The integrated stress response (ISR) is a conserved translational and transcriptional program affecting metabolism, memory, and immunity. The ISR is mediated by stress-induced phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) that attenuates the guanine nucleotide exchange factor eIF2B. A chemical inhibitor of the ISR, ISRIB, reverses the attenuation of eIF2B by phosphorylated eIF2α, protecting mice from neurodegeneration and traumatic brain injury. We describe a 4.1-angstrom-resolution cryo-electron microscopy structure of human eIF2B with an ISRIB molecule bound at the interface between the β and δ regulatory subunits. Mutagenesis of residues lining this pocket altered the hierarchical cellular response to ISRIB analogs in vivo and ISRIB binding in vitro. Our findings point to a site in eIF2B that can be exploited by ISRIB to regulate translation.
Mode of action of the heme-controlled translational inhibitor: relationship of eukaryotic initiation factor 2-stimulating protein to translation restoring factor
Mutations in the GCD7 subunit of yeast guanine nucleotide exchange factor eIF-2B overcome the inhibitory effects of phosphorylated eIF-2 on translation initiation.
Homologous segments in three subunits of the guanine nucleotide exchange factor eIF2B mediate translational regulation by phosphorylation of eIF2.
Optimal determination of particle orientation, absolute hand, and contrast loss in single-particle electron cryomicroscopy
Electron counting and beam-induced motion correction enable near-atomic-resolution single-particle cryo-EM
High-resolution noise substitution to measure overfitting and validate resolution in 3D structure determination by single particle electron cryomicroscopy
Tools for macromolecular model building and refinement into electron cryo-microscopy reconstructions
Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity
Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound
Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response
Paradoxical Sensitivity to an Integrated Stress Response Blocking Mutation in Vanishing White Matter Cells
Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury
Cellular eIF2B subunit localization: implications for the integrated stress response and its control by small molecule drugs
Small Molecule Modulation of the Integrated Stress Response Governs the Keratoconic Phenotype In Vitro
Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response
Norovirus infection results in eIF2α independent host translation shut-off and remodels the G3BP1 interactome evading stress granule formation
The Integrated Stress Response and Phosphorylated Eukaryotic Initiation Factor 2α in Neurodegeneration.
Integrated Stress Response Inhibitor Reverses Sex-Dependent Behavioral and Cell-Specific Deficits after Mild Repetitive Head Trauma.
Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model
Small molecule ISRIB suppresses the integrated stress response within a defined window of activation
Discovery and Preliminary Characterization of Translational Modulators that Impair the Binding of eIF6 to 60S Ribosomal Subunits
Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis.
Repurposing ribosome-targeting antibiotics to overcome resistance to venetoclax in acute myeloid leukemia.
Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease
Adaptive Protein Translation by the Integrated Stress Response Maintains the Proliferative and Migratory Capacity of Lung Adenocarcinoma Cells.
ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.
Brain Injury & Trauma
brain injury after impact to the head is due to both immediate mechanical effects and delayed responses of neural tissues.