drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans.
drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans.
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DOI：
10.1111/j.1474-9726.2010.00580.x
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发表时间：
2010-08
期刊：
影响因子：
7.8
通讯作者：
Hsu AL
中科院分区：
文献类型：
--
作者：
Ching TT;Paal AB;Mehta A;Zhong L;Hsu AL
饮食限制(DR)导致了寿命的显著延长，同时在广泛的物种中保持了年轻得多的动物的生理。在这里，我们研究了DRR-2，一个最近发现的DR反应基因，在决定线虫寿命方面的作用。抑制DRR-2已被证明可以延长寿命。然而，DRR-2影响寿命的分子机制仍不清楚。我们报道了DRR-2编码人真核细胞翻译起始因子4H(EIF4H)的同源基因，其功能是介导mRNA翻译的起始步骤。DRR-2的分子功能通过DRR-2与多聚体的结合以及在DRR-2基因敲除动物中观察到的蛋白质合成速度的降低而得到验证。以前的研究也表明，DR可能会触发DRR-2表达的调节减少，从而启动其长寿反应。通过研究DRR-2表达增加对DR动物的影响，我们发现DRR-2在很大一部分对DR的长寿反应中是必不可少的。雷帕霉素(TOR)途径的营养传感靶点已被证明介导了DR在线虫中的长寿效应。我们的遗传分析结果表明，eIF4H/DRR-2在TOR下游发挥作用，但与S6K/PHA-4途径平行，介导DR的寿命效应。我们的发现共同揭示了eIF4H/DRR-2在TOR介导的DR长寿反应中的重要作用。
Dietary restriction (DR) results in a robust increase in lifespan while maintaining the physiology of much younger animals in a wide range of species. Here, we examine the role of drr-2, a DR-responsive gene recently identified, in determining the longevity of C. elegans. Inhibition of drr-2 has been shown to increase longevity. However, the molecular mechanisms by which drr-2 influence longevity remain unknown. We report here that drr-2 encodes an ortholog of human eukaryotic translation initiation factor 4H (eIF4H), whose function is to mediate the initiation step of mRNA translation. The molecular function of DRR-2 is validated by the association of DRR-2 with polysomes and by the decreased rate of protein synthesis observed in drr-2 knockdown animals. Previous studies have also suggested that DR might trigger a regulated reduction in drr-2 expression to initiate its longevity response. By examining the effect of increasing drr-2 expression on DR animals, we find that drr-2 is essential for a large portion of the longevity response to DR. The nutrient sensing target of rapamycin (TOR) pathway has been shown to mediate the longevity effects of DR in C. elegans. Results from our genetic analyses suggest that eIF4H/DRR-2 functions downstream of TOR, but in parallel to the S6K/PHA-4 pathway to mediate the lifespan effects of DR. Together, our findings reveal an important role for eIF4H/drr-2 in the TOR-mediated longevity responses to DR.
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