The general control nonderepressible-2 kinase mediates stress response and longevity induced by target of rapamycin inactivation in Caenorhabditis elegans

Aging Cell. 2013 Oct;12(5):742-51. doi: 10.1111/acel.12101. Epub 2013 Jun 28.

Abstract

The general control nonderepressible 2 (GCN2) kinase is a nutrient-sensing pathway that responds to amino acids deficiency and induces a genetic program to effectively maintain cellular homeostasis. Here we established the conserved role of Caenorhabditis elegans GCN-2 under amino acid limitation as a translation initiation factor 2 (eIF2) kinase. Using a combination of genetic and molecular approaches, we showed that GCN-2 kinase activity plays a central role in survival under nutrient stress and mediates lifespan extension conferred by dietary restriction (DR) or inhibition of the major nutrient-sensing pathway, the target of rapamycin (TOR). We also demonstrated that the GCN-2 and TOR signaling pathways converge on the PHA-4/FoxA transcription factor and its downstream target genes to ensure survival of the whole organism under a multitude of stress conditions, such as nutrient scarcity or environmental stresses. This is one step forward in the understanding of evolutionary conserved mechanisms that confer longevity and healthspan.

Keywords: Caenorhabditis elegans; PHA-4; aging; general control nonderepressible 2; target of rapamycin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factors / genetics
  • Activating Transcription Factors / metabolism
  • Amino Acid Sequence
  • Animals
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Gene Expression
  • Longevity / drug effects
  • Longevity / genetics
  • Longevity / physiology*
  • Male
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Signal Transduction
  • Stress, Physiological / physiology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Activating Transcription Factors
  • Caenorhabditis elegans Proteins
  • Eukaryotic Initiation Factor-2
  • Protein Kinases
  • gcn-2 protein, C elegans
  • TOR Serine-Threonine Kinases