A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy
A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy
复制标题
DOI：
10.1073/pnas.0712145105
复制
发表时间：
2008-03-04
影响因子：
11.1
通讯作者：
Finkel, Toren
中科院分区：
文献类型：
--
作者：
Lee, In Hye;Cao, Liu;Finkel, Toren
我们证明了NAD依赖性去乙酰化酶Sirt 1在自噬调节中的作用。特别是，Sirt 1的瞬时表达增加足以刺激自噬的基础速率。此外，我们发现Sirt 1（-/-）小鼠胚胎成纤维细胞在饥饿条件下不能完全激活自噬。用野生型而不是去乙酰化酶失活的Sirt 1突变体重建可以恢复这些细胞中的自噬。我们进一步证明了Sirt 1可以与自噬机制的几个重要组成部分形成分子复合物，包括自噬基因（Atg）5，Atg 7和Atg 8。在体外，Sirt 1可以以NAD依赖的方式直接使这些组分脱乙酰化。Sirt 1的缺乏导致已知在培养细胞以及胚胎和新生儿组织中自噬所需的蛋白质的乙酰化显著升高。最后，我们发现Sirt 1-/-小鼠部分类似于Atg 5（-/-）小鼠，包括受损细胞器的积累，能量稳态的破坏和围产期早期死亡率。此外，代谢底物丙酮酸的子宫内递送延长了Sirt 1-/-幼仔的存活。这些结果表明，Sirt 1去乙酰化酶是一个重要的自噬在体内调节器，并提供了一个联系sirtuin功能和整体细胞反应有限的营养。
We demonstrate a role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. In particular, transient increased expression of Sirt1 is sufficient to stimulate basal rates of autophagy. In addition, we show that Sirt1(-/-) mouse embryonic fibroblasts do not fully activate autophagy under starved conditions. Reconstitution with wild-type but not a deacetylase-inactive mutant of Sirt1 restores autophagy in these cells. We further demonstrate that Sirt1 can form a molecular complex with several essential components of the autophagy machinery, including autophagy genes (Atg)5, Atg7, and Atg8. In vitro, Sirt1 can, in an NAD-dependent fashion, directly deacetylate these components. The absence of Sirt1 leads to markedly elevated acetylation of proteins known to be required for autophagy in both cultured cells and in embryonic and neonatal tissues. Finally, we show that Sirt1-/- mice partially resemble Atg5(-/-) mice, including the accumulation of damaged organelles, disruption of energy homeostasis, and early perinatal mortality. Furthermore, the in utero delivery of the metabolic substrate pyruvate extends the survival of Sirt1-/- pups. These results suggest that the Sirt1 deacetylase is an important in vivo regulator of autophagy and provide a link between sirtuin function and the overall cellular response to limited nutrients.