Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals.
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.Oncogene (2006) 25, 5787-5800. doi:10.1038/sj.onc.1209576; published online 24 April 2006.[1]References
- Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals. Wu, Y., Fan, Y., Xue, B., Luo, L., Shen, J., Zhang, S., Jiang, Y., Yin, Z. Oncogene (2006) [Pubmed]
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