1. drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans
- Author
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Alisha B. Paal, Ao Lin Hsu, Avni Mehta, Tsui Ting Ching, and Linda Zhong
- Subjects
Genetics ,Aging ,Gene knockdown ,biology ,media_common.quotation_subject ,EIF4H ,Longevity ,Cell Biology ,biology.organism_classification ,Eukaryotic translation ,RNA interference ,Eukaryotic initiation factor ,Initiation factor ,Caenorhabditis elegans ,media_common - Abstract
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 Caenorhabditis elegans. Inhibition of drr-2 has been shown to increase longevity. However, the molecular mechanisms by which drr-2 influences 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.
- Published
- 2010