The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly

Previously, we identified ISRIB as a potent inhibitor of the integrated stress response (ISR) and showed that ISRIB makes cells resistant to the effects of eIF2α phosphorylation and enhances long-term memory in rodents (Sidrauski et al., 2013). Here, we show by genome-wide in vivo ribosome profiling that translation of a restricted subset of mRNAs is induced upon ISR activation. ISRIB substantially reversed the translational effects elicited by phosphorylation of eIF2α and induced no major changes in translation or mRNA levels in unstressed cells. eIF2α phosphorylation-induced stress granule (SG) formation was blocked by ISRIB. Strikingly, ISRIB addition to stressed cells with pre-formed SGs induced their…

• HH
  Howard Hughes Medical Institute
• KF
  Kinship Foundation

  Award: Searle Scholars Program 11-SSP-229
• CI
  Carnegie Institution of Washington
• NI
  National Institutes of Health

  Award: T32GM007231