Morley James F, Morimoto Richard I
Department of Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, USA.
Mol Biol Cell. 2004 Feb;15(2):657-64. doi: 10.1091/mbc.e03-07-0532. Epub 2003 Dec 10.
The correlation between longevity and stress resistance observed in long-lived mutant animals suggests that the ability to sense and respond to environmental challenges could be important for the regulation of life span. We therefore examined the role of heat shock factor (HSF-1), a master transcriptional regulator of stress-inducible gene expression and protein folding homeostasis, in the regulation of longevity. Down-regulation of hsf-1 by RNA interference suppressed longevity of mutants in an insulin-like signaling (ILS) pathway that functions in the nervous system of Caenorhabditis elegans to influence aging. hsf-1 was also required for temperature-induced dauer larvae formation in an ILS mutant. Using tissue-specific expression of wild-type or dominant negative HSF-1, we demonstrated that HSF-1 acts in multiple tissues to regulate longevity. Down-regulation of individual molecular chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals. However, suppression by individual chaperones was to a lesser extent, suggesting an important role for networks of chaperones. The interaction of ILS with HSF-1 could represent an important molecular strategy to couple the regulation of longevity with an ancient genetic switch that governs the ability of cells to sense and respond to stress.
在长寿突变动物中观察到的寿命与抗应激能力之间的相关性表明，感知和应对环境挑战的能力可能对寿命调节很重要。因此，我们研究了热休克因子（HSF-1）在寿命调节中的作用，HSF-1是应激诱导基因表达和蛋白质折叠稳态的主要转录调节因子。通过RNA干扰下调hsf-1可抑制秀丽隐杆线虫神经系统中发挥作用以影响衰老的胰岛素样信号（ILS）通路突变体的寿命。在ILS突变体中，温度诱导的滞育幼虫形成也需要hsf-1。使用野生型或显性负性HSF-1的组织特异性表达，我们证明HSF-1在多个组织中发挥作用以调节寿命。下调HSF-1的单个分子伴侣（转录靶点）也会降低长寿突变体而非野生型动物的寿命。然而，单个伴侣的抑制作用较小，表明伴侣网络具有重要作用。ILS与HSF-1的相互作用可能代表了一种重要的分子策略，将寿命调节与一个古老的遗传开关联系起来，该开关控制细胞感知和应对压力的能力。
