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Eukaryotic Initiation Factor 5B (eIF5B) Cooperates with eIF1A and eIF5 to Facilitate uORF2-Mediated Repression of ATF4 Translation

1
Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive W, Lethbridge, AB T1K 3M4, Canada
2
Canadian Centre for Behavioral Neuroscience (CCBN), Department of Neuroscience, University of Lethbridge, 4401 University Drive W, Lethbridge, AB T1K 3M4, Canada
3
Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(12), 4032; https://doi.org/10.3390/ijms19124032
Received: 25 November 2018 / Revised: 8 December 2018 / Accepted: 10 December 2018 / Published: 13 December 2018
(This article belongs to the Special Issue Translational Control)
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Abstract

A variety of cellular stresses lead to global translation attenuation due to phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2), which decreases the availability of the eIF2-GTP-Met-tRNAi ternary complex. However, a subset of mRNAs continues to be translated by non-canonical mechanisms under these conditions. In fact, although translation initiation of activating transcription factor 4 (ATF4) is normally repressed by an upstream open reading frame (uORF), a decreased availability of ternary complex leads to increased translation of the main ATF4-coding ORF. We show here that siRNA-mediated depletion of eIF5B—which can substitute for eIF2 in delivering Met-tRNAi—leads to increased levels of ATF4 protein in mammalian cells. This de-repression is not due to phosphorylation of eIF2α under conditions of eIF5B depletion. Although eIF5B depletion leads to a modest increase in the steady-state levels of ATF4 mRNA, we show by polysome profiling that the depletion of eIF5B enhances ATF4 expression primarily at the level of translation. Moreover, eIF5B silencing increases the expression of an ATF4-luciferase translational reporter by a mechanism requiring the repressive uORF2. Further experiments suggest that eIF5B cooperates with eIF1A and eIF5, but not eIF2A, to facilitate the uORF2-mediated repression of ATF4 translation. View Full-Text
Keywords: eukaryotic initiation factor 5B (eIF5B); eIF1A; eIF2A; upstream open reading frames (uORFs); Activating Transcription Factor 4 (ATF4); eukaryotic initiation factor 2α (eIF2α) eukaryotic initiation factor 5B (eIF5B); eIF1A; eIF2A; upstream open reading frames (uORFs); Activating Transcription Factor 4 (ATF4); eukaryotic initiation factor 2α (eIF2α)
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Ross, J.A.; Bressler, K.R.; Thakor, N. Eukaryotic Initiation Factor 5B (eIF5B) Cooperates with eIF1A and eIF5 to Facilitate uORF2-Mediated Repression of ATF4 Translation. Int. J. Mol. Sci. 2018, 19, 4032.

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