Journal
VIROLOGY
Volume 412, Issue 2, Pages 284-296Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2010.12.051
Keywords
Hepatitis C virus; TGF-beta 1; Furin; Thrombospondin-1; HCV replication; ROS; Calcium
Categories
Funding
- American Cancer Society, Illinois Division, Inc. [09-14]
- NIH/NIAID [R21:AI078532]
- Rosalind Franklin University of Medicine and Science-H.M.
- Bligh Cancer Research Fund
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In this study, we demonstrated the molecular mechanisms of TGF-beta 1 induction as well as proteolytic activation in HCV (JFH-1)-infected cells. Our studies showed the synthesis and secretion of TGF-beta 1 in HCV-infected cells which was reduced in the presence of Ca2+ chelators, an inhibitor of mitochondrial Ca2+ uptake, and antioxidants. We also showed that the expression of HCV NS proteins NS3/4A, and NS5A can induce TGF-beta 1 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-beta 1 activity. Using siRNA approach we demonstrated that HCV-induced furin and thrombospondin-1 (TSP-1) are involved in the proteolytic activation of TGF-beta 1. Our results also suggest that TGF-beta 1 positively regulates HCV RNA replication. Collectively, these observations provide insight into the mechanism of TGF-beta 1 activation, which likely manifest in liver fibrosis associated with hepatitis C infection. (C) 2011 Elsevier Inc. All rights reserved.
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