biostudies-literatureSekine YWellcome TrustDaiichi Sankyo Foundation of Life ScienceJapan Society for the Promotion of Science1027-30https://www.ebi.ac.uk/biostudies/studies/S-EPMC4538794biostudies-literatureUnknown348(6238)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. ThusScience (New York, N.Y.)Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound.PMC4538794100140084812/Z/08/Z084812Zyryanova ARon DHarding HPSekine YFischer PMCrespillo-Casado AfalseStress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound.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. Thus2015-01-01T00:00:00Z2015 May2025-04-19T19:46:14.043Z2019-03-27T01:56:53ZS-EPMC45387942585897910.1126/science.aaa6986