Pharmacological brake-release of mRNA translation enhances cognitive memory
Howard Hughes Medical Institute · University of California, San Francisco · +3 more institutions
Abstract
Phosphorylation of the α-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2α kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2α. This collection of signaling pathways is termed the 'integrated stress response' (ISR). eIF2α phosphorylation diminishes protein synthesis, while allowing preferential translation of some mRNAs. Starting with a cell-based screen for inhibitors of PERK signaling, we identified a small molecule, named ISRIB, that potently (IC50 = 5 nM) reverses the effects of eIF2α phosphorylation. ISRIB reduces the viability of cells subjected to…
Citation impact
- FWCI
- 18.20
- Percentile
- 100%
- References
- 47
Authors
18- CSCarmela SidrauskiCorresponding
Howard Hughes Medical Institute, University of California, San Francisco
- DADiego Acosta‐Alvear
Howard Hughes Medical Institute, University of California, San Francisco
- AKArkady Khoutorsky
McGill University
- PVP. Vedantham
University of California, San Francisco
- BRBrian R. Hearn
University of California, San Francisco
Topics & keywords
- Integrated stress response
- Phosphorylation
- eIF2
- Memory consolidation
- Cell biology
- Protein kinase R
- Endoplasmic reticulum
- Translation (biology)