Translation of 5' leaders is pervasive in genes resistant to eIF2 repression
- Lomonosov Moscow State University, Russia
- University College Cork, Ireland
- Trinity College Dublin, Ireland
Abstract
Eukaryotic cells rapidly reduce protein synthesis in response to various stress conditions. This can be achieved by the phosphorylation-mediated inactivation of a key translation initiation factor, eIF2. However, the persistent translation of certain mRNAs is required for deployment of an adequate stress response. We carried out ribosome profiling of cultured human cells under conditions of severe stress induced with sodium arsenite. Although this led to a ~4.5-fold general translational repression, the protein coding ORFs of certain individual mRNAs exhibited resistance to the inhibition. Nearly all resistant transcripts possess at least one efficiently translated uORF that repress translation of the main coding ORF under normal conditions. Site specific mutagenesis of two identified stress resistant mRNAs (PPP1R15B and IFRD1) demonstrated that a single uORF is sufficient for eIF2-mediated translation control in both cases. Phylogenetic analysis suggests that at least two regulatory uORFs (namely in SLC35A4 and MIEF1) encode functional protein products.
Article and author information
Author details
Reviewing Editor
- Nahum Sonenberg, McGill University, Canada
Version history
- Received: July 12, 2014
- Accepted: January 22, 2015
- Accepted Manuscript published: January 26, 2015 (version 1)
- Version of Record published: February 13, 2015 (version 2)
Copyright
© 2015, Andreev et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Translation of 5' leaders is pervasive in genes resistant to eIF2 repression
eLife 4:e03971.
https://doi.org/10.7554/eLife.03971
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