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.
Highlights
The idea that ATF4 is a common downstream target that integrates signaling from PERK and other eukaryotic initiation factor-2 (eIF2) kinases has led to the eIF2ϳP/ ATF4 pathway being collectively referred to as the integrated stress response (ISR) [4]
EIF2ϳP Is Required for CHOP Transcription and Translation— In response to ER stress, eIF2ϳP triggers preferential translation of ATF4 mRNA concurrent with repressed global translation initiation
The 5Ј-leader of the CHOP mRNA has a single upstream ORF (uORF), which is a significant barrier to CHOP translation in nonstressed conditions (Fig. 8)
Summary
With eIF2ϳP induced by stress, scanning ribosomes bypass the inhibitory uORF by a process suggested to involve reduced efficiency of translation at initiation codons with a poor Kozak consensus sequence. The wild-type CHOPLuc mRNA was found to be preferentially associated with large polysomes in MEF cells treated with thapsigargin, and this transcript was the most abundant in the disome fraction in the absence of stress (Fig. 5).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
