Glutathione S-transferase Mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that can activate the c-Jun N-terminal kinase and the p38 signaling pathways. It plays a critical role in cytokine- and stress-in duced apoptosis, To further characterize the mechanism of the regulation of the ASK1 signal, we searched for ASK1-interacting proteins employing the y east two-hybrid method. The yeast two-hybrid assay indicated that mouse glu tathione S-transferase Mu 1-1 (mGSTM1-1), an enzyme involved in the metabol ism of drugs and xenobiotics, interacted with ASK1, We subsequently confirm ed that mGSTM1-1 physically associated with ASK1 both in vivo and in vitro. The in vitro binding assay indicated that the C-terminal portion of mGSTM1 -1 and the N-terminal region of ASK1 were crucial for binding one another. Furthermore, mGSTM1-1 suppressed stress-stimulated ASK1 activity in culture d cells. mGSTM1-1 also blocked ASK1 oligomerization, The ASK1 inhibition by mGSTM1-1 occurred independently of the glutathione-conjugating activity of mGSTM1-1, Moreover, mGSTM1-1 repressed ASK1-dependent apoptotic cell death . Taken together, our findings suggest that mGSTM1-1 functions as an endoge nous inhibitor of ASK1. This highlights a novel function for mGSTM1-1 insof ar as mGSTM1-1 may modulate stress-mediated signals by repressing ASK1, and this activity occurs independently of its well-known catalytic activity in intracellular glutathione metabolism.