title: Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound.
abstract: The integrated stress response (ISR) modulates messenger RNA translation to regulate the mammalian unfolded protein response (UPR), immunity, and memory formation. A chemical ISR inhibitor, ISRIB, enhances cognitive function and modulates the UPR in vivo. To explore mechanisms involved in ISRIB action, we screened cultured mammalian cells for somatic mutations that reversed its effect on the ISR. Clustered missense mutations were found at the amino-terminal portion of the delta subunit of guanine nucleotide exchange factor (GEF) eIF2B. When reintroduced by CRISPR-Cas9 gene editing of wild-type cells, these mutations reversed both ISRIB-mediated inhibition of the ISR and its stimulatory effect on eIF2B GEF activity toward its substrate, the translation initiation factor eIF2, in vitro. Thus, ISRIB targets an interaction between eIF2 and eIF2B that lies at the core of the ISR.
authors: University of Cambridge, Cambridge Institute for Medical Research (CIMR), the Wellcome Trust MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0XY, UK. dr360@medschl.cam.ac.uk ys412@cam.ac.uk.
authors: Yusuke
authors: Y
authors: Sekine
authors: University of Cambridge, Cambridge Institute for Medical Research (CIMR), the Wellcome Trust MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0XY, UK.
authors: Alisa
authors: A
authors: Zyryanova
authors: University of Cambridge, Cambridge Institute for Medical Research (CIMR), the Wellcome Trust MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0XY, UK.
authors: Ana
authors: A
authors: Crespillo-Casado
authors: Division of Medicinal Chemistry and Structural Biology, School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK.
authors: Peter M
authors: PM
authors: Fischer
authors: University of Cambridge, Cambridge Institute for Medical Research (CIMR), the Wellcome Trust MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0XY, UK.
authors: Heather P
authors: HP
authors: Harding
authors: University of Cambridge, Cambridge Institute for Medical Research (CIMR), the Wellcome Trust MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0XY, UK. dr360@medschl.cam.ac.uk ys412@cam.ac.uk.
authors: David
authors: D
authors: Ron
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D003412:Cricetulus; D003514:Cyclohexylamines / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics* / Q000378:metabolism; D005820:Genetic Testing; D008568:Memory / Q000187:drug effects*; D020125:Mutation, Missense; D018697:Nootropic Agents / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000276:immunology
chemical_list: C000599093:2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide; D000081:Acetamides; D003514:Cyclohexylamines; D015852:Eukaryotic Initiation Factor-2; D020717:Eukaryotic Initiation Factor-2B; D018697:Nootropic Agents