TY - JOUR TI - The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly AU - Sidrauski, Carmela AU - McGeachy, Anna M AU - Ingolia, Nicholas T AU - Walter, Peter A2 - Ron, David VL - 4 PY - 2015 DA - 2015/02/26 SP - e05033 C1 - eLife 2015;4:e05033 DO - 10.7554/eLife.05033 UR - https://doi.org/10.7554/eLife.05033 AB - 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. KW - integrated stress response KW - eIF2 KW - unfolded protein response KW - ISRIB KW - protein synthesis KW - ribosome profiling JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -