Interferon alpha-inducible protein 27 (IFI27) inhibits hepatitis B virus (HBV) transcription through downregulating cellular transcription factor C/EBPα

作者：Xiaoyang Yu, Cheng‐Der Liu, Sheng Shen, Elena S. Kim, Zhentao Liu, Hu Zhang, Ning Sun, Yuanjie Liu, Pia M. Martensen, Yufei Huang, Haitao Guo · 发表于：Journal of Virology · 年份：2025 · DOI：10.1128/jvi.01509-25 · 被引用次数：6 · 研究领域：Hepatitis B Virus Studies、Hepatitis C virus research、Viral Infections and Outbreaks Research

Interferon alpha (IFNα) is the only approved immunomodulatory drug for chronic hepatitis B treatment, exerting its antiviral effects through the induction of interferon-stimulated genes (ISGs). To identify key antiviral ISGs that inhibit hepatitis B virus (HBV) replication, we performed transcriptome analysis of IFNα-treated HepG2-NTCP cells and found that IFI27 was among the most differentially expressed genes. The high inducibility of IFI27 by IFNα was further validated in primary human hepatocytes. Overexpression of IFI27 significantly suppressed HBV replication in both HBV-transfected and -infected cells, primarily by reducing HBV RNA transcription. Conversely, IFI27 knockdown markedly diminished the antiviral effect of IFNα in HBV-infected cells. IFI27 is predominantly localized in the cytoplasm, and RNA-seq analysis revealed that IFI27 inhibits HBV transcription without drastically altering the host transcriptome, indicating that IFI27 does not inhibit HBV transcription directly or through altering the transcription of cellular transcription factors or inducing antiviral signaling pathways. Instead, we found that IFI27 suppresses HBV transcription by promoting the ubiquitination-dependent proteasomal degradation of C/EBPα in the cytoplasm, a cellular transcription factor critical for HBV RNA transcription. Further investigation identified the E3 ubiquitin ligase SKP2 as a key mediator of this process, facilitating IFI27-induced C/EBPα ubiquitination and degradation. Not...