Inhibition of Cytochrome c Release in Fas-mediated Signaling Pathway in Transgenic Mice Induced to Express Hepatitis C Viral Proteins

Persistent hepatitis C virus (HCV) infection often progresses to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Numerous viruses have been reported to escape from apoptotic mechanism to maintain persistent infection. In the present study, we characterized the effect of HCV proteins on t...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-04, Vol.276 (15), p.12140-12146
Main Authors: Machida, Keigo, Tsukiyama-Kohara, Kyoko, Seike, Eiji, Toné, Shigenobu, Shibasaki, Futoshi, Shimizu, Masumi, Takahashi, Hidemi, Hayashi, Yukiko, Funata, Nobuaki, Taya, Choji, Yonekawa, Hiromichi, Kohara, Michinori
Format: Article
Language:English
Subjects:
AE1 protein
AE2 protein
Animals
ANS2 protein
Apoptosis - physiology
Caspases - metabolism
cytochrome c
Cytochrome c Group - metabolism
E1 protein
E2 protein
Fas antigen
fas Receptor - physiology
Hepacivirus - metabolism
Hepatitis C virus
Liver - metabolism
Mice
Mice, Inbred BALB C
Mice, Transgenic
NS2 protein
Signal Transduction - physiology
Viral Proteins - metabolism
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Summary:Persistent hepatitis C virus (HCV) infection often progresses to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Numerous viruses have been reported to escape from apoptotic mechanism to maintain persistent infection. In the present study, we characterized the effect of HCV proteins on the Fas signal using HCV transgenic mice, which expressed core, E1, E2, and NS2 proteins, regulated by the Cre/loxP switching system. The transgene expression of HCV transgenic mice caused resistance to Fas antibody stimulated lethality. Apoptotic cell death in the liver of HCV protein expressing mice was significantly reduced compared with nonexpressing mice. Histopathological analysis and DNA fragmentation analysis revealed that the HCV proteins suppressed Fas-mediated apoptotic cell death. To identify the target pathway of HCV proteins, we characterized caspase activity. The activation of caspase-9 and -3/7 but not caspase-8 was inhibited by HCV proteins. Cytochromec release from mitochondria was inhibited in HCV protein expressing mice. These results indicated that the expression of HCV proteins may directly or indirectly inhibit Fas-mediated apoptosis and death in mice by repressing the release of cytochrome cfrom mitochondria, thereby suppressing caspase-9 and -3/7 activation. These results suggest that HCV may cause persistent infection, as a result of suppression of Fas-mediated cell death.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M010137200