Small hepatitis delta antigen selectively binds to target mRNA in hepatic cells: a potential mechanism by which hepatitis D virus downregulates glutathioneS-transferase P1 and induces liver injury and hepatocarcinogenesis

Abstract

Liver co-infection by hepatitis B virus (HBV) and hepatitis D virus (HDV) can result in a severe form of hepatocellular carcinoma with poor prognosis. Co-infection with HDV and HBV causes more deleterious effects than infection with HBV alone. Clinical research has shown that glutathione S-transferase P1 (GSTP1), a tumor suppressor gene, is typically down-regulated in liver samples from hepatitis-infected patients. In the present study, our data indicated that small HDV antigen (s-HDAg) could specifically bind to GSTP1 mRNA and significantly down-regulate GSTP1 protein expression. For the human fetal hepatocyte cell line L-02, cells transfected with s-HDAg, along with decreased GSTP1 expression, there was a significant accumulation of reactive oxygen species (ROS) and increased apoptotic ratios. Restoring GSTP1 expression through silencing s-HDAg via RNAi or over-expressing exogenous GSTP1 could largely recover the abnormal cell status. Our results revealed a novel potential mechanism of HDV-induced liver injury and hepatocarcinogenesis: s-HDAg can inhibit GSTP1 expression by directly binding to GSTP1 mRNA, which leads to accumulation of cellular ROS, resulting in high cellular apoptotic ratios and increased selective pressure for malignant transformation. To our knowledge, this is the first study to examine s-HDAg-specific pathogenic mechanisms through potential protein-RNA interactions.

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“…Secondly, both isoforms of HDAg have been shown to interact with and strongly repress both HBV enhancer sequences, with a direct impact on HBV replication [92]. Thirdly, HDAg, being an RNA-binding protein that has recently been shown to interact with specific cellular RNAs [93], [94], [95], may bind to HBV mRNAs and selectively affect their stability. Finally, accumulating evidence suggests that, in HBV-infected patients, integrated HBV DNA is an abundant source of HBsAg, even in the absence of HBV replication [96], [97], [98].…”

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“…Hundreds of millions of infected individuals have chronic hepatitis B (CHB), which represents a serious threat to public health (1,2). China is a moderately endemic area of HBV infection, the treatment of which is thus one of the serious challenges for China's medical community (3,4). After initial acute infection, certain individuals continue to be infected, the disease gradually turns into CHB.…”

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“…On the contrary, microsomal glutathione S-transferase 1 (MGST1) was decreased by Cov-miR-2 with miR-4505 (Figure 3). Since glutathione S-transferase downregulation was observed in hepatitis D virus infection and its downregulation was implicated in liver injury [57]. MGST1 downregulation may be related with lung injury in SARS-CoV-2 infection.…”