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Curr Biol. 2019 Mar 4;29(5):737-749.e5. doi: 10.1016/j.cub.2019.01.029. Epub 2019 Feb 14.

Regulation of the Elongation Phase of Protein Synthesis Enhances Translation Accuracy and Modulates Lifespan.

Author information

1
Nutrition & Metabolism, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Centre for Biological Sciences, University of Southampton, Southampton, UK.
2
Departamento de Microbiologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
3
School of Biosciences, University of Kent, Canterbury, UK.
4
School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia; Hopwood Centre for Neurobiology, South Australian Health & Medical Research Institute, Adelaide, SA, Australia.
5
Nutrition & Metabolism, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
6
Centre for Biological Sciences, University of Southampton, Southampton, UK.
7
Nutrition & Metabolism, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Centre for Biological Sciences, University of Southampton, Southampton, UK; School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia; Hopwood Centre for Neurobiology, South Australian Health & Medical Research Institute, Adelaide, SA, Australia. Electronic address: christopher.proud@sahmri.com.

Abstract

Maintaining accuracy during protein synthesis is crucial to avoid producing misfolded and/or non-functional proteins. The target of rapamycin complex 1 (TORC1) pathway and the activity of the protein synthesis machinery are known to negatively regulate lifespan in many organisms, although the precise mechanisms involved remain unclear. Mammalian TORC1 signaling accelerates the elongation stage of protein synthesis by inactivating eukaryotic elongation factor 2 kinase (eEF2K), which, when active, phosphorylates and inhibits eEF2, which mediates the movement of ribosomes along mRNAs, thereby slowing down the rate of elongation. We show that eEF2K enhances the accuracy of protein synthesis under a range of conditions and in several cell types. For example, our data reveal it links mammalian (m)TORC1 signaling to the accuracy of translation. Activation of eEF2K decreases misreading or termination readthrough errors during elongation, whereas knocking down or knocking out eEF2K increases their frequency. eEF2K also promotes the correct recognition of start codons in mRNAs. Reduced translational fidelity is known to correlate with shorter lifespan. Consistent with this, deletion of the eEF2K ortholog or other factors implicated in translation fidelity in Caenorhabditis elegans decreases lifespan, and eEF2K is required for lifespan extension induced by nutrient restriction. Our data uncover a novel mechanism linking nutrient supply, mTORC1 signaling, and the elongation stage of protein synthesis, which enhances the accuracy of protein synthesis. Our data also indicate that modulating translation elongation and its fidelity affects lifespan.

KEYWORDS:

Caenorhabditis elegans; caloric restriction; eEF2; eEF2K; elongation; lifespan; mTOR; tRNA; translation fidelity

PMID:
30773367
DOI:
10.1016/j.cub.2019.01.029

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