The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response
Open accessAbstract
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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Cites
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An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative Stress
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Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay
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Feedback Inhibition of the Unfolded Protein Response by GADD34-Mediated Dephosphorylation of eIF2α
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Pharmacological brake-release of mRNA translation enhances cognitive memory
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Self-citationYe, J., Kumanova, M., Hart, L. S., Sloane, K., Zhang, H., De Panis, D. N., Bobrovnikova‐Marjon, E., Diehl, J. A., Ron, D., & Koumenis, C. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.81 · Cited by 701
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The integrated stress response: From mechanism to disease
Costa-Mattioli, M., & Walter, P. (2020) · Science · doi:10.1126/science.aat5314 · Cited by 1,617
Self-citationAdamson, B., Norman, T. M., Jost, M., Cho, M. Y., Nuñez, J. K., Chen, Y., Villalta, J. E., Gilbert, L. A., Horlbeck, M. A., Hein, M. Y., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.048 · Cited by 1,193
Self-citationEndoplasmic reticulum stress signalling-from basic mechanisms to clinical applications
Almanza, A., Carlesso, A., Chintha, C., Creedican, S., Doultsinos, D., Leuzzi, B., Luís, A., McCarthy, N., Montibeller, L., More, S., et al. (2019) · The FEBS Journal · doi:10.1111/febs.14608 · Cited by 1,034
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Mitochondrial stress is relayed to the cytosol by an OMA1–DELE1–HRI pathway
Guo, X., Aviles, G., Liu, Y., Tian, R., Unger, B. A., Lin, Y.-H. T., Wiita, A. P., Xu, K., Correia, M. A., & Kampmann, M. (2020) · Nature · doi:10.1038/s41586-020-2078-2 · Cited by 674
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Metadata
- Authors
- 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.
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2015-04-15
- Volume
- 4
- Pages
- e07314-e07314
- ISSN
- 2050-084X (ISSN-L)
- OpenAlex
- W2102049218
- Cited by
- 256
- References
- 54
- FWCI
- 15.72
- Type
- journal article
- Language
- en
- Open access
- gold
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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 the integrated stress response. eLife. https://doi.org/10.7554/elife.07314
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