Hepatitis C virus nonstructural 5B protein regulates tumor necrosis factor alpha signaling through effects on cellular IkappaB kinase.
Hepatitis C virus (HCV) NS5B protein is a membrane-associated phosphoprotein that possesses an RNA-dependent RNA polymerase activity. We recently reported that NS5A protein interacts with TRAF2 and modulates tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB and Jun N-terminal protein kinase (JNK). Since NS5A and NS5B are the essential components of the HCV replication complex, we examined whether NS5B could modulate TNF-alpha-induced NF-kappaB and JNK activation. In this study, we have demonstrated that TNF-alpha-induced NF-kappaB activation is inhibited by NS5B protein in HEK293 and hepatic cells. Furthermore, NS5B protein inhibited both TRAF2- and IKK-induced NF-kappaB activation. Using coimmunoprecipitation assays, we show that NS5B interacts with IKKalpha. Most importantly, NS5B protein in HCV subgenomic replicon cells interacted with endogenous IKKalpha, and then TNF-alpha-mediated IKKalpha kinase activation was significantly decreased by NS5B. Using in vitro kinase assay, we have further found that NS5B protein synergistically activated TNF-alpha-mediated JNK activity in HEK293 and hepatic cells. These data suggest that NS5B protein modulates TNF-alpha signaling pathways and may contribute to HCV pathogenesis.
Choi
Soo-Ho
SH
Ilsong Institute of Life Science, Hallym University, 1 Ockcheon-dong, Chuncheon 200-702, South Korea.
Park
Kyu-Jin
KJ
Ahn
Byung-Yoon
BY
Jung
Guhung
G
Lai
Michael M C
MM
Hwang
Soon B
SB
D000818:Animals; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D017930:Genes, Reporter; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000032:analysis / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins; D008156:Luciferases; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4