NDLI: Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Jiang, Li Narasimhan, Jana Wek, Ronald C. Zhou, Donghui Palam, L. Reddy Staschke, Kirk A.
Description	Author Affiliation: Zhou D ( Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.)
Abstract	Phosphorylation of eukaryotic initiation factor 2 (eIF2) is an important mechanism regulating global and gene-specific translation in response to different environmental stresses. Central to the eIF2 kinase response is the preferential translation of ATF4 mRNA, encoding a transcriptional activator of genes involved in stress remediation. In this report, we addressed whether there are additional transcription factors whose translational expression is regulated by eIF2 kinases. We show that the expression of the basic zipper transcriptional regulator ATF5 is induced in response to many different stresses, including endoplasmic reticulum stress, arsenite exposure, and proteasome inhibition, by a mechanism requiring eIF2 phosphorylation. ATF5 is subject to translational control as illustrated by the preferential association of ATF5 mRNA with large polyribosomes in response to stress. ATF5 translational control involves two upstream open reading frames (uORFs) located in the 5'-leader of the ATF5 mRNA, a feature shared with ATF4. Mutational analyses of the 5'-leader of ATF5 mRNA fused to a luciferase reporter suggest that the 5'-proximal uORF1 is positive-acting, allowing scanning ribosomes to reinitiate translation of a downstream ORF. During non-stressed conditions, when eIF2 phosphorylation is low, ribosomes reinitiate translation at the next ORF, the inhibitory uORF2. Phosphorylation of eIF2 during stress delays translation reinitiation, allowing scanning ribosomes to bypass uORF2, and instead translate the ATF5 coding region. In addition to translational control, ATF5 mRNA levels are significantly reduced in ATF4-/- mouse embryo fibroblasts, suggesting that ATF4 contributes to basal ATF5 transcription. These results demonstrate that eIF2 kinases direct the translational expression of multiple transcription regulators by a mechanism involving delayed translation reinitiation.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	11
Volume Number	283
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2008-03-14
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Activating Transcription Factor 4 Metabolism Activating Transcription Factors Eukaryotic Initiation Factor-2 Protein Biosynthesis Animals Enzyme Inhibitors Pharmacology Fibroblasts Mice Molecular Sequence Data Open Reading Frames Phosphorylation Research Support, N.I.H., Extramural Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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