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: The inhibitory effect of uORFs in the translation of the intact atf-5 mRNA was also greatly ameliorated in response to amino acid limitation, as this was recapitulated through RNAi-mediated silencing of AARSs genes. Transgenic BRF140 worms subjected to krs-1(RNAi) showed enhanced fluorescent signal in neurons, hypodermis, muscles, and intestine (Fig. 3). The fluorescence intensity in the few L3-arrested progeny (F1) of the RNAi-treated animals (P0) almost attained the brightness of BRF152 worms. This enhancement was dependent on GCN-2 function as we showed by expressing the same intact atf-5 transgene in the gcn-2(ok871) background (BRF144 in Fig. 3). Only the basal signal in varying cells and the autofluorescence of the intestine were observed. Similar results (Fig. S2) were obtained by inactivating an arginyl-tRNA synthetase (rrt-1) gene. The gcn-2-dependent induction of atf-5::gfp mirrored the gcn-2-dependent phosphorylation of eIF2α upon amino acid limitation. Consequently, direct inactivation of eIF2α by RNAi, instead of phosphorylation, bypasses the requirement for gcn-2 resulting in upregulation of atf-5::gfp transgene in both N2 and gcn-2 worms (Fig. S2). We also observed a gcn-2-independent induction of atf-5::gfp transgene after treatment of worms with a potent inducer of ER stress, tunicamycin (Fig. S2). Thus, the two uORFs direct the translational activation of the C. elegans atf-5 gene under nutrient or other stresses, in agreement with the yeast gcn4 and mammalian atf4 homologs.
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.