Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
PLoS Genet. 2011 Sep;7(9):e1002235. doi: 10.1371/journal.pgen.1002235. Epub 2011 Sep 1.
The conserved DAF-16/FOXO transcription factors and SIR-2.1/SIRT1 deacetylases are critical for diverse biological processes, particularly longevity and stress response; and complex regulation of DAF-16/FOXO by SIR-2.1/SIRT1 is central to appropriate biological outcomes. Caenorhabditis elegans Host Cell Factor 1 (HCF-1) is a longevity determinant previously shown to act as a co-repressor of DAF-16. We report here that HCF-1 represents an integral player in the regulatory loop linking SIR-2.1/SIRT1 and DAF-16/FOXO in both worms and mammals. Genetic analyses showed that hcf-1 acts downstream of sir-2.1 to influence lifespan and oxidative stress response in C. elegans. Gene expression profiling revealed a striking 80% overlap between the DAF-16 target genes responsive to hcf-1 mutation and sir-2.1 overexpression. Subsequent GO-term analyses of HCF-1 and SIR-2.1-coregulated DAF-16 targets suggested that HCF-1 and SIR-2.1 together regulate specific aspects of DAF-16-mediated transcription particularly important for aging and stress responses. Analogous to its role in regulating DAF-16/SIR-2.1 target genes in C. elegans, the mammalian HCF-1 also repressed the expression of several FOXO/SIRT1 target genes. Protein-protein association studies demonstrated that SIR-2.1/SIRT1 and HCF-1 form protein complexes in worms and mammalian cells, highlighting the conservation of their regulatory relationship. Our findings uncover a conserved interaction between the key longevity determinants SIR-2.1/SIRT1 and HCF-1, and they provide new insights into the complex regulation of FOXO proteins.
保守的 DAF-16/FOXO 转录因子和 SIR-2.1/SIRT1 去乙酰化酶对于各种生物过程至关重要，特别是寿命和应激反应；SIR-2.1/SIRT1 对 DAF-16/FOXO 的复杂调节是适当的生物学结果的核心。秀丽隐杆线虫宿主细胞因子 1（HCF-1）是先前被证明作为 DAF-16 的共阻遏物的长寿决定因素。我们在这里报告，HCF-1 是连接 SIR-2.1/SIRT1 和 DAF-16/FOXO 的调节环中的一个不可或缺的参与者，在蠕虫和哺乳动物中都是如此。遗传分析表明，hcf-1 作为 sir-2.1 的下游因子，影响秀丽隐杆线虫的寿命和氧化应激反应。基因表达谱分析显示，hcf-1 突变和 sir-2.1 过表达对 DAF-16 靶基因的影响有 80%的重叠。随后对 HCF-1 和 SIR-2.1 共同调控的 DAF-16 靶基因的 GO-term 分析表明，HCF-1 和 SIR-2.1 一起调节 DAF-16 介导的转录的特定方面，这些方面对于衰老和应激反应尤为重要。类似于其在调节秀丽隐杆线虫中的 DAF-16/SIR-2.1 靶基因的作用，哺乳动物的 HCF-1 也抑制了几个 FOXO/SIRT1 靶基因的表达。蛋白质-蛋白质相互作用研究表明，SIR-2.1/SIRT1 和 HCF-1 在蠕虫和哺乳动物细胞中形成蛋白质复合物，突出了它们调节关系的保守性。我们的发现揭示了关键长寿决定因素 SIR-2.1/SIRT1 和 HCF-1 之间的保守相互作用，并为 FOXO 蛋白的复杂调节提供了新的见解。
