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

Xie, Jianling, de Souza Alves, Viviane, von der Haar, Tobias, O'Keefe, Louise, Lenchine, Roman V, Jensen, Kirk B, Liu, Riu, Coldwell, Mark J, Wang, Xuemin, Proud, Christopher G. and others. (2019) Regulation of the Elongation Phase of Protein Synthesis Enhances Translation Accuracy and Modulates Lifespan. Current Biology, 29 . pp. 1-13. ISSN 0960-9822. (doi:10.1016/j.cub.2019.01.029) (KAR id:72655)

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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.

Item Type: Article
DOI/Identification number: 10.1016/j.cub.2019.01.029
Uncontrolled keywords: Caenorhabditis elegans; caloric restriction; eEF2; eEF2K; elongation; lifespan; mTOR; tRNA; translation fidelity
Subjects: Q Science > QP Physiology (Living systems)
Q Science > QR Microbiology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Tobias von der Haar
Date Deposited: 20 Feb 2019 13:42 UTC
Last Modified: 14 Feb 2020 00:00 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/72655 (The current URI for this page, for reference purposes)
von der Haar, Tobias: https://orcid.org/0000-0002-6031-9254
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