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Regulation of translation initiation factor eIF2B at the hub of the integrated stress response

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Phosphorylation of the translation initiation factor eIF2 is one of the most widely used and well‐studied mechanisms cells use to respond to diverse cellular stresses. Known as the integrated stress response (ISR), the control pathway uses modulation of protein synthesis to reprogram gene expression and restore homeostasis. Here the current knowledge of the molecular mechanisms of eIF2 activation and its control by phosphorylation at a single‐conserved phosphorylation site, serine 51 are discussed with a major focus on the regulatory roles of eIF2B and eIF5 where a current molecular view of ISR control of eIF2B activity is presented. How genetic disorders affect eIF2 or eIF2B is discussed, as are syndromes where excess signaling through the ISR is a component. Finally, studies into the action of recently identified compounds that modulate the ISR in experimental systems are discussed; these suggest that eIF2B is a potential therapeutic target for a wide range of conditions. This article is categorized under: Translation > Translation Regulation
Overview of translational control of eIF2 during the ISR. Left, main steps in activation of eIF2 for translation that typically repress uORF mediated translation. Right, ISR by reversible phosphorylation of eIF2α (red arrows) mediated by specific kinases (red text and arrows) to promote uORF translation and that is reversed by the action of PP1 phosphatase complexes (green text and arrows)
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ISRIB binds at the eIF2Bβδ dimer interface. Top view (a) and front zoom view (b) of ISRIB (red) binding to human eIF2B decamer, from cryo‐EM analyses (PDB file 6CAJ) (Tsai et al., )
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Model for eIF2/eIF2B interactions during eIF2 activation and in the ISR. Cartoon model of eIF2 activation (black arrows, steps 1–6) and the ISR (red arrows, steps 7–10) based on the structures shown in Figures and and the interactions described in detail in the text. Subunit‐colored curved arrows are used to indicate movement or conformational flexibility
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The structure of eIF2B. (a) “Top view” of the eIF2B decamer from Schizosaccharomyces pombe (PDB file 5B04) (Kashiwagi et al., ) showing one half of the regulatory core and catalytic arm 1 as both transparent surface and SSE and catalytic arm 2 as SSE only. One copy of the independent 2BεGEF domain from Saccharomyces cerevisiae (PDB file 1PAQ) (Boesen, Mohammad, Pavitt, & Andersen, ) is also shown with SSE and transparent surface. Residues discussed in the text are highlighted. (b) Rotated views of eIF2B decamer as in panel (a), with one half in SSE only view. “Front” view (left) showing the (2Bβδ)2 core and “back” view (right) showing the 2Bα dimer. (c) Cartoons showing intersubunit interactions as lines connecting circles representing each subunit within the decamer (top) and eIF2 interaction regions (bottom)
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The structure of eIF2 TC. (a) eIF2 bound to tRNAiMet and the GTP analog GDPCP, drawn with Chimera software using the PDB file 3JAP. A transparent surface and secondary structure elements (SSE) are shown. Ser51 is highlighted in space‐fill (red). eIF2 shown is taken from a larger partial yeast PIC structure (PDB file 3JAP) (Llacer et al., ). (b) Cartoon image indicating major protein interaction partners important in the ISR
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Effects of ISR on mRNA‐ribosome interactions. (a) Typical polysome profiles (A260 profile) from cell extracts sedimented on 15–50% sucrose gradients from active and stressed cells. Cartoon of ribosome engagement with single ORF mRNA (b) or uORF bearing mRNA (c) under variable levels of eIF2 phosphorylation during the ISR. Table summarizes translation state for different mRNA classes
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