Walter Lab

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    • The Unfolded Protein Response and IRE1 Signaling in Health and Disease
    • Organellar quality control, dynamics, and inheritance
    • RNA processing in the unfolded protein response
    • The integrated stress response and its role in cognition
    • ATF6-branch signaling through regulated proteolysis
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Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response

Sidrauski C, Tsai JC, Kampmann M, Hearn BR, Vedantham P, Jaishankar P, Sokabe M, Mendez A, Newton BW, Tang EL, Verschueren E, Johnson JR, Krogan NJ, Fraser CS, Weissman JS, Renslo AR, Walter P. Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. eLife 4:e07314, 2015
(PMCID : PMC4426669) (PMID : 25875391) (PDF)

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.


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