Abstract
BackgroundHepatitis C virus (HCV) is the leading cause of liver fibrosis, cirrhosis and hepatocellular carcinoma. It is believed that continuous liver cell apoptosis contributes to HCV pathogenesis. Recent studies have shown that HCV infection can sensitize host cells to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis, but the mechanism by which HCV regulates the TRAIL pathway remains unclear.Methods and ResultsUsing a sub-genomic replicon and full length virus, JFH-1, we demonstrate that HCV can sensitize host cells to TRAIL-induced apoptosis by up-regulating two TRAIL receptors, death receptor 4 (DR4) and death receptor 5 (DR5). Furthermore, the HCV replicon enhanced transcription of DR5 via Sp1, and the HCV-mediated up-regulation of DR4 and DR5 required MEK1 activity. HCV infection also stimulated the activity of MEK1, and the inhibition of MEK1 activity or the knockdown of MEK1 increased the replication of HCV.ConclusionsOur studies demonstrate that HCV replication sensitizes host cells to TRAIL-induced apoptosis by up-regulating DR4 and DR5 via a MEK1 dependent pathway. These findings may help to further understand the pathogenesis of HCV infection and provide a therapeutic target.
Highlights
TNF-related apoptosis-inducing ligand (TRAIL), known as Apo2L, is a member of the tumor necrosis factor (TNF) super family [1]
Our studies demonstrate that Hepatitis C virus (HCV) replication sensitizes host cells to TRAIL-induced apoptosis by upregulating death receptor 4 (DR4) and death receptor 5 (DR5) via a MEK1 dependent pathway
Recent studies have shown that TRAIL induces apoptosis in virus-infected cells, including cells infected with hepatitis B virus, hepatitis C virus (HCV), human immunodeficiency virus, and respiratory syncytial virus [3,4,5,6,7]
Summary
TNF-related apoptosis-inducing ligand (TRAIL), known as Apo2L, is a member of the tumor necrosis factor (TNF) super family [1]. The binding of TRAIL to DR4 or DR5 results in receptor trimerization and cell apoptosis via the recruitment of Fasassociated death domain (FADD) to the C terminus of the receptors. FADD recruits an apoptosis-initiator caspase (caspase 8 or caspase 10) via its death effecter domain to form the death-inducing signaling complex, which allows for auto activation of caspases [9]. In type 1 cells, caspase 3 is activated and cleaves many cellular proteins to induce apoptosis. In type 2 cells, the apoptosis signal is augmented by the mitochondrial pathway, which involves the activation of caspase 9 following the loss of the mitochondrial membrane potential and Apaf-1 activation [10]. Recent studies have shown that HCV infection can sensitize host cells to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis, but the mechanism by which HCV regulates the TRAIL pathway remains unclear
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