Selective Inhibition of a Regulatory Subunit of Protein Phosphatase 1 Restores Proteostasis
Abstract
Many biological processes are regulated through the selective dephosphorylation of proteins. Protein serine-threonine phosphatases are assembled from catalytic subunits bound to diverse regulatory subunits that provide substrate specificity and subcellular localization. We describe a small molecule, guanabenz, that bound to a regulatory subunit of protein phosphatase 1, PPP1R15A/GADD34, selectively disrupting the stress-induced dephosphorylation of the α subunit of translation initiation factor 2 (eIF2α). Without affecting the related PPP1R15B-phosphatase complex and constitutive protein synthesis, guanabenz prolonged eIF2α phosphorylation in human stressed cells, adjusting the protein production rates to levels manageable by available chaperones. This favored protein folding and thereby rescued cells from protein misfolding stress. Thus, regulatory subunits of phosphatases are drug targets, a property used here to restore proteostasis in stressed cells.
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Science
Volume 332 | Issue 6025
1 April 2011
1 April 2011
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Copyright © 2011, American Association for the Advancement of Science.
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Submission history
Received: 8 December 2010
Accepted: 11 February 2011
Published in print: 1 April 2011
Acknowledgments
We thank A. Merritt and C. Wallace for biotinylated guanabenz, J. Hastie for purified recombinant PP1c, anonymous reviewers for suggestions, and M. Goedert for advice on the manuscript. Supported by the UK Medical Research Council. D.R. is a Wellcome Trust Principal Research Fellow. A.B. is a co-inventor on patent WO/2008/041133.
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- Pavel Tsaytler et al.
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