%0 Journal Article %A Deng, Lin %A Chen, Ming %A Tanaka, Motofumi %A Ku, Yonson %A Itoh, Tomoo %A Shoji, Ikuo %A Hotta, Hak %T HCV upregulates Bim through the ROS/JNK signalling pathway, leading to Bax-mediated apoptosis %D 2015 %J Journal of General Virology, %V 96 %N 9 %P 2670-2683 %@ 1465-2099 %R https://doi.org/10.1099/jgv.0.000221 %I Microbiology Society, %X We previously reported that hepatitis C virus (HCV) infection induces Bax-triggered, mitochondrion-mediated apoptosis by using the HCV J6/JFH1 strain and Huh-7.5 cells. However, it was still unclear how HCV-induced Bax activation. In this study, we showed that the HCV-induced activation and mitochondrial accumulation of Bax were significantly attenuated by treatment with a general antioxidant, N-acetyl cysteine (NAC), or a specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, with the result suggesting that the reactive oxygen species (ROS)/JNK signalling pathway is upstream of Bax activation in HCV-induced apoptosis. We also demonstrated that HCV infection transcriptionally activated the gene for the pro-apoptotic protein Bim and the protein expression of three major splice variants of Bim (BimEL, BimL and BimS). The HCV-induced increase in the Bim mRNA and protein levels was significantly counteracted by treatment with NAC or SP600125, suggesting that the ROS/JNK signalling pathway is involved in Bim upregulation. Moreover, HCV infection led to a marked accumulation of Bim on the mitochondria to facilitate its interaction with Bax. On the other hand, downregulation of Bim by siRNA (small interfering RNA) significantly prevented HCV-mediated activation of Bax and caspase 3. Taken together, these observations suggest that HCV-induced ROS/JNK signalling transcriptionally activates Bim expression, which leads to Bax activation and apoptosis induction. %U https://www.microbiologyresearch.org/content/journal/jgv/10.1099/jgv.0.000221