SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α
SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α
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DOI：
10.1074/jbc.m501485200
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发表时间：
2005-04-22
影响因子：
4.8
通讯作者：
Finkel, T
中科院分区：
文献类型：
--
作者：
Nemoto, S;Fergusson, MM;Finkel, T
在低等生物中，NAD依赖性脱乙酰酶Sir 2的表达增加可延长寿命。这种寿命延长的机制仍然不完全清楚。在这里，我们研究了SIRT 1（与Sir 2最接近的哺乳动物直系同源物）过表达的细胞效应。在PC 12细胞中，NAD依赖性去乙酰化酶SIRT 1的表达增加可使细胞耗氧量降低约25%。我们进一步证明，SIRT 1表达可以改变线粒体生物合成辅激活因子PGC-1 α的转录活性。此外，SIRT 1和PGC-1 α直接相互作用，可以作为分子复合物进行免疫共沉淀。SIRT 1的ADP-核糖基转移酶结构域中的单个氨基酸突变抑制SIRT 1与PGC-1 α的相互作用，但不影响SIRT 1与p53或Foxo 3a的相互作用。我们进一步表明PGC-1 α在体内被乙酰化。这种乙酰化通过用SIRT 1抑制剂烟酰胺处理或通过表达转录辅激活因子p300来增强。最后，我们证明了SIRT 1在体外和体内都催化PGC-1 α脱乙酰化。这些结果提供了sirtuins之间的直接联系，sirtuins是一个与寿命决定相关的蛋白质家族，PGC-1 α是一种调节细胞代谢的辅活化剂。
In lower organisms, increased expression of the NAD-dependent deacetylase Sir2 augments lifespan. The mechanism through which this life extension is mediated remains incompletely understood. Here we have examined the cellular effects of overexpression of SIRT1, the closest mammalian ortholog of Sir2. In PC12 cells, increased expression of the NAD-dependent deacetylase SIRT1 reduces cellular oxygen consumption by similar to 25%. We further demonstrate that SIRT1 expression can alter the transcriptional activity of the mitochondrial biogenesis coactivator PGC-1 alpha. In addition, SIRT1 and PGC-1 alpha directly interact and can be co-immunoprecipitated as a molecular complex. A single amino acid mutation in the putative ADP-ribosyltransferase domain of SIRT1 inhibits the interaction of SIRT1 with PGC-1 alpha but does not effect the interaction of SIRT1 with either p53 or Foxo3a. We further show that PGC-1 alpha is acetylated in vivo. This acetylation is augmented by treatment with the SIRT1 inhibitor nicotinamide or by expression of the transcriptional coactivator p300. Finally we demonstrate that SIRT1 catalyzes PGC-1 alpha deacetylation both in vitro and in vivo. These results provide a direct link between the sirtuins, a family of proteins linked to lifespan determination and PGC-1 alpha, a coactivator that regulates cellular metabolism.