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Cell Rep. 2018 Oct 2;25(1):199-211.e6. doi: 10.1016/j.celrep.2018.09.009.

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

Author information

1
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Heraklion 71110, Greece; Institute for Genome Stability in Ageing and Disease, Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, 50931 Cologne, Germany.
2
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Heraklion 71110, Greece.
3
Institute for Genome Stability in Ageing and Disease, Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital Cologne, 50931 Cologne, Germany.
4
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Heraklion 71110, Greece; Department of Basic Sciences, School of Medicine, University of Crete, Heraklion 71110, Greece. Electronic address: tavernarakis@imbb.forth.gr.

Abstract

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.

KEYWORDS:

aging; eukaryotic initiation factor 4E; mRNA decapping; mRNA translation; processing bodies; protein synthesis; proteostasis; stress response

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