Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response

By Phoebe D. Lu, H. Harding, D. Ron. Journal of Cell Biology, 2004

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Stress-induced eukaryotic translation initiation factor 2 (eIF2) α phosphorylation paradoxically increases translation of the metazoan activating transcription factor 4 (ATF4), activating the integrated stress response (ISR), a pro-survival gene expression program. Previous studies implicated the 5′ end of the ATF4 mRNA, with its two conserved upstream ORFs (uORFs), in this translational regulation. Here, we report on mutation analysis of the ATF4 mRNA which revealed that scanning ribosomes initiate translation efficiently at both uORFs and ribosomes that had translated uORF1 efficiently reinitiate translation at downstream AUGs. In unstressed cells, low levels of eIF2α phosphorylation favor early capacitation of such reinitiating ribosomes directing them to the inhibitory uORF2, which precludes subsequent translation of ATF4 and represses the ISR. In stressed cells high levels of eIF2α phosphorylation delays ribosome capacitation and favors reinitiation at ATF4 over the inhibitory uORF2. These features are common to regulated translation of GCN4 in yeast. The metazoan ISR thus resembles the yeast general control response both in its target genes and its mechanistic details.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3185cb5648aa87cc5381065535e4e09e421f6f06

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Citations in the corpus

The role for endoplasmic reticulum stress in diabetes mellitus. (2008, background): “During ER stress, however, the presence of high levels of eIF2 phosphorylation delays the capacitation of scanning ribosomes, favoring reinitiation at the ATF4 initiation codon and resulting in increased ATF4 translation (88, 89).”
Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action (2006, background): “This is the case for yeast GCN4 and mammalian activating transcription factor 4 (ATF-4), ATF-3, and CAT-1 mRNAs (79, 134, 232, 386).”
GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. (2005, positive): “These GCN2-responsive mRNAs include potent transcriptional regulators such as GCN4p in yeast (Natarajan et al., 2001) and ATF4 in animal cells (Harding et al., 2000a; Lu et al., 2004; Vattem and Wek, 2004).”
The endoplasmic reticulum stress response in immunity and autoimmunity (2008, background): “Interestingly, phosphorylated EIF2α increases the expression levels of the transcription factor ATF4 by bypassing the inhibitory upstream open reading frames in ATF4 mRNA that ordinarily impair translation under resting condition”
CG methylated microarrays identify a novel methylated sequence bound by the CEBPB|ATF4 heterodimer that is active in vivo (2013, background): “CEBPB is constitutively expressed in cells, while ATF4 protein is induced by cellular stress (Lu et al. 2004; Vattem and Wek 2004) and potentially heterodimerizes with CEBPB to bind new DNA sequences (Vinson et al.”
The integrated stress response (2016, positive): “…(S/T) eIF2 a kinases that are activated by distinct stress stimuli [12]. eIF2 a phosphorylation causes a reduction in global protein synthesis while allowing the translation of selected genes including activating transcription factor 4 (ATF4), aiding cell survival and recovery [13].”
From acute ER stress to physiological roles of the Unfolded Protein Response (2006, background): “The best-studied example in mammalian cells is the eIF2a phosphorylation-dependent translation of activating transcription factor 4 (ATF4) mRNA.(17,18)”
Ribosome profiling provides evidence that large non-coding RNAs do not encode proteins (2013, background): “(We note that overlapping translation can act as a regulatory mechanism [Lu et al., 2004] or even produce alternative functional proteins [e.g., Ink/ARF (Sharpless and DePinho, 1999)].)”