title: Hepatitis C Virus Nonstructural Protein 5A Inhibits MG132-Induced Apoptosis of Hepatocytes in Line with NF-κB-Nuclear Translocation.
abstract: BACKGROUND
  Hepatitis C virus (HCV) infection is one of the major causes of cirrhosis and hepatocellular carcinoma. HCV nonstructural protein 5A (NS5A) is an attractive antiviral target and plays an important role in HCV replication as well as hepatocarcinogenesis. The aim of this study was to assess the effect of HCV NS5A protein in the abrogation of apoptotic cell death induced by the proteasome inhibitor MG132.
  
  
  METHODS
  Apoptotic responses to MG132 and the expression of molecules involved in NF-κB signaling pathways in human hepatocytes were investigated with or without the expression of HCV NS5A.
  
  
  RESULTS
  HCV NS5A protected HepG2 cells against MG132-induced apoptosis, in line with NF-κB-nuclear translocation. A similar NF-κB-nuclear translocation was observed in Huh7 cells infected with HCV JFH1. In agreement with this, after treatment with MG132, HCV NS5A could elevate the transcription of several NF-κB target genes such as BCL2 and BCLXL to inhibit MG132-induced apoptosis in hepatocytes. HCV HCV NS5A also enhanced phosphorylation of IκBα. Consistent with a conferred prosurvival advantage, HCV NS5A reduced MG132-induced poly(adenosine diphosphate-ribose) polymerase cleavage.
  
  
  CONCLUSIONS
  HCV NS5A expression enhances phosphorylation of IκBα, liberates NF-κB for nuclear translocation and downregulates MG132-induced apoptotic pathways in human hepatocytes. It is possible that the disruption of proteasome-associated apoptosis plays a role in the pathogenesis of HCV infection.
authors.affiliation: Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
authors.forename: Xia
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kanda
authors.affiliation: Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wu
authors.affiliation: Departments of Molecular Virology, Chiba University, Graduate School of Medicine, Chiba, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakamoto
authors.affiliation: Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
authors.forename: Reina
authors.initials: R
authors.lastname: Sasaki
authors.affiliation: Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Haga
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.affiliation: Departments of Molecular Virology, Chiba University, Graduate School of Medicine, Chiba, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shirasawa
authors.affiliation: Departments of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokosuka
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D016328:NF-kappa B; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde