The forkhead transcription factor, DAF-16, a downstream target of the insulin/IGF-I signaling pathway in C. elegans, is indispensable both for lifespan regulation and stress resistance. The molecular mechanisms involved in regulating DAF-16 transcriptional activation remain undefined. Here, we have identified an E3 ubiquitin ligase, RLE-1 (regulation of longevity by E3), which regulates aging in C. elegans. Disruption of RLE-1 expression in C. elegans increases lifespan; this extension of lifespan is due to elevated DAF-16 protein but not to changes of daf-16 mRNA levels. We have also found that RLE-1 catalyzes DAF-16 ubiquitination, leading to degradation by the proteasome. Elimination of RLE-1 expression in C. elegans causes increased transcriptional activation and sustained nuclear localization of DAF-16. Overexpression of DAF-16 in rle-1 mutants increases worm lifespan, while disruption of DAF-16 expression in rle-1 mutants reverses their longevity. Thus, RLE-1 is an E3 ubiquitin ligase of DAF-16 that regulates C. elegans aging.

译文

:叉头转录因子DAF-16是线虫中胰岛素/ IGF-1信号传导途径的下游靶标,对于寿命调节和抗逆性都是必不可少的。调节DAF-16转录激活所涉及的分子机制仍然不确定。在这里,我们已经确定了一种E3泛素连接酶RLE-1(E3调节寿命),该酶调节秀丽隐杆线虫的衰老。秀丽隐杆线虫中RLE-1表达的破坏增加了寿命;寿命的延长是由于DAF-16蛋白升高,而不是daf-16 mRNA水平的变化。我们还发现RLE-1催化DAF-16泛素化,导致蛋白酶体降解。消除秀丽隐杆线虫中的RLE-1表达会导致DAF-16的转录激活增加和持续的核定位。 DAF-16在rle-1突变体中的过表达延长了蠕虫的寿命,而在rle-1突变体中破坏DAF-16的表达则逆转了它们的寿命。因此,RLE-1是DAF-16的一种E3泛素连接酶,可调节秀丽线虫的衰老。

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