Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation

Lakshmi Reddy Palam, Thomas D. Baird, Ronald Wek

Research output: Contribution to journalArticle

173 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)10939-10949
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number13
DOIs
StatePublished - Apr 1 2011

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Eukaryotic Initiation Factor-2
Phosphorylation
Open Reading Frames
Genes
Ribosomes
Gene Expression
Gene expression
Apoptosis
Energy Metabolism
Scanning
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. / Palam, Lakshmi Reddy; Baird, Thomas D.; Wek, Ronald.

In: Journal of Biological Chemistry, Vol. 286, No. 13, 01.04.2011, p. 10939-10949.

Research output: Contribution to journalArticle

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