Michishita Eriko, Park Jean Y, Burneskis Jenna M, Barrett J Carl, Horikawa Izumi
Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Mol Biol Cell. 2005 Oct;16(10):4623-35. doi: 10.1091/mbc.e05-01-0033. Epub 2005 Aug 3.
Sir2 is a NAD+-dependent protein deacetylase that extends lifespan in yeast and worms. This study examines seven human proteins homologous to Sir2 (SIRT1 through SIRT7) for cellular localization, expression profiles, protein deacetylation activity, and effects on human cell lifespan. We found that: 1) three nuclear SIRT proteins (SIRT1, SIRT6, and SIRT7) show different subnuclear localizations: SIRT6 and SIRT7 are associated with heterochromatic regions and nucleoli, respectively, where yeast Sir2 functions; 2) SIRT3, SIRT4, and SIRT5 are localized in mitochondria, an organelle that links aging and energy metabolism; 3) cellular p53 is a major in vivo substrate of SIRT1 deacetylase, but not the other six SIRT proteins; 4) SIRT1, but not the other two nuclear SIRT proteins, shows an in vitro deacetylase activity on histone H4 and p53 peptides; and 5) overexpression of any one of the seven SIRT proteins does not extend cellular replicative lifespan in normal human fibroblasts or prostate epithelial cells. This study supports the notion that multiple human SIRT proteins have evolutionarily conserved and nonconserved functions at different cellular locations and reveals that the lifespan of normal human cells, in contrast to that of lower eukaryotes, cannot be manipulated by increased expression of a single SIRT protein.
Sir2是一种依赖烟酰胺腺嘌呤二核苷酸（NAD+）的蛋白质脱乙酰酶，可延长酵母和蠕虫的寿命。本研究检测了七种与Sir2同源的人类蛋白质（SIRT1至SIRT7）的细胞定位、表达谱、蛋白质脱乙酰化活性以及对人类细胞寿命的影响。我们发现：1）三种核SIRT蛋白（SIRT1、SIRT6和SIRT7）表现出不同的亚核定位：SIRT6和SIRT7分别与异染色质区域和核仁相关，而酵母Sir2在这些区域发挥作用；2）SIRT3、SIRT4和SIRT5定位于线粒体，线粒体是一个将衰老与能量代谢联系起来的细胞器；3）细胞中的p53是SIRT1脱乙酰酶在体内的主要底物，但不是其他六种SIRT蛋白的底物；4）SIRT1，而非其他两种核SIRT蛋白，对组蛋白H4和p53肽段具有体外脱乙酰酶活性；5）七种SIRT蛋白中的任何一种过表达均不能延长正常人成纤维细胞或前列腺上皮细胞的细胞复制寿命。本研究支持这样一种观点，即多种人类SIRT蛋白在不同细胞位置具有进化上保守和不保守的功能，并揭示与低等真核生物不同，正常人细胞的寿命不能通过单一SIRT蛋白表达的增加来调控。
