Abstract
Hepatitis C virus (HCV) replication is associated with endoplasmic reticulum (ER) and its infection triggers ER stress. In response to ER stress, ER overload response (EOR) can be activated, which involves the release of Ca2+ from ER, production of reactive oxygen species (ROS) and activation of nuclear factor κB (NF-κB). We have previously reported that HCV NS4B expression activates NF-κB via EOR-Ca2+-ROS pathway. Here, we showed that NS4B expression and HCV infection activated cancer-related NF-κB signaling pathway and induced the expression of cancer-related NF-κB target genes via EOR-Ca2+-ROS pathway. Moreover, we found that HCV-activated EOR-Ca2+-ROS pathway had profound effects on host cell viability and HCV replication. HCV infection induced human hepatocyte death by EOR-Ca2+-ROS pathway, whereas activation of EOR-Ca2+-ROS-NF-κB pathway increased the cell viability. Meanwhile, EOR-Ca2+-ROS-NF-κB pathway inhibited acute HCV replication, which could alleviate the detrimental effect of HCV on cell viability and enhance chronic HCV infection. Together, our findings provide new insights into the functions of EOR-Ca2+-ROS-NF-κB pathway in natural HCV replication and pathogenesis.
Highlights
endoplasmic reticulum (ER) is a cellular organelle that controls several critical aspects of cellular processes such as cellular protein folding and post-translational modifications
As Hepatitis C virus (HCV) infection leads to hepatocellular carcinoma (HCC), the effects of NS4B on nuclear factor κB (NF-κB) target genes related to cancer were analyzed by real time RT-PCR and Western blot
HCV infection may lead to chronic hepatitis, liver cirrhosis and HCC, which cause a serious burden on global public health and prompt many efforts to elucidate HCV replication and pathogenesis [26]
Summary
ER is a cellular organelle that controls several critical aspects of cellular processes such as cellular protein folding and post-translational modifications. Increasing evidence indicates that virus infection often disturbs ER homeostasis and leads to ER stress response, which has profound effects on virus replication and pathogenesis [1,2]. Role of EOR in Human Hepatocyte Viability and HCV Replication and analysis, decision to publish, or preparation of the manuscript
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