Ferritin heavy chain is the host factor responsible for HCV-induced inhibition of apoB-100 production and is required for efficient viral infection

J Proteome Res. 2012 May 4;11(5):2786-97. doi: 10.1021/pr201128s. Epub 2012 Apr 10.

Abstract

Hepatic fat export occurs by apolipoprotein B-100-containing lipoprotein production, whereas impaired production leads to liver steatosis. Hepatitis C virus (HCV) infection is associated to dysregulation of apoB-100 secretion and steatosis; however, the molecular mechanism by which HCV affects the apoB-100 secretion is not understood. Here, combining quantitative proteomics and computational biology, we propose ferritin heavy chain (Fth) as being the cellular determinant of apoB-100 production inhibition. By means of molecular analyses, we found that HCV nonstructural proteins and NS5A appear to be sufficient for inducing Fth up-regulation. Fth in turn was found to inhibit apoB-100 secretion leading to increased intracellular degradation via proteasome. Notably, intracellular Fth down-regulation by siRNA restores apoB-100 secretion. The inverse correlation between ferritin and plasma apoB-100 concentrations was also found in JFH-1 HCV cell culture systems (HCVcc) and HCV-infected patients. Finally, Fth expression was found to be required for robust HCV infection. These observations provide a further molecular explanation for the onset of liver steatosis and allow for hypothesizing on new therapeutic and antiviral strategies.

MeSH terms

  • Apoferritins / metabolism*
  • Apolipoprotein B-100 / antagonists & inhibitors*
  • Apolipoprotein B-100 / blood
  • Cell Line, Tumor
  • Computational Biology
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Fatty Liver / virology
  • Gene Expression Regulation, Viral*
  • Hepacivirus / genetics
  • Hepacivirus / metabolism
  • Hepacivirus / pathogenicity*
  • Hepatitis C / pathology
  • Hepatitis C / virology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hepatocytes / virology
  • Host-Pathogen Interactions
  • Humans
  • Isotope Labeling
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Interaction Maps
  • Proteolysis
  • Proteomics / methods
  • Transfection
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism

Substances

  • Apolipoprotein B-100
  • NS-5 protein, hepatitis C virus
  • Viral Nonstructural Proteins
  • Apoferritins
  • Proteasome Endopeptidase Complex