Maintenance of Proteostasis by P Body-Mediated Regulation of eIF4E Availability during Aging in Caenorhabditis elegans

Abstract

Summary: Aging is accompanied by a pervasive collapse of proteostasis, while reducing general protein synthesis promotes longevity across taxa. Here, we show that the eIF4E isoform IFE-2 is increasingly sequestered in mRNA processing (P) bodies during aging and upon stress in Caenorhabditis elegans. Loss of the enhancer of mRNA decapping EDC-3 causes further entrapment of IFE-2 in P bodies and lowers protein synthesis rates in somatic tissues. Animals lacking EDC-3 are long lived and stress resistant, congruent with IFE-2-deficient mutants. Notably, neuron-specific expression of EDC-3 is sufficient to reverse lifespan extension, while sequestration of IFE-2 in neuronal P bodies counteracts age-related neuronal decline. The effects of mRNA decapping deficiency on stress resistance and longevity are orchestrated by a multimodal stress response involving the transcription factor SKN-1, which mediates lifespan extension upon reduced protein synthesis. Our findings elucidate a mechanism of proteostasis control during aging through P body-mediated regulation of protein synthesis in the soma. : Rieckher et al. uncover a mechanism modulating protein synthesis during aging in the Caenorhabditis elegans soma, through association of the mRNA translation initiation factor eIF4E with mRNA processing (P) bodies (PBs). Effects on longevity are mediated by attenuation of global protein synthesis in somatic tissues via the sequestration of eIF4E in PBs. Keywords: aging, eukaryotic initiation factor 4E, mRNA decapping, mRNA translation, processing bodies, protein synthesis, proteostasis, stress response