Format

Send to

Choose Destination
Elife. 2015 Apr 15;4:e07314. doi: 10.7554/eLife.07314.

Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response.

Author information

1
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
2
Howard Hughes Medical Institution, University of California, San Francisco, San Francisco, United States.
3
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.
4
Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, United States.
5
QB3, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States.

Abstract

The general translation initiation factor eIF2 is a major translational control point. Multiple signaling pathways in the integrated stress response phosphorylate eIF2 serine-51, inhibiting nucleotide exchange by eIF2B. ISRIB, a potent drug-like small molecule, renders cells insensitive to eIF2α phosphorylation and enhances cognitive function in rodents by blocking long-term depression. ISRIB was identified in a phenotypic cell-based screen, and its mechanism of action remained unknown. We now report that ISRIB is an activator of eIF2B. Our reporter-based shRNA screen revealed an eIF2B requirement for ISRIB activity. Our results define ISRIB as a symmetric molecule, show ISRIB-mediated stabilization of activated eIF2B dimers, and suggest that eIF2B4 (δ-subunit) contributes to the ISRIB binding site. We also developed new ISRIB analogs, improving its EC50 to 600 pM in cell culture. By modulating eIF2B function, ISRIB promises to be an invaluable tool in proof-of-principle studies aiming to ameliorate cognitive defects resulting from neurodegenerative diseases.

KEYWORDS:

ISRIB; biochemistry; cell biology; eIF2; eIF2B; human; integrated stress response; protein synthesis; unfolded protein response

PMID:
25875391
PMCID:
PMC4426669
DOI:
10.7554/eLife.07314
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center