title: Hepatitis C virus-induced furin and thrombospondin-1 activate TGF-β1: role of TGF-β1 in HCV replication.
abstract: In this study, we demonstrated the molecular mechanisms of TGF-β1 induction as well as proteolytic activation in HCV (JFH-1)-infected cells. Our studies showed the synthesis and secretion of TGF-β1 in HCV-infected cells which was reduced in the presence of Ca(2+) chelators, an inhibitor of mitochondrial Ca(2+) uptake, and antioxidants. We also showed that the expression of HCV NS proteins NS3/4A, and NS5A can induce TGF-β1 by cell-based luciferase assay. Furthermore, mutational analysis revealed that the functionally active protease domain of NS3 and N-terminus domain of NS5A are required for TGF-β1 activity. Using siRNA approach we demonstrated that HCV-induced furin and thrombospondin-1 (TSP-1) are involved in the proteolytic activation of TGF-β1. Our results also suggest that TGF-β1 positively regulates HCV RNA replication. Collectively, these observations provide insight into the mechanism of TGF-β1 activation, which likely manifest in liver fibrosis associated with hepatitis C infection.
authors.affiliation: Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA.
authors.forename: Lance D
authors.initials: LD
authors.lastname: Presser
authors.forename: Adam
authors.initials: A
authors.lastname: Haskett
authors.forename: Gulam
authors.initials: G
authors.lastname: Waris
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004252:DNA Mutational Analysis; D045683:Furin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020868:Gene Silencing; D017930:Genes, Reporter; D016174:Hepacivirus / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D002352:Carrier Proteins; D045683:Furin; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases; D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase