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 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-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.

Mechanism of Hepatitis C Virus (HCV)-induced Osteopontin and Its Role in Epithelial to Mesenchymal Transition of Hepatocytes

“…2D). No significant cytotoxicity was observed in mock-and HCV-infected cells treated with these inhibitors as shown by us earlier (12). Taken together, these results suggest that HCV-mediated altered Ca 2ϩ signaling in the ER and elevation of ROS production in the mitochondria are critical for OPN induction as well as secretion.…”

“…Oxidative stress and steatosis is suggested to play a critical role in the development of liver injury or HCC in chronic HCV infection (9,10). Our previous studies have shown the induction of oxidative stress in human hepatoma cells expressing HCV proteins or infected with HCV (11,12).…”

“…HCV Activates OPN via Ca 2ϩ Signaling and Elevation of ROSOur previous studies have shown that HCV-induced Ca 2ϩ signaling and elevation of ROS play a key role in the cell signaling cascade (12,23,25,26). To determine whether HCV-induced Ca 2ϩ signaling and induction of ROS activate OPN, mock-and HCV-infected cells were incubated with nontoxic doses of antioxidant (NAC), an inhibitor of mitochondrial Ca 2ϩ uptake (Ru360), intracellular Ca 2ϩ chelator (BAPTA-AM), and extracellular Ca 2ϩ chelator (EGTA).…”

Association between TGFB1 915G/C polymorphism and susceptibility to chronic hepatitis C virus infection: A meta-analysis

“…HCV infection is characterized by the impairment of HCV-specific effector T-cell responses, suggesting that TGF-β1, as an effector cytokine, possibly contributes to the long-term persistence of HCV infection (16). Furthermore, Presser et al (38) demonstrated that TGF-β1 positively regulates HCV RNA replication. The 915G/C polymorphism in TGFB1 is associated with TGF-β1 levels.…”

Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus

“…core, E1, E2, NS3/4A, NS4B, and NS5A) (5), with core being the most potent inducer (10,11). Several mechanisms have been identified by which HCV infection can lead to the induction of ROS/RNS, including mitochondrial alterations (12)(13)(14)(15)(16); redistribution of calcium between the ER, cytoplasm, and mitochondria (17)(18)(19)(20)(21)(22)(23); increased expression of NADPH oxidases (24,25); enhanced expression of CYP2E1 (26 -29); as well as ER stress and the unfolded protein response (10,18,22,30,31). Oxidative stress also impacts the HCV life cycle at the level of replication and translation and can lead to viral genome heterogeneity, possibly facilitating viral escape from immune detection (32)(33)(34)(35)(36).…”