Translation of 5′ leaders is pervasive in genes resistant to eIF2 repression

eLife

Patrick BF O'Connor¹  Dmitry E Andreev²  Paul Cormican²  Sergey E Dmitriev²  Pavel V Baranov²  Ivan N Shatsky³  Derek W Morris³  Elaine M Kenny³  Ilya M Terenin³  Ciara Fahey⁴ 

[1] School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland;Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia;Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland;School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland;

关键词: upstream open reading frame;    eukaryotic initiation factor 2;    integrated stress response;    ribosome profiling;    5′ leader translation;    bicistronic mRNA;   

DOI  :  10.7554/eLife.03971

来源: DOAJ

【 摘 要 】

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, eukaryotic initiation factor 2 (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 5.4-fold general translational repression, the protein coding open reading frames (ORFs) of certain individual mRNAs exhibited resistance to the inhibition. Nearly all resistant transcripts possess at least one efficiently translated upstream open reading frame (uORF) that represses 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.

【 授权许可】

Unknown