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iScience. 2019 Oct 25;20:466-480. doi: 10.1016/j.isci.2019.09.031. Epub 2019 Sep 26.

Cross Talk between eIF2α and eEF2 Phosphorylation Pathways Optimizes Translational Arrest in Response to Oxidative Stress.

Author information

1
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: marisa3593@gmail.com.
2
School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research and Center for Stress Signaling Networks, Xiamen University, Xiamen 361102, China.
3
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
4
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research and Center for Stress Signaling Networks, Xiamen University, Xiamen 361102, China. Electronic address: dwolf@xmu.edu.cn.

Abstract

The cellular stress response triggers a cascade of events leading to transcriptional reprogramming and a transient inhibition of global protein synthesis, which is thought to be mediated by phosphorylation of eukaryotic initiation factor-2α (eIF2α). Using mouse embryonic fibroblasts (MEFs) and the fission yeast S. pombe, we report that rapid translational arrest and cell survival in response to hydrogen peroxide-induced oxidative stress do not rely on eIF2α kinases and eIF2α phosphorylation. Rather, H2O2 induces a block in elongation through phosphorylation of eukaryotic elongation factor 2 (eEF2). Kinetic and dose-response analyses uncovered cross talk between the eIF2α and eEF2 phosphorylation pathways, indicating that, in MEFs, eEF2 phosphorylation initiates the acute shutdown in translation, which is maintained by eIF2α phosphorylation. Our results challenge the common conception that eIF2α phosphorylation is the primary trigger of translational arrest in response to oxidative stress and point to integrated control that may facilitate the survival of cancer cells.

KEYWORDS:

Biological Sciences; Cell Biology; Molecular Biology; Molecular Mechanism of Gene Regulation; Molecular Microbiology

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