Abstract
Hepatitis B virus (HBV) is the major causative factor of chronic viral hepatitis, liver cirrhosis, and hepatocellular carcinoma. We previously demonstrated that a proinflammatory cytokine IL-1β reduced the level of HBV RNA. However, the mechanism underlying IL-1β-mediated viral RNA reduction remains incompletely understood. In this study, we report that immune regulator Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) can reduce HBV RNA in hepatocytes. MCPIP1 expression level was higher in the liver tissue of HBV-infected patients and mice. Overexpression of MCPIP1 decreased HBV RNA, whereas ablating MCPIP1 in vitro enhanced HBV production. The domains responsible for RNase activity or oligomerization, were required for MCPIP1-mediated viral RNA reduction. The epsilon structure of HBV RNA was important for its antiviral activity and cleaved by MCPIP1 in the cell-free system. Lastly, knocking out MCPIP1 attenuated the anti-HBV effect of IL-1β, suggesting that MCPIP1 is required for IL-1β-mediated HBV RNA reduction. Overall, these results suggest that MCPIP1 may be involved in the antiviral effect downstream of IL-1β.
Highlights
Hepatitis B virus (HBV), an enveloped DNA virus that relies on reverse transcription for replication and its persistent infection increases the risk of hepatocellular carcinoma[1]
We found that the expression of Monocyte chemotactic protein-1-induced protein 1 (MCPIP1), MCPIP2, and MCPIP4, but not that of MCPIP3, was increased in the liver tissue taken from patients with chronic HBV infection (n = 122), compared to healthy patients (n = 6) (Fig. S1A), based on the expression profiling of chronic hepatitis B (CHB) liver (GSE83148)[9]
We found that MCPIP1 protein was increased (Fig. 4D), and this led us to assess the contribution of MCPIP1 to the IL-1β-mediated anti-HBV activity in hepatocytes
Summary
Hepatitis B virus (HBV), an enveloped DNA virus that relies on reverse transcription for replication and its persistent infection increases the risk of hepatocellular carcinoma[1]. Reverse-transcriptase inhibitors are used in anti-HBV treatments and efficiently suppress viral replication in hepatocytes with little side effect. They cannot completely eradicate the virus from the patients and emergence of drug resistant virus warrants investigation of novel targets for antiviral therapy. Regarding HBV, the 5′ and 3′ ends of its pregenomic RNA (pgRNA) contain two epsilon structures, comprising 60 nt bulged stem-loops with UGU loop sequence. We hypothesized that MCPIP1 targeted the epsilon stem-loop structure of viral RNA and investigated the role of MCPIPs in HBV infection. We found that MCPIP1 reduces HBV RNA, most likely by cleaving epsilon structure of pgRNA, and acts downstream of IL-1β-mediated antiviral pathway
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