bjoern;Schumacher, Bjoern;Alt, Frederick W.
通讯作者：
Alt, Frederick W.
影响因子：
3.7
作者：
Bruzzone S;Fruscione F;Morando S;Ferrando T;Poggi A;Garuti A;D'Urso A;Selmo M;Benvenuto F;Cea M;Zoppoli G;Moran E;Soncini D;Ballestrero A;Sordat B;Patrone F;Mostoslavsky R;Uccelli A;Nencioni A
通讯作者：
Nencioni A
影响因子：
64.5
作者：
Mostoslavsky, R;Chua, KF;Alt, FW
通讯作者：
Alt, FW