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

Ssang Goo Cho, Yong Hee Lee, Hee Sae Park, Kanghyun Ryoo, Keon Wook Kang, Jihyun Park, Soo Jung Eom, Myung Jin Kim, Tong Shin Chang, Soo Yeon Choi, Jaekyung Shim, Youngho Kim, Mi Sook Dong, Min Jae Lee, Sang Geon Kim, Hidenori Ichijo, Eui Ju Choi

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307 Citations (Scopus)

Abstract

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. mG-STM1-1 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.

Original languageEnglish
Pages (from-to)12749-12755
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number16
DOIs
Publication statusPublished - 2001 Apr 20

ASJC Scopus subject areas

  • Biochemistry

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  • Cite this

    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. (2001). Glutathione S-Transferase Mu Modulates the Stress-activated Signals by Suppressing Apoptosis Signal-regulating Kinase 1. Journal of Biological Chemistry, 276(16), 12749-12755. https://doi.org/10.1074/jbc.M005561200