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

Abstract

SummaryAging 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.

A collection of toolkit strains reveals distinct localization and dynamics of membrane-associated transcripts in epithelia

“…The plates were allowed to dry at room temperature for 30 minutes, then L4 stage worms were picked to the vehicle and cycloheximide-containing plates. The worms were incubated for 2 h at 22 C (Papandreou et al, 2020;Rieckher et al, 2018). To perform the FRAP experiment, the worms were mounted on a 2% agar pad with 0.1% tetramisole and were photobleached in a small defined region of interest (ROI) with 3.95 s dwelling time at 25% transmission of a 40 mW argon laser using a Nikon A1R laser scanning confocal equipped with a 60x/ 1.40 NA oil immersion objective lens (Nikon, Tokyo, Japan).…”

eIF4E and Interactors from Unicellular Eukaryotes

“…This is due to different life stages requiring particular reprogramming of expressed proteins. As mentioned, different variants of eIF4E in conjunction with partner 4E-BPs also help to regulate mRNA selection under differing developmental conditions in multicellular eukaryotic organisms [1][2][3][4][5][6][7][8][9][10][11][12]. As mainly post-transcriptional regulation of gene expression exists for protozoans, it may require variations of initiation factors to favor expression of certain stage-specific mRNAs.…”

Eukaryotic initiation factor EIF-3.G augments mRNA translation efficiency to regulate neuronal activity

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