Two Distinct Phases of Virus-induced Nuclear Factor κB Regulation Enhance Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated Apoptosis in Virus-infected Cells

• Published in: The Journal of biological chemistry 2003-05, Vol.278 (20), p.18092
• Main Authors: Penny Clarke, Suzanne M. Meintzer, Lisa A. Moffitt, Kenneth L. Tyler
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M300265200

Cellular transcription factors are often utilized by infecting viruses to promote viral growth and influence cell fate. We have previously shown that nuclear factor κB (NF-κB) is activated after reovirus infection and that this activation is required for virus-induced apoptosis. In this report we identify a second phase of reovirus-induced NF-κB regulation. We show that at later times post-infection NF-κB activation is blocked in reovirus-infected cells. This results in the termination of virus-induced NF-κB activity and the inhibition of tumor necrosis factor α and etoposide-induced NF-κB activation in infected cells. Reovirus-induced inhibition of NF-κB activation occurs by a mechanism that prevents IκBα degradation and that is blocked in the presence of the viral RNA synthesis inhibitor, ribavirin. Reovirus-induced apoptosis is mediated by tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in a variety of epithelial cell lines. Herein we show that ribavirin inhibits reovirus-induced apoptosis in TRAIL-resistant HEK293 cells and prevents the ability of reovirus infection to sensitize TRAIL-resistant cells to TRAIL-induced apoptosis. Furthermore, TRAIL-induced apoptosis is enhanced in HEK293 cells expressing IκBΔN2, which blocks NF-κB activation. These results indicate that the ability of reovirus to inhibit NF-κB activation sensitizes HEK293 cells to TRAIL and facilitates virus-induced apoptosis in TRAIL-resistant cells. Our findings demonstrate that two distinct phases of virus-induced NF-κB regulation are required to efficiently activate host cell apoptotic responses to reovirus infection.