title: HCV NS4B induces apoptosis through the mitochondrial death pathway.
abstract: The hepatitis C virus (HCV) NS4B protein is known to induce the formation of a membranous web that is thought to be the site of viral RNA replication. However, the exact functions of NS4B remain poorly characterized. In this study, we found that NS4B induced apoptosis in 293T cells and Huh7 cells, as confirmed by Hoechst staining, DNA fragmentation, and annexin V/PI assays. Furthermore, protein immunoblot analysis demonstrated that NS4B triggered the cleavage of caspase 3, caspase 7, and poly(ADP-ribose) polymerase (PARP). Further studies revealed that NS4B induced the activation of caspase 9, the reduction of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. However, NS4B expression did not trigger XBP1 mRNA splicing and increase the expression of binding immunoglobulin protein (BiP, or GRP78) and C/EBP homologous protein (CHOP), which serves as the indicators of ER stress. Taken together, our results suggest that HCV NS4B induces apoptosis through the mitochondrial death pathway.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.forename: Jin-Jing
authors.initials: JJ
authors.lastname: Guo
authors.forename: Sheng-Li
authors.initials: SL
authors.lastname: Zhu
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Ao
authors.forename: Ming-Zhen
authors.initials: MZ
authors.lastname: Jing
authors.forename: Ying-Long
authors.initials: YL
authors.lastname: She
authors.forename: Zheng-Hui
authors.initials: ZH
authors.lastname: Wu
authors.forename: Lin-Bai
authors.initials: LB
authors.lastname: Ye
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D016174:Hepacivirus / Q000472:pathogenicity*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059748:Proteolysis; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C080107:NS4B protein, flavivirus; D017361:Viral Nonstructural Proteins; D037521:Virulence Factors; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9