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Review
. 2012 May 1;3(3):307-21.
doi: 10.3945/an.112.002113.

Eukaryotic Initiation Factor 2 Phosphorylation and Translational Control in Metabolism

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Free PMC article
Review

Eukaryotic Initiation Factor 2 Phosphorylation and Translational Control in Metabolism

Thomas D Baird et al. Adv Nutr. .
Free PMC article

Abstract

Regulation of mRNA translation is a rapid and effective means to couple changes in the cellular environment with global rates of protein synthesis. In response to stresses, such as nutrient deprivation and accumulation of misfolded proteins in the endoplasmic reticulum, phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α~P) reduces general translation initiation while facilitating the preferential translation of select transcripts, such as that encoding activating transcription factor 4 (ATF4), a transcriptional activator of genes subject to the integrated stress response (ISR). In this review, we highlight the translational control processes regulated by nutritional stress, with an emphasis on the events triggered by eIF2α~P, and describe the family of eukaryotic initiation factor 2 kinases and the mechanisms by which each sense different stresses. We then address 3 questions. First, what are the mechanisms by which eIF2α~P confers preferential translation on select mRNA and what are the consequences of the gene expression induced by the ISR? Second, what are the molecular processes by which certain stresses can differentially activate eIF2α~P and ATF4 expression? The third question we address is what are the modes of cross-regulation between the ISR and other stress response pathways, such as the unfolded protein response and mammalian target of rapamycin, and how do these regulatory schemes provide for gene expression programs that are tailored for specific stresses? This review highlights recent advances in each of these areas of research, emphasizing how eIF2α~P and the ISR can affect metabolic health and disease.

Conflict of interest statement

Author disclosures: T.D. Baird and R.C. Wek, no conflicts of interest.

Figures

Figure 1
Figure 1
Regulation of translation initiation is a rapid means for coupling nutrient deprivation and other stress conditions with levels of protein synthesis. This illustration shows the dissociation of the 80S ribosome complex into the individual 40S and 60S ribosomal subunits, which participate in translation initiation in conjunction with additional translation factors to initiate protein synthesis. Cap-dependent initiation of translation can be divided into 2 key events: the binding of the eukaryotic initiation factor 4f complex to the 7-methyl guanosine 5′ cap and the subsequent recruitment and scanning of the 43S complex, composed of eIF2-GTP-Met-tRNAMeti and other translation initiation factors attached to the 40S ribosomal subunit. After recognition of the start codon by the scanning 43S preinitiation complex, a 60S subunit joins to form an actively translating 80S ribosome. During conditions of low stress and high nutrient availability, an abundance of active eukaryotic initiation factor (eIF) 4F and eIF2 ternary complexes promotes high levels of cap-dependent translation. Nutritional stresses, such as amino acid or glucose deprivation, signal for a rapid reduction in global translation through phosphorylation of eIF2α (eIF2α~P) and repression of mammalian target of rapamycin (mTORC)1. Enhanced eIF2α~P leads to inhibition of eIF2B and lowered exchange of eIF2-GDP to eIF2-GTP. mTORC1 can enhance cap-dependent translation by 2 mechanisms. First, mTORC1 enhances phosphorylation of 4E-BP1 and 4E-BP2, leading to release of this inhibitory protein from eIF4E, the cap-binding subunit of eIF4F. Second, mTORC1 triggers S6 kinase phosphorylation of eIF4B, which then associates with the eIF4A subunit of eIF4F, enhancing eIF4A helicase function that expedites ribosome scanning during translation. In addition to nutritional stresses, perturbations in ER function activates PERK-induced eIF2α~P, effectively reducing the influx of nascent peptides to the overloaded protein-folding machinery. GCN2, general control nonderepressible; GEF, guanine nucleotide exchange factor; mTORC1, mammalian target of rapamycin complex 1; PERK, PKR-like endoplasmic reticulum kinase; tRNA, transfer RNA.
Figure 2
Figure 2
A family of eukaryotic initiation factor (eIF) 2α kinases are activated in response to diverse stress conditions. The eIF2α kinases possess a related protein kinase domain (red box) that is flanked by distinct regulatory sequences, which facilitate induction of phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α~P) in response to different stress conditions. Due to differences in the length of the characteristic insert sequences shared among eukaryotic initiation fact (eIF) 2α kinases, the size of the protein kinase domain differs among family members. The eIF2α kinase general control nonderepressible (GCN) 2 contains a RWD sequence that associates with the activator protein GCN1, a partial kinase domain required for GCN2 activation, histidyl-tRNA synthetase–related sequences (HisRS) that directly bind uncharged tRNA, which accumulate during nutritional stress, and a carboxy terminal region that facilitates GCN2 dimerization and its ribosome association. Note many of the functional features of these domains are based on studies for yeast GCN2, which shares the same domain arrangement (6). PKR-like endoplasmic reticulum kinase (PERK) contains an endoplasmic reticulum (ER) transmembrane segment (TM) that divides this eukaryotic initiation factor (eIF) 2α kinase in 2. The carboxy terminal protein kinase domain catalyzes eIF2α~P. The amino terminal portion features a signal sequence (SS), facilitating translocation of this portion of PERK into the lumen of the ER, and sequences related to the unfolded protein response sensor IRE1, which are suggested to monitor accumulation of unfolded protein in this organelle. HRI contains 2 regions that bind to heme, 1 at the amino-terminal portion of HRI and the second in the insert region of the protein kinase domain, which can repress this eIF2α kinase (29). Low levels of iron lead to reduced amounts of heme in erythroid cells, which triggers a release from this repressing mechanism and enhanced eIF2α~P. As a consequence, the availability of heme is tightly coupled to globin synthesis, the predominant translation product in erythroid tissues. PKR participates in an antiviral defense mechanism triggered by interferon. Two double-stranded RNA binding motifs (dsRBM) associate with double-stranded RNA that can accumulate in cells infected by viruses, leading to PKR autophosphorylation and enhanced eIF2α~P (30). Lowered protein synthesis would reduce viral replication and proliferation. HisRS, histidyl-tRNA synthetase; Rib assoc, ribosome association; TM, transmembrane.
Figure 3
Figure 3
Mechanisms of preferential translation during phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α~P). A, In the delayed translation reinitiation model, 2 upstream open reading frames (uORF) (red boxes) in the 5′ leader of the ATF4 mRNA direct preferential translation (4). The 5′-proximal uORF1 is a positive-acting element that facilitates retention of the scanning 40S subunit and resumption of scanning 5′ to 3′, leading inevitably to reinitiation at a downstream start codon. During nonstressed conditions, when eIF2α~P is low and eukaryotic initiation factor (eIF) 2-GTP levels are abundant, the scanning ribosome readily acquires the eIF2 ternary complex (eIF-TC) and reinitiates translation at the next available uORF, i.e., uORF2. The reacquisition of eIF2-TC is indicated by the darker shading in the scanning 40S ribosome. The uORF2 overlaps out-of-frame with the coding sequence (blue box) and, when translated, prevents synthesis of ATF4, as depicted by the dissociation of the small and large subunits after termination of uORF2 translation. During nutrient deprivation and other stressful events, there is an increase in eIF2α~P, which lowers the levels of eIF2-GTP. As a consequence, the 40S ribosome, which continues scanning after the translation of uORF1, needs additional time to reacquire the limiting eIF2-TC. This delay in reinitiation of translation allows for the 40S ribosome to scan through the uORF2 initiation codon. During the interval between the initiation codons of the uORF2 and the ATF4 coding region, the 40S ribosome obtains the limiting eIF2-TC (dark shading) and translates the ATF4 open reading frame. B, Translation of CHOP mRNA is inhibited during nonstress conditions by the presence of a single inhibitory uORF, which, when translated, functions to block translation elongation or termination, as illustrated by the bar symbol. This inhibitory uORF encodes a 34-amino acid residue sequence that is well conserved among vertebrates (10). In the bypass model of translational control, stress-induced eIF2α~P facilitates leaky ribosome scanning through the inhibitory uORF, which is suggested to result from the poor Kozak context of the start codons in the uORF. Consequently, the scanning ribosome initiates translation at the CHOP coding region, which features an initiation codon containing a strong Kozak consensus sequence.
Figure 4
Figure 4
Transcriptional regulation of ATF4 enables differential expression of integrated stress response (ISR) genes. In response to nutritional deprivation and other diverse stress conditions, phosphorylation of eukaryotic initiation factor (eIF) 2α by general control nonderepressible (GCN) 2 or PKR-like endoplasmic reticulum kinase (PERK) represses global translation. Additionally, phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α~P) preferentially enhances the translation of ATF4. Increased levels of the ATF4 transcription factor triggers the transcription of a gene expression program collectively referred to as the ISR. Expression of ATF4 is also subject to transcriptional regulation. Transcriptional activation in response to the indicated stress conditions serves to provide high levels of mRNA available for preferential translation during eIF2α~P, thus enhancing the ISR. Alternatively, transcriptional repression reduces the levels of ATF4 mRNA available for translation. In this case, there is discordant induction of the ISR, with eIF2α~P reducing global protein synthesis, but low expression levels of ATF4 and its target genes. ER, endoplasmic reticulum.

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