Mutations in a translation initiation factor identify the target of a memory-enhancing compound

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Science  09 Apr 2015:
DOI: 10.1126/science.aaa6986

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The integrated stress response (ISR) modulates mRNA 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 N-terminal portion of the delta subunit of guanine nucleotide exchange factor (GEF) eIF2B. When reintroduced by CRISPR-Cas9 gene editing of wildtype 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.

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