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. Y. Sekine, A. Zyryanova, A. Crespillo-Casado, P. M. Fischer, H. P. Harding, D. Ron, Mutations in a translation initiation factor identify the target of a memory-enhancing compound. Science 348 , 1027–1030 (2015). [Abstract][Full Text] A. G. Hinnebusch, Blocking stress response for better memory? Science 348 , 967–968 (2015). [Abstract][Full Text]