The general control nonderepressible-2 kinase mediates stress response and longevity induced by target of rapamycin inactivation in Caenorhabditis elegans.
Bottom Line: 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.
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.Show MeSH
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Mentions: In C. elegans, the sole homolog of yeast/mammalian GCN2 is encoded by the gene Y81G3A.3 (gcn-2) and phosphorylates the eIF2α subunit at the putative phosphorylation site Ser49 (Nukazuka et al., 2008). Lately, it was shown that GCN-2 is required for the induced phospho-eIF2α levels during mitochondrial or osmotic stress (Baker et al., 2012; Lee & Strange, 2012), but its function during nutrient deprivation or other stresses has not been established. The predicted GCN-2 protein of 1696 amino acids shares 24.2% identity (40.7% similarity) with human HsGCN2 and 21% identity (35.3% similarity) with yeast ScGCN2 (EMBOSS Align-EMBL/EBI), having all the functional domains that characterize the kinase across species (Fig. 1A). To investigate the function of GCN-2, we used the existing gcn-2 mutants (ok871 and ok886), both of which have an in-frame deletion (Wormbase WS230), lacking part of the internal coding sequence (Fig. 1A). In both gcn-2 alleles, we detected a truncated mRNA transcript (lanes 1 and 2 in Fig. 1B, left pane) expressed at the same levels as the wild-type (N2) transcript (Fig. 1B, right pane). By measuring the basal levels of eIF2α phosphorylation in whole protein extracts of N2 worms subjected to gcn-2(RNAi) (lane 2 in Fig. 1C) or of each gcn-2 mutant (lanes 3–4 in Fig. 1C), compared to untreated animals (lane 1 in Fig. 1C), we verified that both ok871 and ok886 are loss-of-function alleles of gcn-2.
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.