Li Wensheng, Gao Beixue, Lee Sang-Myeong, Bennett Karen, Fang Deyu
Department of Otolaryngology-Head & Neck Surgery, University of Missouri School of Medicine, One Hospital Dr., Columbia, MO 65212, USA.
Dev Cell. 2007 Feb;12(2):235-46. doi: 10.1016/j.devcel.2006.12.002.
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.
叉头转录因子DAF-16是秀丽隐杆线虫胰岛素/IGF-I信号通路的下游靶点，对寿命调节和抗逆性均不可或缺。目前，调控DAF-16转录激活的分子机制尚不清楚。在此，我们鉴定出一种E3泛素连接酶RLE-1（由E3调控寿命），它参与调控秀丽隐杆线虫的衰老过程。破坏秀丽隐杆线虫中RLE-1的表达可延长其寿命；寿命的延长是由于DAF-16蛋白水平升高，而非daf-16 mRNA水平的变化。我们还发现，RLE-1催化DAF-16的泛素化，导致其被蛋白酶体降解。在秀丽隐杆线虫中消除RLE-1的表达会导致DAF-16的转录激活增加及其在细胞核中的持续定位。在rle-1突变体中过表达DAF-16可延长线虫寿命，而在rle-1突变体中破坏DAF-16的表达则会逆转其长寿表型。因此，RLE-1是DAF-16的E3泛素连接酶，可调控秀丽隐杆线虫的衰老过程。
