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

doi:10.7554/eLife.07314

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 journal › Article › peer-review

192 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 language	English
Article number	e07314
Journal	eLife
Volume	2015
Issue number	4
DOIs	https://doi.org/10.7554/eLife.07314
State	Published - 15 Apr 2015
Externally published	Yes

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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), Article e07314. https://doi.org/10.7554/eLife.07314

@article{dbc5e4ebc993464ba2c71ef5fe29ec95,

title = "Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes theintegrated stress response",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2015, eLife. All rights reserve.",

year = "2015",

month = apr,

day = "15",

doi = "10.7554/eLife.07314",

language = "English",

volume = "2015",

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Sidrauski, C, Tsai, JC, Kampmann, M, Hearn, BR, Vedantham, P, Jaishankar, P, Sokabe, M, Mendez, AS, Newton, BW, Tang, EL, Verschueren, E, Johnson, JR, Krogan, NJ, Fraser, CS, Weissman, JS, Renslo, AR & Walter, P 2015, 'Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes theintegrated stress response', eLife, vol. 2015, no. 4, e07314. https://doi.org/10.7554/eLife.07314

TY - JOUR

T1 - Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes theintegrated stress response

AU - Sidrauski, Carmela

AU - Tsai, Jordan C.

AU - Kampmann, Martin

AU - Hearn, Brian R.

AU - Vedantham, Punitha

AU - Jaishankar, Priyadarshini

AU - Sokabe, Masaaki

AU - Mendez, Aaron S.

AU - Newton, Billy W.

AU - Tang, Edward L.

AU - Verschueren, Erik

AU - Johnson, Jeffrey R.

AU - Krogan, Nevan J.

AU - Fraser, Christopher S.

AU - Weissman, Jonathan S.

AU - Renslo, Adam R.

AU - Walter, Peter

PY - 2015/4/15

Y1 - 2015/4/15

N2 - 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.

AB - 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.

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U2 - 10.7554/eLife.07314

DO - 10.7554/eLife.07314

M3 - Article

C2 - 25875391

AN - SCOPUS:84928141313

SN - 2050-084X

VL - 2015

JO - eLife

JF - eLife

IS - 4

M1 - e07314

ER -

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

Abstract

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