DOI: 10.1126/science.1101902. A Selective Inhibitor of eIF2α Dephosphorylation Protects Cells from ER Stress

A Selective Inhibitor of eIF2α Dephosphorylation Protects Cells from ER Stress

10.1126/science.1101902

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit α (eIF2α). Salubrinal also blocks eIF2α dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2α dephosphorylation may be useful in diseases involving ER stress or viral infection. More broadly, salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events.

Bibliography

Boyce, M., Bryant, K. F., Jousse, C., Long, K., Harding, H. P., Scheuner, D., Kaufman, R. J., Ma, D., Coen, D. M., Ron, D., & Yuan, J. (2005). A Selective Inhibitor of eIF2Î± Dephosphorylation Protects Cells from ER Stress. Science, 307(5711), 935â939.

Authors 11

Michael Boyce (first)
Kevin F. Bryant (additional)
Céline Jousse (additional)
Kai Long (additional)
Heather P. Harding (additional)
Donalyn Scheuner (additional)
Randal J. Kaufman (additional)
Dawei Ma (additional)
Donald M. Coen (additional)
David Ron (additional)
Junying Yuan (additional)

References 32 Referenced 1,247

10.1101/gad.13.10.1211
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R. J. Kaufman, in Translational Control of Gene Expression, N. Sonenberg, J. W. B. Hershey, M. B. Mathews, Eds. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2000), pp. 503–528. / Translational Control of Gene Expression (2000)
J. J. Chen, in Translational Control of Gene Expression, N. Sonenberg, J. W. B. Hershey, M. B. Mathews, Eds. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2000), pp. 529–546. / Translational Control of Gene Expression (2000)
M. Boyce et al . unpublished data.
10.1093/emboj/17.19.5708
10.1021/jm010066k
10.1038/343651a0
10.1002/elps.1150181133
M. Boyce J. S. Minden J. Yuan unpublished observations.
10.1073/pnas.92.23.10516
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10.1126/science.2173860
10.1128/jvi.63.2.759-768.1989
We thank J. Alvarez J.-J. Chen J. Glaven O. Gozani R. King T. Mitchison F. Roth S. Ryeom M. Shair C.T. Walsh and members of the Yuan lab for reagents and advice and J. Follen and D. Hayes of the Harvard Institute of Chemistry and Cell Biology for tireless help with small molecule screening. Supported by NIH grants R37-AG012859 and GM64703 (J.Y.); DDK42394 (R.J.K.); AI26077 AI19838 and NS35138 (D.M.C.); and ES08681 and DK47119 (D.R.); NSF (M.B.); grant KGCX2-SW-209 from the Chinese Academy of Sciences; and grant 20228205 from the National Natural Science Foundation of China (D.M.).

Dates

Type	When
Created	20 years, 6 months ago (Feb. 10, 2005, 11:46 a.m.)
Deposited	1 year, 7 months ago (Jan. 9, 2024, 7:56 p.m.)
Indexed	3 days, 1 hour ago (Aug. 22, 2025, 12:46 a.m.)
Issued	20 years, 6 months ago (Feb. 11, 2005)
Published	20 years, 6 months ago (Feb. 11, 2005)
Published Print	20 years, 6 months ago (Feb. 11, 2005)

Funders 0

None

BibTeX

@article{Boyce_2005, title={A Selective Inhibitor of eIF2α Dephosphorylation Protects Cells from ER Stress}, volume={307}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1101902}, DOI={10.1126/science.1101902}, number={5711}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Boyce, Michael and Bryant, Kevin F. and Jousse, Céline and Long, Kai and Harding, Heather P. and Scheuner, Donalyn and Kaufman, Randal J. and Ma, Dawei and Coen, Donald M. and Ron, David and Yuan, Junying}, year={2005}, month=feb, pages={935–939} }

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