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.
Highlights
The ability of most organisms to survive relies on their capability to rapidly trigger a coordinated systemic response upon nutrient or environmental stresses
A GCN-2-dependent phosphorylation of eIF2a under amino acid limitation In C. elegans, the sole homolog of yeast/mammalian general control nonderepressible 2 (GCN2) is encoded by the gene Y81G3A.3 and phosphorylates the eIF2a subunit at the putative phosphorylation site Ser49 (Nukazuka et al, 2008)
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)
Summary
The ability of most organisms to survive relies on their capability to rapidly trigger a coordinated systemic response upon nutrient or environmental stresses. Phosphorylation of eIF2a under stress results in inhibition of global protein synthesis, which is accompanied by favored translation of specific mRNAs that adapt the organism to stress These mRNAs include potent transcription factors such as GCN4 in yeast (Natarajan et al, 2001) and ATF4 in mammals (Harding et al, 2003). The proposed model for the translation of these mRNAs, under amino acid limitation, involves the upstream open reading frames (uORFs) that are located in their 5′-UTR (Tzamarias & Thireos, 1988; Vattem & Wek, 2004) These uORFs are preferentially translated in the nonstressed condition, leading to synthesis of incorrect peptides and precluding translation of the authentic gene initiation site (Hinnebusch, 2005). The inhibitory effect of eIF2a phosphorylation to the levels of the active ternary complex increases the probability that ribosomal scanning will bypass the uORFs, and translation re-initiation will occur at the canonical gcn or atf initiation site
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