Glutathione S-transferase Mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1
Glutathione S-transferase Mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1
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DOI：
10.1074/jbc.m005561200
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发表时间：
2001-04-20
影响因子：
4.8
通讯作者：
Choi, EJ
中科院分区：
文献类型：
--
作者：
Cho, SG;Lee, YH;Choi, EJ
细胞凋亡信号调节蛋白1(ASK1)是一种丝裂原激活的蛋白激酶，可激活c-jun氨基末端和p38信号通路。它在细胞因子和胁迫诱导的细胞凋亡中起着关键作用，为了进一步研究ASK1信号的调控机制，我们利用酵母双杂交方法寻找与ASK1相互作用的蛋白。酵母双杂交实验表明，小鼠谷胱甘肽S转移酶MU1-1(MGSTM1-1)是一种参与药物和外源物质代谢的酶，它与ASK1相互作用，从而证实了MGSTM1-1在体内和体外都与ASK1有物理联系。体外结合实验表明，mGSTM1-1的C-末端和ASK1的N-末端是相互结合的关键区域。此外，mGSTM1-1抑制应激刺激的培养细胞中的ASK1活性。MGSTM1-1也可抑制ASK1的寡聚，其抑制ASK1的作用不依赖于mGSTM1-1的谷胱甘肽结合活性，而且mGSTM1-1还抑制ASK1依赖的细胞死亡。综上所述，我们的发现表明mGSTM1-1作为ASK1的内源性抑制物发挥作用。这突出了mGSTM1-1的一个新功能，即mGSTM1-1可能通过抑制ASK1来调制应激介导的信号，并且这种活性独立于其在细胞内谷胱甘肽代谢中的催化活性而发生。
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.