SIRT3 Functions in the Nucleus in the Control of Stress-Related Gene Expression
SIRT3 Functions in the Nucleus in the Control of Stress-Related Gene Expression
复制标题
DOI：
10.1128/mcb.00822-12
复制
发表时间：
2012-12-01
影响因子：
5.3
通讯作者：
Reinberg, Danny
中科院分区：
文献类型：
--
作者：
Iwahara, Toshinori;Bonasio, Roberto;Reinberg, Danny
SIRT 3是NAD（+）依赖性蛋白脱乙酰酶的Sir 2家族的成员，其在许多生物体中促进长寿。SIRT 3的加工短形式是一种完善的线粒体蛋白，其脱乙酰酶活性调节各种代谢过程。然而，全长（FL）SIRT 3在细胞核中的存在及其功能的重要性仍然存在争议。我们以前的研究表明，核FL SIRT 3作为组蛋白脱乙酰酶的功能，是转录抑制时，人工招募到一个报告基因。在这里，我们报告说，核FL SIRT 3受到细胞应激条件下，包括氧化应激和紫外线照射的快速降解，而线粒体加工的形式是不受影响的。FL SIRT 3降解由泛素-蛋白酶体途径介导，至少部分通过SKP 2的泛素蛋白连接酶（E3）活性介导。最后，我们通过染色质免疫沉淀显示，一些核SIRT 3的靶基因在应激刺激引起的SIRT 3降解后被去抑制。因此，SIRT 3在细胞核中表现出以前未被认识到的作用，调节一些应激相关和细胞核编码的线粒体基因的表达。
SIRT3 is a member of the Sir2 family of NAD(+)-dependent protein deacetylases that promotes longevity in many organisms. The processed short form of SIRT3 is a well-established mitochondrial protein whose deacetylase activity regulates various metabolic processes. However, the presence of full-length (FL) SIRT3 in the nucleus and its functional importance remain controversial. Our previous studies demonstrated that nuclear FL SIRT3 functions as a histone deacetylase and is transcriptionally repressive when artificially recruited to a reporter gene. Here, we report that nuclear FL SIRT3 is subjected to rapid degradation under conditions of cellular stress, including oxidative stress and UV irradiation, whereas the mitochondrial processed form is unaffected. FL SIRT3 degradation is mediated by the ubiquitin-proteasome pathway, at least partially through the ubiquitin protein ligase (E3) activity of SKP2. Finally, we show by chromatin immunoprecipitation that some target genes of nuclear SIRT3 are derepressed upon degradation of SIRT3 caused by stress stimuli. Thus, SIRT3 exhibits a previously unappreciated role in the nucleus, modulating the expression of some stress-related and nuclear-encoded mitochondrial genes.