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Role of Eif2α Kinases in Translational Control and Adaptation to Cellular Stress

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Role of Eif2α Kinases in Translational Control and Adaptation to Cellular Stress Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Role of eIF2α Kinases in Translational Control and Adaptation to Cellular Stress Ronald C. Wek Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202–5126 Correspondence: [email protected] A central mechanism regulating translation initiation in response to environmental stress involves phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Phos- phorylation of eIF2α causes inhibition of global translation, which conserves energy and facilitates reprogramming of gene expression and signaling pathways that help to restore protein homeostasis. Coincident with repression of protein synthesis, many gene transcripts involved in the stress response are not affected or are even preferentially translated in response to increased eIF2α phosphorylation by mechanisms involving upstream open reading frames (uORFs). This review highlights the mechanisms regulating eIF2α kinases, the role that uORFs play in translational control, and the impact that alteration of eIF2α phosphorylation by gene mutations or small molecule inhibitors can have on health and disease. aintenance of protein homeostasis re- store protein homeostasis. Key themes in the Mquires appropriate regulation of transla- review will be the mechanisms regulating tion, as well as protein folding, transport, and eIF2α kinases, the role that upstream open read- degradative processes. Environmental stresses ing frames (uORFs) play in translational con- and physiological stimuli can rapidly disrupt trol, and the impact that altered P-eIF2α levels protein homeostasis, triggering cell-adaptive re- by gene mutations or small molecule inhibitors sponses that are critical to restore the integrity of can have on health and disease. the proteome. However, the functionality of the adaptive responses can decline or be altered PHOSPHORYLATION OF eIF2α DIRECTS with chronic stress or with aging, leading to dis- TRANSLATION CONTROL eases that can afflict multiple organs, including the neural system and those contributing to A major mechanism regulating the initiation metabolic health. This review addresses the phase of protein synthesis involves P-eIF2α at role of translational control in adaptive re- serine-51. The eIF2, combined with guanosine sponses to environmental stresses and the pro- triphosphate (GTP), is critical for providing ini- cesses by which phosphorylation of the α sub- tiator methionyl-transfer RNA (tRNA) (Met- α Met unit of eukaryotic initiation factor 2 (P-eIF2 ) tRNAi ) to the 43S preinitiation complex can modulate translation genome wide to re- that contains the small ribosomal subunit and Editors: Michael B. Mathews, Nahum Sonenberg, and John W.B. Hershey Additional Perspectives on Translation Mechanisms and Control available at www.cshperspectives.org Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a032870 1 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press R.C. Wek a myriad of additional translation initiation fac- phate), the large 60S ribosomal subunit then tors. In the predominant pathway, the preinitia- joins to form the 80S ribosome, which carries tion complex then combines with the 50-7-meth- out the elongation phase of protein synthesis. ylguanosine “cap” of messenger RNA (mRNA) To facilitate the next round of translation initia- and scans processively 50-to30- along the leader tion, GDP associated with eIF2 needs to be ex- of the transcript in search of an initiation codon. changed for GTP, a process catalyzed by a gua- Met Complementary binding of the Met-tRNAi nine nucleotide exchange factor, eIF2B. In to the start codon in the P site of the 40S ribo- response to diverse stresses, P-eIF2α alters this somal subunit triggers cessation of scanning and translation factor so that it binds tightly to a reg- hydrolysis of GTP associated with eIF2. Follow- ulatory portion of eIF2B, thus inhibiting the re- ing release of eIF2•GDP (guanosine diphos- cycling of eIF2•GDP to the active GTP-bound Amino acid starvation, ER stress, UV irradiation, high salinity, unfolded protein, proteasome inhibition, calcium release, viral infection lipid composition GCN2 PERK PP1 PP1 GADD34 CReP P (Ser-51) β α β α γ γ elF2 P-elF2 Global translation ATF4 bZIP Genes involved in dimerization ATF4 Transcription and translation, partner metabolism and transport, redox, and protein folding and processing Figure 1. Phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α) regulates global and gene- specific translation. The eIF2α kinases general control nonderepressible 2 (GCN2) and protein kinase R (PKR)- like endoplasmic reticulum (ER) kinase (PERK) are activated by nutritional stress or perturbations in the ER, respectively. Type 1 protein phosphatase complex (PP1c) combines with CReP to dephosphorylate eIF2α during basal conditions and GADD34 in feedback control of the integrated stress response (ISR). Phosphorylation of eIF2α reduces global translation initiation coincident with preferential translation of ATF4, encoding a basic zipper (bZIP) transcriptional activator that dimerizes with other transcript factors to regulate transcription of ISR genes that function in adaptation to stress. 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a032870 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press eIF2α Kinases and Translational Control form (Fig. 1). As a consequence, there is lowered translated gene is ATF4, which features uORFs • Met “ eIF2 GTP and delivery of the Met-tRNAi to embedded in its mRNA that serve as a bar ribosomes, culminating in a sharp reduction in code” for scanning ribosomes for selective global translation initiation. translation (Harding et al. 2000a; Lu et al. Repression of translation initiation is an ef- 2004; Vattem and Wek 2004). ATF4 is a basic ficient mechanism to conserve energy and nu- zipper (bZIP) transcription factor of genes in- trients, which are amply consumed by protein volved in nutrient import, metabolism, and al- synthesis. Furthermore, lowering general trans- leviation of oxidative stress (Harding et al. lation allow cells to reconfigure gene expression 2003). Because P-eIF2α and ATF4 are induced and signaling pathways that optimize stress al- by diverse stresses, this pathway is referred to as leviation. For example, arrest of translational the integrated stress response (ISR) (Harding initiation by increased levels of P-eIF2α leads et al. 2003). In mammals, there are four different to polysome disassembly that triggers formation eIF2α kinases, each containing distinct regula- of stress granules, which are cytosolic foci of tory domains that serve to sense the cell stress untranslated mRNAs and associated 40S ribo- environment through engagement with regula- somal subunits and proteins (Kedersha et al. tory ligands and proteins. This review will focus 2013; Ivanov et al. 2017). Stress granules serve on two of the eIF2α kinase family members, as a triage center, sorting incoming messenger general control nonderepressible 2 (GCN2 or ribonucleoproteins for mRNA decay or seques- EIFAK4) and protein kinase R (PKR)-like en- tration for eventual return to the cytoplasm for doplasmic reticulum (ER) kinase (PERK or translation. Therefore, stress granules are critical EIF2AK3), which respond to perturbations in for reprogramming gene expression. Signaling the cytosol and ER, respectively (Fig. 1). The proteins and enzymes can also be recruited to other eIF2α kinases include HRI (EIF2AK1), stress granules, influencing their respective cel- which primarily functions to balance globin lular pathways. synthesis with heme availability during erythro- Inhibition of global protein synthesis also poiesis, and PKR (EIF2AK2), which participates reshapes the proteome, as proteins that are labile in the innate immune response to viral infection. will rapidly be depleted from cells. The biolog- In the example of GCN2, starvation for ami- ical consequences of these proteomic changes no acids enhance P-eIF2α levels and translation- are shown by the activation of nuclear factor al control, which quickly limits incorporation of κB (NF-κB) in response to accumulation of P- amino acids into nascent polypeptides. In addi- eIF2α and ultraviolet (UV) irradiation (Wu et tion to the protein kinase domain, GCN2 has a al. 2004; Jiang and Wek 2005). NF-κB is a tran- regulatory region homologous to histidyl-tRNA scriptional regulator of genes involved in inflam- synthetase (HARS), which binds to uncharged mation, cell proliferation, and apoptosis, and is tRNAs that accumulate during deprivation for inhibited by binding to IκBα. Lowered synthesis nutrients (Wek et al. 1989, 1995; Dong et al. of IκBα as a consequence of induced P-eIF2α, 2000). Binding to uncharged tRNA is thought combined with rapid turnover of IκBα protein, to lead to conformational changes in GCN2 that causes a release of IκBα from NF-κBthatfacili- trigger autophosphorylation and release of in- tates NF-κB entry into the nucleus for targeted hibitory interactions between the regulatory re- transcriptional regulation. gions of GCN2 and the kinase domain, resulting in increased P-eIF2α (Lageix
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