CHOPing Away at Stress Damage♦

♦ See referenced article, J. Biol. Chem. 2011, 286, 10939–10949

In response to environmental stress, cells undergo rapid changes in global and gene-specific translation. A central player in this change in translational control is eIF2, which becomes phosphorylated under stress and rapidly reduces protein synthesis, thus lowering energy expenditure and facilitating reprogramming of gene expression to remediate stress damage. In this Paper of the Week, Lakshmi Reddy Palam and colleagues show that the stress-induced phosphorylation of eIF2 causes preferential translation of the transcriptional regulator CHOP by a mechanism involving a single upstream ORF (uORF) located in the 5′-leader of the CHOP mRNA. The accumulation of CHOP is critical for stress-induced apoptosis. In the absence of stress and during low eIF2 phosphorylation, translation of the uORF prevents translation of the downstream CHOP coding region. However, during stress, enhanced eIF2 phosphorylation causes ribosomes to bypass the uORF and instead translate the CHOP open reading frame. 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.

Phosphorylation of eIF2α facilitates ribosome bypass of an inhibitory uORF, which enhances translation of the CHOP coding region.