Abstract
The nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) is a phosphoprotein possessing various functions. We have previously reported that the HCV NS5A protein interacts with tumor necrosis factor (TNF) receptor-associated factor (TRAF) domain of TRAF2 (Park, K.-J., Choi, S.-H., Lee, S. Y., Hwang, S. B., and Lai, M. M. C. (2002) J. Biol. Chem. 277, 13122-13128). Both TNF-alpha- and TRAF2-mediated nuclear factor-kappaB (NF-kappaB) activations were inhibited by NS5A-TRAF2 interaction. Because TRAF2 is required for the activation of both NF-kappaB and c-Jun N-terminal kinase (JNK), we investigated HCV NS5A protein for its potential capacity to modulate TRAF2-mediated JNK activity. Using in vitro kinase assay, we have found that NS5A protein synergistically activated both TNF-alpha- and TRAF2-mediated JNK in human embryonic kidney 293T cells. Furthermore, synergism of NS5A-mediated JNK activation was inhibited by dominant-negative form of MEK kinase 1. Our in vivo binding data show that NS5A does not inhibit interaction between TNF receptor-associated death domain and TRAF2 protein, indicating that NS5A and TRAF2 may form a ternary complex with TNF receptor-associated death domain. These results indicate that HCV NS5A protein modulates TNF signaling of the host cells and may play a role in HCV pathogenesis.
Highlights
The nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) is a phosphoprotein possessing various functions
NS5A Protein Potentiates tumor necrosis factor (TNF)-␣-induced Jun N-terminal kinase (JNK)/Stress-activated Protein Kinase Activation in human embryonic kidney (HEK) 293T Cells—Previous studies have shown that TNF-␣ induces activation of both transcription factor nuclear factor-B (NF-B) [34] and the JNK [23, 35] through TNFR1
We found that TNF-␣-induced JNK activity was significantly increased by NS5A protein in hepatocyte-derived HepG2
Summary
The nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) is a phosphoprotein possessing various functions. Using in vitro kinase assay, we have found that NS5A protein synergistically activated both TNF-␣- and TRAF2-medidated JNK in human embryonic kidney 293T cells. The effects of HCV NS5A protein on JNK activation induced by TNF and TRAF2 were investigated.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have