Glutathione S-Transferase Mu Modulates the Stress-activated Signals by Suppressing Apoptosis Signal-regulating Kinase 1

• Published in: The Journal of biological chemistry Vol. 276; no. 16; pp. 12749 - 12755
• Main Authors: Cho, S G, Lee, Y H, Park, H S, Ryoo, K, Kang, K W, Park, J, Eom, S J, Kim, M J, Chang, T S, Choi, S Y, Shim, J, Kim, Y, Dong, M S, Lee, M J, Kim, S G, Ichijo, H, Choi, E J
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 20-04-2001
• Subjects: Animals; Binding Sites; Cloning, Molecular; Glutathione Transferase - metabolism; Isoenzymes - metabolism; JNK Mitogen-Activated Protein Kinases; Liver - enzymology; Luciferases - genetics; MAP Kinase Kinase Kinase 5; MAP Kinase Kinase Kinases - chemistry; MAP Kinase Kinase Kinases - metabolism; MAP Kinase Signaling System - physiology; Mice; Mitogen-Activated Protein Kinases - metabolism; Proto-Oncogene Proteins c-jun - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Saccharomyces cerevisiae; Transcription, Genetic
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M005561200

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-induced apoptosis. 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 mouse glutathione S -transferase Mu 1-1 (mGSTM1-1), an enzyme involved in the metabolism of drugs and xenobiotics, interacted with ASK1. We subsequently
confirmed 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 cultured 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 endogenous inhibitor of ASK1. This highlights a novel function for mGSTM1-1 insofar 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.