title: The general control nonderepressible-2 kinase mediates stress response and longevity induced by target of rapamycin inactivation in Caenorhabditis elegans.
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.
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Center of Basic Research II, Athens, 11527, Greece; School of Medicine, University of Athens, Athens, 11527, Greece.
authors.forename: Aris
authors.initials: A
authors.lastname: Rousakis
authors.forename: Arsenios
authors.initials: A
authors.lastname: Vlassis
authors.forename: Anna
authors.initials: A
authors.lastname: Vlanti
authors.forename: Stefania
authors.initials: S
authors.lastname: Patera
authors.forename: George
authors.initials: G
authors.lastname: Thireos
authors.forename: Popi
authors.initials: P
authors.lastname: Syntichaki
mesh_terms: D051696:Activating Transcription Factors / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D015870:Gene Expression; D008136:Longevity / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051696:Activating Transcription Factors; D029742:Caenorhabditis elegans Proteins; D015852:Eukaryotic Initiation Factor-2; D011494:Protein Kinases; C578467:gcn-2 protein, C elegans; D058570:TOR Serine-Threonine Kinases
keywords: Caenorhabditis elegans; PHA-4; aging; general control nonderepressible 2; target of rapamycin