The hepatitis C virus NS2 protein is an inhibitor of CIDE-B-induced apoptosis

Abstract : Chronic hepatitis C virus (HCV) infection frequently leads to liver cancer. To determine the viral factor(s) potentially involved in viral persistence, we focused our work on NS2, a viral protein of unknown function. To assign a role for NS2, we searched for cellular proteins that interact with NS2. Performing a two-hybrid screen on a human liver cDNA library, we found that NS2 interacted with the liver-specific pro-apoptotic CIDE-B protein. Binding specificity of NS2 for CIDE-B was confirmed by cell-free assays associated with colocalization studies and coprecipitation experiments on human endogenous CIDE-B. CIDE-B, a member of the novel CIDE family of apoptosis-inducing factors, has been reported to show strong cell death-inducing activity in its C-terminal domain. We show that this CIDE-B killing domain is involved in the NS2 interaction. NS2 binding was sufficient to inhibit CIDE-B-induced apoptosis because an NS2 deletion mutant unable to interact with CIDE-B in vitro lost its capacity to interfere with CIDE-B cell death activity. Although it has been reported that CIDE-B-induced apoptosis is characterized by mitochondrial localization, the precise apoptotic mechanism remained unknown. Here, we show that CIDE-B induced cell death in a caspase-dependent manner through cytochrome c release from mitochondria. Furthermore, we found that NS2 counteracted the cytochrome c release induced by CIDE-B. In vivo, the CIDE-B protein level was extremely low in adenovirus-infected transgenic mice expressing the HCV polyprotein compared with that in wild-type mice. We suggest that NS2 interferes with the CIDE-B-induced death pathway and participates in HCV strategies to subvert host cell defense.
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https://hal.archives-ouvertes.fr/hal-02239686
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Submitted on : Thursday, August 1, 2019 - 3:50:12 PM
Last modification on : Saturday, August 3, 2019 - 1:21:00 AM

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  • HAL Id : hal-02239686, version 1

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L. Erdtmann, N. Franck, H. Lerat, J. Le Seyec, D. Gilot, et al.. The hepatitis C virus NS2 protein is an inhibitor of CIDE-B-induced apoptosis. Journal of Biological Chemistry, 2003, 278 (20), pp.18256--18264. ⟨hal-02239686⟩

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