Article ; Online: Deficiency of SCAP inhibits HBV pathogenesis via activation of the interferon signaling pathway.
2023 Volume 585, Page(s) 248–258
Abstract: Hepatitis B virus (HBV) infects the liver and is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Approaches for an effective cure are thwarted by limited knowledge of virus-host interactions. Herein, we identified SCAP as a novel ... ...
| Abstract | Hepatitis B virus (HBV) infects the liver and is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Approaches for an effective cure are thwarted by limited knowledge of virus-host interactions. Herein, we identified SCAP as a novel host factor that regulates HBV gene expression. SCAP, 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 replication; furthermore, knockdown of SREBP2 but not SREBP1, the downstream effectors of SCAP, reduced HBs antigen production from HBV infected primary hepatocytes. We also demonstrated that knockdown of SCAP resulted in activation of interferons (IFNs) and IFN stimulated genes (ISGs). Conversely, ectopic expression of SREBP2 in SCAP-deficient cells restored expression of IFNs and ISGs. Importantly, expression of SREBP2 restored HBV production in SCAP knockdown cells, suggesting that SCAP participates in HBV replication through an effect on IFN production via its downstream effector SREBP2. This observation was further confirmed by blocking IFN signaling by an anti-IFN antibody, which restored HBV infection in SCAP-deficient cells. This led to the conclusion that SCAP regulates the IFN pathway through SREBP, thereby affecting the HBV lifecycle. This is the first study to reveal the involvement of SCAP in regulation of HBV infection. These results may facilitate development of new antiviral strategies against HBV. |
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| MeSH term(s) | Humans ; Hepatitis B/genetics ; Hepatitis B virus/physiology ; Interferons/pharmacology ; Liver Neoplasms ; Signal Transduction ; Sterol Regulatory Element Binding Protein 1 |
| Chemical Substances | Interferons (9008-11-1) ; Sterol Regulatory Element Binding Protein 1 ; SREBP cleavage-activating protein |
| Language | English |
| Publishing date | 2023-07-09 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 200425-2 |
| ISSN | 1096-0341 ; 0042-6822 |
| ISSN (online) | 1096-0341 |
| ISSN | 0042-6822 |
| DOI | 10.1016/j.virol.2023.07.001 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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