The Evolutionarily Conserved Longevity Determinants HCF-1 and SIR-2.1/SIRT1 Collaborate to Regulate DAF-16/FOXO

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转录因子与SIR-2.1/SIRT1脱乙酰酶参与调控多种生物学过程，尤其在寿命调控与应激响应中发挥关键作用；而SIR-2.1/SIRT1对DAF-16/FOXO的复杂调控是实现恰当生物学效应的核心环节。秀丽隐杆线虫（Caenorhabditis elegans）的宿主细胞因子1（Host Cell Factor 1，HCF-1）是此前被证实可作为DAF-16共阻遏物的寿命调控决定因子。本研究报道，HCF-1是连接蠕虫与哺乳动物中SIR-2.1/SIRT1与DAF-16/FOXO调控环路的核心组成部分。遗传分析显示，在秀丽隐杆线虫中，hcf-1位于sir-2.1的下游，可影响线虫寿命与氧化应激响应能力。基因表达谱分析显示，响应hcf-1突变与sir-2.1过表达的DAF-16靶基因存在高达80%的显著重叠。随后对HCF-1与SIR-2.1共同调控的DAF-16靶基因进行基因本体（Gene Ontology，GO）注释分析，结果表明HCF-1与SIR-2.1共同调控DAF-16介导的转录的特定通路，该通路在衰老与应激响应中尤为关键。与秀丽隐杆线虫中调控DAF-16/SIR-2.1靶基因的功能类似，哺乳动物来源的HCF-1同样可阻遏若干FOXO/SIRT1靶基因的表达。蛋白质-蛋白质相互作用研究证实，SIR-2.1/SIRT1与HCF-1可在蠕虫与哺乳动物细胞中形成蛋白复合物，凸显二者调控关系的保守性。本研究揭示了关键寿命调控因子SIR-2.1/SIRT1与HCF-1之间的保守互作机制，为FOXO蛋白的复杂调控网络提供了新的研究视角。