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Science 332 (6025): 91-94

Copyright © 2011 by the American Association for the Advancement of Science

Selective Inhibition of a Regulatory Subunit of Protein Phosphatase 1 Restores Proteostasis

Pavel Tsaytler,1 Heather P. Harding,2 David Ron,2 Anne Bertolotti1,*

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.

1 MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
2 Institute of Metabolic Sciences, University of Cambridge, Cambridge CB2 0QQ, UK.

* To whom correspondence should be addressed. E-mail: aberto{at}mrc-lmb.cam.ac.uk


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