A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress

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 sel...

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Bibliographic Details
Published in:	Science (American Association for the Advancement of Science) Vol. 307; no. 5711; p. 935
Main Authors:	Boyce, Michael, Bryant, Kevin F, Jousse, Céline, Long, Kai, Harding, Heather P, Scheuner, Donalyn, Kaufman, Randal J, Ma, Dawei, Coen, Donald M, Ron, David, Yuan, Junying
Format:	Journal Article
Language:	English
Published:	United States 11-02-2005
Subjects:	Animals Antigens, Differentiation Apoptosis - drug effects Cell Cycle Proteins Cell Line Cinnamates - pharmacology Cinnamates - toxicity Cytoprotection Dose-Response Relationship, Drug Endoplasmic Reticulum - metabolism Enzyme Inhibitors - pharmacology Eukaryotic Initiation Factor-2 - metabolism Genes, Reporter Herpesvirus 1, Human - drug effects Herpesvirus 1, Human - physiology Keratitis, Herpetic - drug therapy Keratitis, Herpetic - virology Male Mice Oxazoles - pharmacology Oxazoles - toxicity PC12 Cells Phosphoprotein Phosphatases - metabolism Phosphorylation Protein Folding Protein Kinases - metabolism Protein Phosphatase 1 Proteins - metabolism Rats Thiourea - analogs & derivatives Thiourea - pharmacology Thiourea - toxicity Tunicamycin - pharmacology Viral Proteins - metabolism Virus Replication - drug effects
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Summary:	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 alpha (eIF2alpha). Salubrinal also blocks eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2alpha 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.
ISSN:	1095-9203