Novel Role for Glutathione S-Transferase π REGULATOR OF PROTEIN S-GLUTATHIONYLATION FOLLOWING OXIDATIVE AND NITROSATIVE STRESS

Glutathione S-transferase Pi (GST pi) 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 GST pi 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. GST pi is itself redox-regulated. S-Glutathionylation on Cys(47) and Cys(101) autoregulates GST pi, breaks ligand binding interactions with c-Jun NH2-terminal kinase (JNK), and causes GST pi multimer formation, all critical to stress response. Catalysis of S-glutathionylation at low pK cysteines in proteins is a novel property for GST pi and may be a cause for its abundance in tumors and cells resistant to a range of mechanistically unrelated anticancer drugs.