title: Hepatitis C virus core protein modulates TRAIL-mediated apoptosis by enhancing Bid cleavage and activation of mitochondria apoptosis signaling pathway.
abstract: Hepatitis C virus (HCV) is a major human pathogen causing chronic liver disease, which leads to cirrhosis of liver and hepatocellular carcinoma. The HCV core protein, a viral nucleocapsid, has been shown to affect various intracellular events, including cell proliferation and apoptosis. However, the precise mechanisms of the effects are not fully understood. In this study, we show that HCV core protein sensitizes human hepatocellular carcinoma cell line, Huh7, conferred sensitivity to TRAIL-, but not Fas ligand-mediated apoptosis. Huh7 cells are resistant to TRAIL, despite the induction of caspase-8 after TRAIL engagement. However, HCV core protein induces TRAIL apoptosis signaling via sequential induction of caspase-8, Bid cleavage, activation of mitochondrial pathway, and effector caspase-3. HCV core protein also induces activation of caspase-9 after TRAIL engagement, and the induction of TRAIL sensitivity by HCV core protein could be reversed by caspase-9 inhibitor. Therefore, the HCV core protein-induced TRAIL-mediated apoptosis is dependent upon activation of caspase-8 downstream pathway to convey the death signal to mitochondria, leading to activation of mitochondrial signaling pathway and breaking the apoptosis resistance. These results combined indicate that the HCV core protein enhances TRAIL-, but not Fas ligand-mediated apoptotic cell death in Huh7 cells via a mechanism dependent on the activation of mitochondria apoptosis signaling pathway. These results suggest that HCV core protein may have a role in immune-mediated liver cell injury by modulation of TRAIL-induced apoptosis.
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ai-Hsiang
authors.initials: AH
authors.lastname: Chou
authors.forename: Hwei-Fang
authors.initials: HF
authors.lastname: Tsai
authors.forename: Yi-Ying
authors.initials: YY
authors.lastname: Wu
authors.forename: Chung-Yi
authors.initials: CY
authors.lastname: Hu
authors.forename: Lih-Hwa
authors.initials: LH
authors.lastname: Hwang
authors.forename: Ping-I
authors.initials: PI
authors.lastname: Hsu
authors.forename: Ping-Ning
authors.initials: PN
authors.lastname: Hsu
mesh_terms: D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology / Q000821:virology; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000276:immunology; D053222:Fas Ligand Protein; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D006868:Hydrolysis; D007155:Immunologic Factors / Q000502:physiology*; D008024:Ligands; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology / Q000821:virology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011499:Protein Processing, Post-Translational / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D014758:Viral Core Proteins / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007155:Immunologic Factors; D008024:Ligands; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; D019014:fas Receptor; C069130:nucleocapsid protein, Hepatitis C virus; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases