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A Selective Inhibitor of eIF2 Dephosphorylation Protects Cells from ER Stress
Michael Boyce,1Kevin F. Bryant,2*Céline Jousse,3*Kai Long,4*Heather P. Harding,3Donalyn Scheuner,5Randal J. Kaufman,5Dawei Ma,4Donald M. Coen,2David Ron,3Junying Yuan1
Most protein phosphatases have little intrinsic substrate specificity,making selective pharmacological inhibition of specific dephosphorylationreactions a challenging problem. In a screen for small moleculesthat protect cells from endoplasmic reticulum (ER) stress, weidentified salubrinal, a selective inhibitor of cellular complexesthat dephosphorylate eukaryotic translation initiation factor2 subunit (eIF2). Salubrinal also blocks eIF2 dephosphorylationmediated by a herpes simplex virus protein and inhibits viralreplication. These results suggest that selective chemical inhibitorsof eIF2 dephosphorylation may be useful in diseases involvingER stress or viral infection. More broadly, salubrinal demonstratesthe feasibility of selective pharmacological targeting of cellulardephosphorylation events.
1 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. 2 Department of Biological Chemistry and Molecular Pharmacology and Committee on Virology, Harvard Medical School, Boston, MA 02115, USA. 3 Skirball Institute, New York University School of Medicine, New York, NY 10016, USA. 4 Shanghai Institute of Organic Chemistry, Shanghai, China. 5 Department of Biological Chemistry and Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: jyuan{at}hms.harvard.edu
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(eIF2
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