Wu Y, Fan Y, Xue B, Luo L, Shen J, Zhang S, Jiang Y, Yin Z
Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, JiangSu, People's Republic of China.
Oncogene. 2006 Sep 21;25(42):5787-800. doi: 10.1038/sj.onc.1209576. Epub 2006 Apr 24.
Human glutathione S-transferase P1-1 (GSTP1-1) is an ubiquitously expressed protein that plays an important role in the detoxification and xenobiotics metabolism. It has been shown that GSTP1-1 interacts with c-Jun NH(2)-terminal kinase (JNK) and suppresses its activity. Here, we report a novel function of GSTP1-1 in regulating tumor necrosis factor-alpha (TNF-alpha)-triggered signaling. The present experiments showed that GSTP1-1 physically associated with tumor necrosis factor receptor-associated factor 2 (TRAF2) in vivo and in vitro. Overexpression of GSTP1-1 inhibited TRAF2-induced activation of both JNK and p38 but not of nuclear factor-kappaB (NF-kappaB). Glutathione S-transferase P1-1 also attenuated TRAF2-enhanced apoptosis signal-regulating kinase 1 (ASK1) autophosphorylation and inhibited TRAF2-ASK1-induced cell apoptosis by suppressing the interaction of TRAF2 and ASK1. Conversely, silencing of GSTP1-1 expression through RNA interference (RNAi) resulted in increase of TNF-alpha-dependent TRAF2-ASK1 association followed by hyper-activation of ASK1 and JNK. A mutant GSTP1-1 lacking TRAF domain-binding motif exhibited a significant decline of capacity to bind TRAF2 and block TRAF2-ASK1 signaling compared with the wild type of GSTP1-1. Moreover, the glutathione-conjugating activity of GSTP1-1 was not involved in the regulation of TRAF2 signaling. These findings indicate that GSTP1-1 plays an important regulatory role in TNF-alpha-induced signaling by forming ligand-binding interactions with TRAF2, which provides a new insight for analysing the protective effects of GSTP1-1 in tumor cells.
人类谷胱甘肽S-转移酶P1-1（GSTP1-1）是一种广泛表达的蛋白质，在解毒和外源性物质代谢中发挥重要作用。研究表明，GSTP1-1与c-Jun氨基末端激酶（JNK）相互作用并抑制其活性。在此，我们报道了GSTP1-1在调节肿瘤坏死因子-α（TNF-α）触发信号方面的新功能。目前的实验表明，GSTP1-1在体内和体外均与肿瘤坏死因子受体相关因子2（TRAF2）发生物理关联。GSTP1-1的过表达抑制了TRAF2诱导的JNK和p38的激活，但不影响核因子-κB（NF-κB）的激活。谷胱甘肽S-转移酶P1-1还减弱了TRAF2增强的凋亡信号调节激酶1（ASK1）的自磷酸化，并通过抑制TRAF2与ASK1的相互作用来抑制TRAF2-ASK1诱导的细胞凋亡。相反，通过RNA干扰（RNAi）沉默GSTP1-1的表达会导致TNF-α依赖性TRAF2-ASK1结合增加，随后ASK1和JNK过度激活。与野生型GSTP1-1相比，缺乏TRAF结构域结合基序的突变型GSTP1-1结合TRAF2和阻断TRAF2-ASK1信号的能力显著下降。此外，GSTP1-1的谷胱甘肽结合活性不参与TRAF2信号的调节。这些发现表明，GSTP1-1通过与TRAF2形成配体结合相互作用，在TNF-α诱导的信号传导中发挥重要的调节作用，这为分析GSTP1-1在肿瘤细胞中的保护作用提供了新的见解。
