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

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Science  03 Mar 2011:
1201396
DOI: 10.1126/science.1201396

Abstract

Many biological processes are regulated through 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. Here, we describe a small-molecule, guanabenz, which 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). Thus, without affecting the related PPP1R15B-phosphatase complex and constitutive protein synthesis, guanabenz prolonged eIF2α phosphorylation in 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.