GSTμ modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1 (ASK1)

다국어 초록 (Multilingual Abstract)

Apoptosis signal-regulating kinase1(ASK1) is a MAP 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-induced apoptosis. In order to further characterize the mechanism of the regulation of the ASK1 signal, we searched for ASK1-interacting proteins employing the yeast two-hybrid method. The yeast two-hybrid assay indicated that glutathione S-transferase Mu(GSTμ), an enzyme involved in the metabolism of drugs and xenobiotics, interacted with ASK1. We subsequently confirmed that GSTμ physically associated with ASK1 both in vivo and in vitro. Furthermore, GSTμ suppressed stress-stimulated ASK1 activity in cultured cells. The ASK1 inhibition by GSTμ occurred independently of the glutathione-conjugating activity of GSTμ. Moreover, ectopic GSTμ repressed ASK1-dependent apoptotic cell death. Taken together, our findings suggest that GSTμ function as an endogenous inhibitor of ASK1. This highlights a novel function for GSTμ in so far as GSTμ may modulate stress-mediated signals by repressing ASK1, and this activity occurs independently of its well-known catalytic activity in intracellular glutathione metabolism.