title: Ferritin heavy chain is the host factor responsible for HCV-induced inhibition of apoB-100 production and is required for efficient viral infection.
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.
authors.affiliation: L. Spallanzani National Institute for Infectious Diseases, IRCCS, via Portuense 292, 00149, Rome, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Mancone
authors.forename: Claudia
authors.initials: C
authors.lastname: Montaldo
authors.forename: Laura
authors.initials: L
authors.lastname: Santangelo
authors.forename: Cristina
authors.initials: C
authors.lastname: Di Giacomo
authors.forename: Viviana
authors.initials: V
authors.lastname: Costa
authors.forename: Laura
authors.initials: L
authors.lastname: Amicone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ippolito
authors.forename: Leopoldo Paolo
authors.initials: LP
authors.lastname: Pucillo
authors.forename: Tonino
authors.initials: T
authors.lastname: Alonzi
authors.forename: Marco
authors.initials: M
authors.lastname: Tripodi
mesh_terms: D001052:Apoferritins / Q000378:metabolism*; D053299:Apolipoprotein B-100 / Q000037:antagonists & inhibitors* / Q000097:blood; D045744:Cell Line, Tumor; D019295:Computational Biology; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006526:Hepatitis C / Q000473:pathology / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007553:Isotope Labeling; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D060066:Protein Interaction Maps; D059748:Proteolysis; D040901:Proteomics / Q000379:methods; D014162:Transfection; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D001052:Apoferritins; D053299:Apolipoprotein B-100; D046988:Proteasome Endopeptidase Complex; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase