Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated 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
Affiliations
Carmela Sidrauski
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institution, University of California, San Francisco, San Francisco, United States
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institution, University of California, San Francisco, San Francisco, United States
Howard Hughes Medical Institution, University of California, San Francisco, San Francisco, United States; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Brian R Hearn
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States; Small Molecule Discovery Center, University of California, San Francisco, San Francisco, United States
Punitha Vedantham
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States; Small Molecule Discovery Center, University of California, San Francisco, San Francisco, United States
Priyadarshini Jaishankar
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States; Small Molecule Discovery Center, University of California, San Francisco, San Francisco, United States
Masaaki Sokabe
Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, United States
Aaron S Mendez
Howard Hughes Medical Institution, University of California, San Francisco, San Francisco, United States; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Billy W Newton
QB3, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States
Edward L Tang
QB3, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States; Gladstone Institutes, San Francisco, United States
QB3, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States
Jeffrey R Johnson
QB3, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States; Gladstone Institutes, San Francisco, United States
Nevan J Krogan
QB3, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States; Gladstone Institutes, San Francisco, United States
Christopher S Fraser
Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, United States
Jonathan S Weissman
Howard Hughes Medical Institution, University of California, San Francisco, San Francisco, United States; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Adam R Renslo
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States; Small Molecule Discovery Center, University of California, San Francisco, San Francisco, United States
Peter Walter
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institution, University of California, San Francisco, San Francisco, United States
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.
