Phosphorylation of eIF2 Facilitates Ribosomal Bypass of an Inhibitory Upstream ORF to Enhance CHOP Translation

• Published in: The Journal of biological chemistry Vol. 286; no. 13; pp. 10939 - 10949
• Main Authors: Palam, Lakshmi Reddy, Baird, Thomas D., Wek, Ronald C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Animals; Apoptosis - physiology; Cell Line; ER Stress; Eukaryotic Initiation Factor-2 - genetics; Eukaryotic Initiation Factor-2 - metabolism; Mice; Open Reading Frames - physiology; Phosphorylation - physiology; Protein Biosynthesis - physiology; Protein Synthesis; Protein Synthesis and Degradation; Ribosomes - genetics; Ribosomes - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stress, Physiological - physiology; Transcription Factor CHOP - biosynthesis; Transcription Factor CHOP - genetics; Translation; Translation Control; Translation Regulation; Translation; Protein Synthesis; ER Stress; Translation Regulation; Translation Control
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M110.216093

In response to different environmental stresses, phosphorylation of eukaryotic initiation factor-2 (eIF2) rapidly reduces protein synthesis, which lowers energy expenditure and facilitates reprogramming of gene expression to remediate stress damage. Central to the changes in gene expression, eIF2 phosphorylation also enhances translation of ATF4, a transcriptional activator of genes subject to the integrated stress response (ISR). The ISR increases the expression of genes important for alleviating stress or alternatively triggering apoptosis. One ISR target gene encodes the transcriptional regulator CHOP whose accumulation is critical for stress-induced apoptosis. In this study, we show that eIF2 phosphorylation induces preferential translation of CHOP by a mechanism involving a single upstream ORF (uORF) located in the 5′-leader of the CHOP mRNA. In the absence of stress and low eIF2 phosphorylation, translation of the uORF serves as a barrier that prevents translation of the downstream CHOP coding region. Enhanced eIF2 phosphorylation during stress facilitates ribosome bypass of the uORF due to its poor start site context, and instead it allows scanning ribosomes to translate CHOP. This new mechanism of translational control explains how expression of CHOP and the fate of cells are tightly linked to the levels of phosphorylated eIF2 and stress damage.