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.
Related
- A Hepatitis B virus pregenomic RNA based minigene transcript utilizes polypyrimidine tract binding protein regulated NXF1-NXT1 nuclear export pathway
- Residue-level predictions of the protein-protein interactions of the hepatitis B virus core and envelope proteins
- The m6A methyltransferase complex protein VIRMA engages hepatitis C virus RNA through a WTAP-independent mechanism
- The hepatitis C virus Core protein is a potent nucleic acid chaperone that directs dimerization of the viral (+) strand RNA in vitro
- Protein inhibitor of retinal membrane guanylyl cyclase rescues photoreceptors from degeneration induced by mutated guanylyl cyclase activating protein
BibTeX
@article{erdtmann2026hepatitis,
title = {{The Hepatitis C Virus NS2 Protein Is an Inhibitor of CIDE-B-induced Apoptosis}},
author = {Lars Erdtmann and Nathalie Franck and Hervé Lerat and Jacques Le Seyec and David Gilot and Isabelle Cannie and Philippe Gripon and Urszula Hibner and Christiane Guguen-Guillouzo},
journal = {Journal of Biological Chemistry},
year = {2026},
month = oct,
doi = {10.1074/jbc.m209732200},
url = {https://hal.science/hal-05784417v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - The Hepatitis C Virus NS2 Protein Is an Inhibitor of CIDE-B-induced Apoptosis
AU - Lars Erdtmann
AU - Nathalie Franck
AU - Hervé Lerat
AU - Jacques Le Seyec
AU - David Gilot
AU - Isabelle Cannie
AU - Philippe Gripon
AU - Urszula Hibner
AU - Christiane Guguen-Guillouzo
PY - 2026
DA - 2026/10/07
JO - Journal of Biological Chemistry
DO - 10.1074/jbc.m209732200
UR - https://hal.science/hal-05784417v1
AB - 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.
SN - 0021-9258
SN - 1083-351X
ER -