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

Carmela Sidrauski, Jordan C. Tsai, Martin Kampmann, Brian R. Hearn, Punitha Vedantham, Priyadarshini Jaishankar, Masaaki Sokabe, Aaron S. Mendez, Billy W. Newton, Edward L. Tang, Erik Verschueren, Jeffrey R. Johnson, Nevan J. Krogan, Christopher S. Fraser, Jonathan S. Weissman, Adam R. Renslo, Peter Walter

Research output: Contribution to journalArticle

118 Scopus citations

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 eIF2a 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 (8-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.

Original languageEnglish (US)
Article numbere07314
JournaleLife
Volume2015
Issue number4
DOIs
StatePublished - Apr 15 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

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    Sidrauski, C., Tsai, J. C., Kampmann, M., Hearn, B. R., Vedantham, P., Jaishankar, P., Sokabe, M., Mendez, A. S., Newton, B. W., Tang, E. L., Verschueren, E., Johnson, J. R., Krogan, N. J., Fraser, C. S., Weissman, J. S., Renslo, A. R., & Walter, P. (2015). Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes theintegrated stress response. eLife, 2015(4), [e07314]. https://doi.org/10.7554/eLife.07314