Novel Role for Glutathione S-Transferase π

Abstract

Glutathione S-transferase Pi (GSTπ) is a marker protein in many cancers and high levels are linked to drug resistance, even when the selecting drug is not a substrate. S-Glutathionylation of proteins is critical to cellular stress response, but characteristics of the forward reaction are not known. Our results show that GSTπ potentiates S-glutathionylation reactions following oxidative and nitrosative stress in vitro and in vivo. Mutational analysis indicated that the catalytic activity of GST is required. GSTπ is itself redox-regulated. S-Glutathionylation on Cys 47 and Cys 101 autoregulates GSTπ, breaks ligand binding interactions with c-Jun NH 2 -terminal kinase (JNK), and causes GSTπ multimer formation, all critical to stress response. Catalysis of S-glutathionylation at low pK cysteines in proteins is a novel property for GSTπ and may be a cause for its abundance in tumors and cells resistant to a range of mechanistically unrelated anticancer drugs. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.