IMPACT is a GCN2 inhibitor that limits lifespan in Caenorhabditis elegans

Abstract

BackgroundThe General Control Nonderepressible 2 (GCN2) kinase is a conserved member of the integrated stress response (ISR) pathway that represses protein translation and helps cells to adapt to conditions of nutrient shortage. As such, GCN2 is required for longevity and stress resistance induced by dietary restriction (DR). IMPACT is an ancient protein that inhibits GCN2.ResultsHere, we tested whether IMPACT down-regulation mimics the effects of DR in C. elegans. Knockdown of the C. elegans IMPACT homolog impt-1 activated the ISR pathway and increased lifespan and stress resistance of worms in a gcn-2-dependent manner. Impt-1 knockdown exacerbated DR-induced longevity and required several DR-activated transcription factors to extend lifespan, among them SKN-1 and DAF-16, which were induced during larval development and adulthood, respectively, in response to impt-1 RNAi.ConclusionsIMPACT inhibits the ISR pathway, thus limiting the activation of stress response factors that are beneficial during aging and required under DR.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0301-2) contains supplementary material, which is available to authorized users.

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“…IMPACT is a protein-coding gene highly expressed in neuronal tissue of mammals, where it promotes neuronal development [70][71][72]. Noteworthily, it substantially contributes to the adaptive response to nutritional stress and dietary restriction (i.e., a reduction in food intake without malnutrition) [70].…”

“…IMPACT is a protein-coding gene highly expressed in neuronal tissue of mammals, where it promotes neuronal development [70][71][72]. Noteworthily, it substantially contributes to the adaptive response to nutritional stress and dietary restriction (i.e., a reduction in food intake without malnutrition) [70]. Under these stress conditions (e.g., amino acids depletion, proteasome inhibition, lack of glucose), IMPACT can inhibit a serine/threonine kinase coded by the General Control Non-derepressible 2 (GCN2) gene [70][71][72][73][74].…”

“…Noteworthily, it substantially contributes to the adaptive response to nutritional stress and dietary restriction (i.e., a reduction in food intake without malnutrition) [70]. Under these stress conditions (e.g., amino acids depletion, proteasome inhibition, lack of glucose), IMPACT can inhibit a serine/threonine kinase coded by the General Control Non-derepressible 2 (GCN2) gene [70][71][72][73][74]. This latter gene, which is not listed among the DEGs, confers an adaptive response through distinct biochemical reactions (e.g., phosphorylation) and stress response genes activation.…”

“…This latter gene, which is not listed among the DEGs, confers an adaptive response through distinct biochemical reactions (e.g., phosphorylation) and stress response genes activation. This cascade of events constitutes the Integrated Stress Response (ISR) pathway [70]. In addition to GCN2 inhibition, IMPACT overexpression also abrogates the phosphorylation of another GCN2 molecular target, i.e., the eukaryotic initiation factor 2, α subunit (eIF2α) [70,73].…”

“…This cascade of events constitutes the Integrated Stress Response (ISR) pathway [70]. In addition to GCN2 inhibition, IMPACT overexpression also abrogates the phosphorylation of another GCN2 molecular target, i.e., the eukaryotic initiation factor 2, α subunit (eIF2α) [70,73]. Interestingly, IMPACT, GCN2 and ISR "molecular sensors" contribute substantially to immune system regulation [71,72,74,75].…”