Hepatitis C Virus Core Protein Activates Nuclear Factor κB-dependent Signaling through Tumor Necrosis Factor Receptor-associated Factor

Abstract

Hepatitis C virus (HCV) core protein, a viral nucleocapsid, has been shown to affect various intracellular events including the nuclear factor κB (NF-κB) signaling supposedly associated with inflammatory response, cell proliferation, and apoptosis. In order to elucidate the effect of HCV core protein on the NF-κB signaling in HeLa and HepG2 cells, a reporter assay was utilized. HCV core protein significantly activated NF-κB signaling in a dose-dependent manner not only in HeLa and HepG2 cells transiently transfected with core protein expression plasmid, but also in HeLa cells induced to express core protein under the control of doxycycline. HCV core protein increased the DNA binding affinity of NF-κB in the electrophoretic mobility shift assay. Acetyl salicylic acid, an IKKβ-specific inhibitor, and dominant negative form of IKKβ significantly blocked NF-κB activation by HCV core protein, suggesting HCV core protein activates the NF-κB pathway mainly through IKKβ. Moreover, the dominant negative forms of TRAF2/6 significantly blocked activation of the pathway by HCV core protein, suggesting HCV core protein mimics proinflammatory cytokine activation of the NF-κB pathway through TRAF2/6. In fact, HCV core protein activated interleukin-1β promoter mainly through NF-κB pathway. Therefore, this function of HCV core protein may play an important role in the inflammatory reaction induced by this hepatotropic virus.