Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity
Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity
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DOI：
10.1073/pnas.0400593101
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发表时间：
2004-07-06
影响因子：
11.1
通讯作者：
Fukamizu, A
中科院分区：
文献类型：
--
作者：
Daitoku, H;Hatta, M;Fukamizu, A
长寿调节基因包括叉头转录因子FOXO和NAD依赖性组蛋白去乙酰化酶沉默信息调节因子2（Sir 2）。遗传学研究表明，Sir 2在胰岛素样信号传导途径中，在FOXO家族的一个成员-β-16上游的秀丽隐杆线虫中起到延长寿命的作用。然而，在Sir 2介导的长寿中需要α-16活性的分子机制仍然未知。在这里，我们表明，可逆乙酰化的Foxo 1（也称为WHIR），小鼠的β-16直系同源物，调节其反式激活功能。cAMP反应元件结合蛋白（CREB）结合蛋白在K242、K245和K262残基处结合并乙酰化Foxo 1，其修饰参与Foxo 1作为转录因子的减弱。相反，Sir 2在被cAMP-反应元件-结合蛋白-结合蛋白乙酰化的残基处结合Foxo 1并使其脱乙酰化。Sir 2被募集到含有胰岛素应答序列的启动子中，并以脱乙酰酶活性依赖的方式增加锰超氧化物歧化酶和p27（kip 1）的表达。我们的研究结果建立了Foxo 1作为Sir 2在哺乳动物系统中的直接和功能性靶点。
Longevity regulatory genes include the Forkhead transcription factor FOXO and the NAD-dependent histone deacetylase silent information regulator 2 (Sir2). Genetic studies demonstrate that Sir2 acts to extend lifespan in Caenorhabditis elegans upstream of DAF-16, a member of the FOXO family, in the insulin-like signaling pathway. However, the molecular mechanisms underlying the requirement of DAF-16 activity in Sir2-mediated longevity remain unknown. Here we show that reversible acetylation of Foxo1 (also known as WHIR), the mouse DAF-16 ortholog, modulates its trans-activation function. cAMP-response element-binding protein (CREB)-binding protein binds and acetylates Foxo1 at the K242, K245, and K262 residues, the modification of which is involved in the attenuation of Foxo1 as a transcription factor. Conversely, Sir2 binds and deacetylates Foxo1 at residues acetylated by cAMP-response element-binding protein-binding protein. Sir2 is recruited to insulin response sequence-containing promoter and increases the expression of manganese superoxide dismutase and p27(kip1) in a deacetylase-activity-dependent manner. Our findings establish Foxo1 as a direct and functional target for Sir2 in mammalian systems.