Report

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

+ See all authors and affiliations

Science  29 May 2015:
Vol. 348, Issue 6238, pp. 1027-1030
DOI: 10.1126/science.aaa6986

You are currently viewing the abstract.

View Full Text

Identification of a memory drug target

ISRIB is a potent inhibitor of the integrated stress response (ISR), which involves the activation of eIF2α-specific kinases, phosphorylation of eIF2α, and consequent down-regulation of global translation levels. ISRIB is also a candidate drug for treating certain memory disorders. ISRIB does not prevent eIF2α phosphorylation and must therefore act downstream of this step. Sekine et al. now report that ISRIB reverses the inhibitory effect of eIF2α phosphorylation on the activity of eIF2B, a dedicated guanine nucleotide exchange factor, enhancing its activity independently of phosphorylation (see the Perspective by Hinnebusch). The authors isolated ISRIB-resistant cells and identified a genetic lesion in a short N-terminal region of eIF2Bδ that appears to be responsible for the observed phenotype.

Science, this issue p. 1027; see also p. 967

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.

View Full Text