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

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

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. Xie et al. report that eukaryotic elongation factor 2 kinase (eEF2K), which impairs the rate of elongation, decreases misreading or termination readthrough errors and promotes the correct recognition of start codons in mRNAs. Depletion of the eEF2K ortholog or other factors implicated in translation fidelity in C. elegans decreases lifespan.

Caenorhabditis elegans, caloric restriction, eEF2, eEF2K, elongation, lifespan, mTOR, translation fidelity, tRNA
0960-9822
737-749.e5
Xie, Jianling
547a1c25-893b-4804-b316-8ac81562acac
de Souza Alves, Viviane
bfdecd90-78c3-43bc-aeee-853d0e5c5fc8
von der Haar, Tobias
e0121621-fc74-42b4-b736-8c1cb7e0bb4d
O'Keefe, Louise
a915b64a-6fbc-4643-a0dd-342b8ef0ed99
Lenchine, Roman V.
1cebfc53-4f7f-49e1-b3c2-52e4290dea20
Jensen, Kirk B.
19cbdf4f-25fb-408c-942f-a73ca1263542
Liu, Rui
5a222bd1-4bfc-4cf6-b541-185395423404
Coldwell, Mark J.
a3432799-ed45-4948-9f7a-2a284d3ec65c
Wang, Xuemin
d6bb4eb2-5687-46ed-b770-cceb22fd792e
Proud, Christopher G.
5832db56-9069-4617-a80d-08b069093dba
Xie, Jianling
547a1c25-893b-4804-b316-8ac81562acac
de Souza Alves, Viviane
bfdecd90-78c3-43bc-aeee-853d0e5c5fc8
von der Haar, Tobias
e0121621-fc74-42b4-b736-8c1cb7e0bb4d
O'Keefe, Louise
a915b64a-6fbc-4643-a0dd-342b8ef0ed99
Lenchine, Roman V.
1cebfc53-4f7f-49e1-b3c2-52e4290dea20
Jensen, Kirk B.
19cbdf4f-25fb-408c-942f-a73ca1263542
Liu, Rui
5a222bd1-4bfc-4cf6-b541-185395423404
Coldwell, Mark J.
a3432799-ed45-4948-9f7a-2a284d3ec65c
Wang, Xuemin
d6bb4eb2-5687-46ed-b770-cceb22fd792e
Proud, Christopher G.
5832db56-9069-4617-a80d-08b069093dba

Xie, Jianling, de Souza Alves, Viviane, von der Haar, Tobias, O'Keefe, Louise, Lenchine, Roman V., Jensen, Kirk B., Liu, Rui, Coldwell, Mark J., Wang, Xuemin and Proud, Christopher G. (2019) Regulation of the Elongation Phase of Protein Synthesis Enhances Translation Accuracy and Modulates Lifespan. Current Biology, 29 (5), 737-749.e5. (doi:10.1016/j.cub.2019.01.029).

Record type: Article

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. Xie et al. report that eukaryotic elongation factor 2 kinase (eEF2K), which impairs the rate of elongation, decreases misreading or termination readthrough errors and promotes the correct recognition of start codons in mRNAs. Depletion of the eEF2K ortholog or other factors implicated in translation fidelity in C. elegans decreases lifespan.

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More information

Accepted/In Press date: 11 January 2019
e-pub ahead of print date: 14 February 2019
Published date: 4 March 2019
Keywords: Caenorhabditis elegans, caloric restriction, eEF2, eEF2K, elongation, lifespan, mTOR, translation fidelity, tRNA

Identifiers

Local EPrints ID: 430955
URI: http://eprints.soton.ac.uk/id/eprint/430955
ISSN: 0960-9822
PURE UUID: a7175a64-8ba2-4490-b1c0-264bda627908
ORCID for Mark J. Coldwell: ORCID iD orcid.org/0000-0002-6243-3886

Catalogue record

Date deposited: 17 May 2019 16:30
Last modified: 07 Oct 2020 01:55

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