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

Elife. 2015 Feb 26;4:e05033. doi: 10.7554/eLife.05033.

Abstract

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 rapid disassembly, liberating mRNAs into the actively translating pool. Restoration of mRNA translation and modulation of SG dynamics may be an effective treatment of neurodegenerative diseases characterized by eIF2α phosphorylation, SG formation, and cognitive loss.

Keywords: ISRIB; cell biology; eIF2; human; integrated stress response; mouse; neuroscience; protein synthesis; ribosome profiling; unfolded protein response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / pharmacology*
  • Animals
  • Cyclohexylamines / pharmacology*
  • Cytoplasmic Granules / drug effects*
  • Eukaryotic Initiation Factor-2 / drug effects*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Phosphorylation
  • Protein Biosynthesis / drug effects*
  • RNA, Messenger / metabolism
  • Ribosomes / metabolism
  • Stress, Physiological*

Substances

  • 2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide
  • Acetamides
  • Cyclohexylamines
  • Eukaryotic Initiation Factor-2
  • RNA, Messenger