drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans.
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.
Ching
Tsui-Ting
TT
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109,USA.
Paal
Alisha B
AB
Mehta
Avni
A
Zhong
Linda
L
Hsu
Ao-Lin
AL
D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D031204:Caloric Restriction; D004032:Diet; D039642:Eukaryotic Initiation Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008136:Longevity / Q000502:physiology*; D008969:Molecular Sequence Data; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D029742:Caenorhabditis elegans Proteins; C553179:DRR-2 protein, C elegans; C111495:EIF4H protein, human; D039642:Eukaryotic Initiation Factors; D017853:Phosphotransferases (Alcohol Group Acceptor); C472494:let-363 protein, C elegans; D038762:Ribosomal Protein S6 Kinases, 70-kDa
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