E2 of Hepatitis C Virus Inhibits Apoptosis

Abstract

Hepatitis C virus (HCV) is the major causative agent of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, and can be involved in very long chronic infections up to 30 years or more. Therefore, it has been speculated that HCV possesses mechanisms capable of modulating host defense systems such as innate and adaptive immunity. To investigate this virus-host interaction, we generated HCV replicons containing various HCV structural proteins and then analyzed the sensitivity of replicon-containing cells to the apoptosis-inducing agent, TRAIL. TRAIL-induced apoptosis was monitored by cleavage of procaspase-3 and procaspase-9 as well as that of their substrate poly(ADP-ribose) polymerase. TRAIL-induced apoptosis was inhibited in cells expressing HCV E2. Moreover, expression of HCV E2 enhanced the colony forming efficiency of replicon-containing cells by 25-fold. Blockage of apoptosis by E2 seems to be related to inhibition of TRAIL-induced cytochrome c release from the mitochondria. Based on these results, we propose that E2 augments persistent HCV infection by blocking host-induced apoptosis of infected cells.

Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and Bortezomib

“…XIAP could influence this event in two ways, directly by ubiquitinating the cleaved form of caspase-8 and causing its degradation, or indirectly by blocking caspase-3, which was previously shown to cleave caspase-8 (Wieder et al, 2001;Lee et al, 2005;Hayakawa et al, 2008). As XIAP was shown to interact with caspases 3, 7 and 9, but not 8 , it is unlikely that the accumulation of the p43/41 forms of caspase-8 is caused directly by XIAP.…”

“…As XIAP was shown to interact with caspases 3, 7 and 9, but not 8 , it is unlikely that the accumulation of the p43/41 forms of caspase-8 is caused directly by XIAP. More likely, XIAP, by inhibiting caspase-3, prevents its positive feedback loop, by which caspase-8 is further cleaved (Wieder et al, 2001;Lee et al, 2005;Hayakawa et al, 2008). Thus, lower levels of XIAP allow the accumulation of the cleaved form of caspase-8.…”

Cellular models for the screening and development of anti-hepatitis C virus agents

“…In this respect, HCV core protein has been shown to inhibit TNFα-or FAS-mediated activation of caspase 8, p21 and p53 expression, or to enhance Bcl-XL, Bcl2 and cyclin D1 expression or the Raf1/MAPK signaling pathways (Hassan et al, 2004;Saito et al, 2006). E2 was reported to inhibit apoptosis by negatively regulating the cytochrome c release from mitochondria after TRAIL activation (Lee et al, 2005). NS3/NS4A protects liver damage in animals treated with lethal doses of TNFα combined with D-galactosamine, while NS3 interacts with and affects p53 activity (Frelin et al, 2006;Tanaka et al, 2006).…”

Advances in Genomic Research on Hepatitis C Virus with a Useful Tool, Replicon System

“…24 This suggests that replicon RNA replicates in a structure surrounded by lipid membrane, i.e. lipid raft.…”

“…18,19 In the full-length HCV RNA replication system, the presence of double strand RNA (dsRNA), consisting of the HCV RNA plus strand and the minus strand, an intermediate replication product, enables easier evaluation of the influence of HCV, including the effect of dsRNA, on host factors, compared with a replicon system with nonstructural regions using a variety of promoters. Since structural proteins are required for the production of viral particles, full-length HCV RNA replication systems have advanced research on in vivo properties of the virus, including packaging, budding, and infection [20][21][22][23][24] (Fig.3).…”