Involvement of the SREBP pathway in HBV pathogenesis via manipulation of interferon signaling

Hepatitis B virus (HBV) infects the liver and is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Approaches for an effective cure for the virus are thwarted by the limited knowledge on virus-host interactions. Herein, we identified SCAP as a novel host factor that regulates HBV gene expression. SCAP which stands for sterol regulatory element-binding protein (SREBP) cleavage-activating protein is an integral membrane protein located in the endoplasmic reticulum. The protein plays a central role in controlling lipid synthesis and uptake by cells. We found that gene silencing of SCAP significantly inhibited HBV production through activation of interferons (IFNs) and interferon stimulated genes (ISGs). Consequently, ectopic expression of SREBP-2, a downstream effector of SCAP in SCAP deficient cells inhibited the IFNs/ISGs expression thereby restoring HBV production. Importantly, treatment of SCAP deficient cells with an interferon blocking antibody also rescued HBV infection. Our results suggest that SCAP via its downstream effector SREBP2 participates in HBV replication through an effect on the interferon production. This observation was further characterized by an increase in HBV production through ectopic expression of SREBP2 compared to control in the parental HepG2-NTCP cells. This is the first study to reveal the involvement of SCAP in regulation of HBV transcription. These results may shed light on development of new antiviral strategies against HBV.