drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans

Aging Cell. 2010 Aug;9(4):545-57. doi: 10.1111/j.1474-9726.2010.00580.x. Epub 2010 Apr 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Caenorhabditis elegans / cytology
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Caloric Restriction*
  • Diet*
  • Eukaryotic Initiation Factors / chemistry
  • Eukaryotic Initiation Factors / genetics
  • Eukaryotic Initiation Factors / metabolism*
  • Humans
  • Longevity / physiology*
  • Molecular Sequence Data
  • Phosphotransferases (Alcohol Group Acceptor) / chemistry
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • RNA Interference
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Sequence Homology, Amino Acid

Substances

  • Caenorhabditis elegans Proteins
  • DRR-2 protein, C elegans
  • EIF4H protein, human
  • Eukaryotic Initiation Factors
  • Phosphotransferases (Alcohol Group Acceptor)
  • let-363 protein, C elegans
  • Ribosomal Protein S6 Kinases, 70-kDa