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A (dis)integrated stress response: Genetic diseases of eIF2α regulators

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Abstract The integrated stress response (ISR) is a conserved mechanism by which eukaryotic cells remodel gene expression to adapt to intrinsic and extrinsic stressors rapidly and reversibly. The ISR is initiated when stress‐activated protein kinases phosphorylate the major translation initiation factor eukaryotic translation initiation factor 2ɑ (eIF2ɑ), which globally suppresses translation initiation activity and permits the selective translation of stress‐induced genes including important transcription factors such as activating transcription factor 4 (ATF4). Translationally repressed messenger RNAs (mRNAs) and noncoding RNAs assemble into cytoplasmic RNA–protein granules and polyadenylated RNAs are concomitantly stabilized. Thus, regulated changes in mRNA translation, stability, and localization to RNA–protein granules contribute to the reprogramming of gene expression that defines the ISR. We discuss fundamental mechanisms of RNA regulation during the ISR and provide an overview of a growing class of genetic disorders associated with mutant alleles of key translation factors in the ISR pathway. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease Translation > Translation Regulation RNA in Disease and Development > RNA in Development
Schematic depicting the roles of the key factors that drive the ISR in translation initiation, stress‐induced gene expression, and stress granule (SG) formation. In unstressed cells, low levels of p‐eIF2ɑ enable high eIF2B function to generate abundant ternary complex (TC) comprised of eIF2, GTP, and Met‐tRNAi. High TC facilitates high global translation activity, suppressing stress‐induced gene expression, and SG formation. Upon stress, stress‐activated protein kinases (HRI, PKR, PERK, and GCN2) increase p‐eIF2ɑ levels and suppress the guanine exchange activity of eIF2B. Resulting limited TC causes reduced global translation activity, SG formation, and stress‐induced gene induction (e.g., ATF4 and PPP1R15A (GADD34)). The GADD34 protein interacts with PP1 to dephosphorylate p‐eIF2ɑ and reverse the ISR
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Diagram representing the predicted impacts of disease‐associated alleles of the CReP gene PPP1R15B and the eIF2ɑ kinase genes on the ISR. (a) Wild‐type cells undergo a normal ISR upon stress that is resolved with GADD34 induction. (b) Cells harboring mutations in PPP1R15B encoding CReP are predicted to reduce p‐eIF2ɑ dephosphorylation in unstressed cells. (c) Loss of eIF2ɑ kinase activity due to disease‐associated alleles of the genes encoding HRI (EIF2AK1), PKR (EIF2AK2), PERK (EIF2AK3), or GCN2 (EIF2AK4) are predicted to reduce eIF2ɑ phosphorylation upon stress
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Diagram depicting the possible impacts of alleles of EIF2S3 and EIF2B1–5 associated with MEHMO syndrome and vanishing White matter (VWM) disease, respectively, on translation initiation and the ISR. (a) In wild‐type cells, the guanine exchange activity of eIF2B ensures abundant ternary complex (TC) to enable translation initiation and suppress stress granule (SG) formation and stress‐induced gene expression. Cells harboring (b) EIF2S3 (eIF2γ) and (c) EIF2B1–5 (eIF2Bɑ, β, γ, δ, ε) mutations are predicted to impair TC formation and perturb translation initiation activity
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Polyadenylated RNA is localized to stress granules during arsenite stress. Human U‐2 OS cells stably expressing the stress granule protein GFP‐G3BP1 (green) were stressed with sodium arsenite (0.5 mM) for 45 min. Fluorescence in situ hybridization was performed with oligo(dT)‐Cy3 probes (red) to detect polyadenylated mRNAs, and nuclei were visualized with DAPI (scale bar 10 μM). Reprinted with permission from Moon et al., 2020.
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Diagrams depicting the protein domains of the integrated stress response protein kinases. HRI contains two heme‐binding (HB) sites and two kinase domains (KD). PKR contains two N‐terminal double‐stranded RNA‐binding domains (DSRBDs), and one KD. PERK contains a signal peptide (SP), a transmembrane domain (TM), and a cytoplasmically located KD. GCN2 contains a pseudokinase domain (PKD), a KD, a histidyl‐tRNA synthetase‐like domain (HisRS), and a ribosome‐binding (RB) region.
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Schematic depicting ATF4 translation during the integrated stress response. Two upstream open reading frames (uORFs) in the 5′ leader of ATF4 regulate its translation. (a) Ternary complex levels are abundant in unstressed conditions enabling the ribosome to recruit another ternary complex in time to reinitiate at the start codon of uORF 2 after translating uORF 1. Because uORF 2 overlaps with the primary ORF of ATF4, this inhibits synthesis of the ATF4 protein. (b) In contrast, ternary complex levels are limited in stressed conditions (i.e., when eIF2α is phosphorylated). As a result, the ribosome is unable to recruit another ternary complex in time to reinitiate at uORF 2, releasing the primary ORF from repression by uORF 2, and allowing ATF4 protein synthesis
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RNA in Disease and Development > RNA in Development
Translation > Translation Regulation
RNA in Disease and Development > RNA in Disease
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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