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Selective mRNA translation by eIF2 phosphorylation during ER stress
Author(s) -
Wek Ronald C,
Baird Thomas D,
Palam Lakshmi Reddy
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.551.10
Subject(s) - polysome , unfolded protein response , integrated stress response , translation (biology) , eif2 , translational regulation , ribosome , endoplasmic reticulum , messenger rna , protein biosynthesis , initiation factor , microbiology and biotechnology , eukaryotic initiation factor , atf4 , biology , chemistry , gene , biochemistry , rna
When the protein flux into the endoplasmic reticulum exceeds its folding capacity, a condition referred to as ER stress, there is an induction of translational and transcriptional gene expression designed to alleviate the underlying stress. This Unfolded Protein Response (UPR) features a global decrease in translation, which is facilitated by PERK phosphorylation of eIF2 (eIF2~P). Coincident with global translational control, eIF2~P directs the preferential translation of mRNAs induced by the UPR. In this study, we use sucrose gradient ultracentrifugation and a genome‐wide microarray approach to measure changes in translational efficiencies for individual mRNAs during ER stress. We find that while many transcripts are repressed during eIF2~P, some appear resistant to stress, while a subset is preferentially translated. ATF5 mRNA showed the greatest shift towards higher polysomes during ER stress. Translation of ATF5 is controlled by a mechanism of delayed ribosome reinitiation. Additionally, CHOP mRNA was shifted substantially towards the higher polysome fractions via a ribosomal bypass of an inhibitory uORF situated in the 5′‐leader of the mRNA. Lastly, we report novel mRNAs involved in protein turnover and synthesis and mRNA processing, which are preferentially translated. Identification of novel preferentially translated genes identifies new control schemes for key regulatory steps in the UPR.