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Journal of Virology, February 1999, p. 1672-1681, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Hepatitis C Virus Core Protein Enhances NF-kappa B Signal Pathway Triggering by Lymphotoxin-beta Receptor Ligand and Tumor Necrosis Factor Alpha

Li-Ru You, Chun-Ming Chen, and Yan-Hwa Wu Lee*

Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan, Republic of China

Received 7 August 1998/Accepted 20 October 1998

Our previous study indicated that the core protein of hepatitis C virus (HCV) can associate with tumor necrosis factor receptor (TNFR)-related lymphotoxin-beta receptor (LT-beta R) and that this protein-protein interaction plays a modulatory effect on the cytolytic activity of recombinant form LT-beta R ligand (LT-alpha 1beta 2) but not tumor necrosis factor alpha (TNF-alpha ) in certain cell types. Since both TNF-alpha /TNFR and LT-alpha 1beta 2/LT-beta R are also engaged in transcriptional activator NF-kappa B activation or c-Jun N-terminal kinase (JNK) activation, the biological effects of the HCV core protein on these regards were elucidated in this study. As demonstrated by the electrophoretic mobility shift assay, the expression of HCV core protein prolonged or enhanced the TNF-alpha or LT-alpha 1beta 2-induced NF-kappa B DNA-binding activity in HuH-7 and HeLa cells. The presence of HCV core protein in HeLa or HuH-7 cells with or without cytokine treatment also enhanced the NF-kappa B-dependent reporter plasmid activity, and this effect was more strongly seen with HuH-7 cells than with HeLa cells. Western blot analysis suggested that this modulation of the NF-kappa B activity by the HCV core protein was in part due to elevated or prolonged nuclear retention of p50 or p65 species of NF-kappa B in core protein-producing cells with or without cytokine treatment. Furthermore, the HCV core protein enhanced or prolonged the Ikappa B-beta degradation triggering by TNF-alpha or LT-alpha 1beta 2 both in HeLa and HuH-7 cells. In contrast to that of Ikappa B-beta , the increased degradation of Ikappa B-alpha occurred only in LT-alpha 1beta 2-treated core-producing HeLa cells and not in TNF-alpha -treated cells. Therefore, the HCV core protein plays a modulatory effect on NF-kappa B activation triggering by both cytokines, though the mechanism of NF-kappa B activation, in particular the regulation of Ikappa B degradation, is rather cell line and cytokine specific. Studies also suggested that the HCV core protein had no effect on TNF-alpha -stimulated JNK activity in both HeLa and HuH-7 cells. These findings, together with our previous study, strongly suggest that among three signaling pathways triggered by the TNF-alpha -related cytokines, the HCV core protein potentiates NF-kappa B activation in most cell types, which in turn may contribute to the chronically activated, persistent state of HCV-infected cells.

* Corresponding author. Mailing address: Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan 112. Phone: 886-2-2826-7124. Fax: 886-2-2826-4843. E-mail: yhwulee{at}ym.edu.tw.

Journal of Virology, February 1999, p. 1672-1681, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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