College of Life Sciences, Wuhan University, Wuhan 430072, China.
Structural Studies Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
Viruses. 2019 May 9;11(5):427. doi: 10.3390/v11050427.
Human hepatitis B virus core protein (HBc) is a structural protein of the hepatitis B virus (HBV) and contributes to HBV regulation of host-cell transcription. However, the mechanisms of transcriptional regulation remain poorly characterized. To dissect the function of HBc, a yeast two-hybrid was performed to identify HBc-binding proteins, and the C-terminal of BRG1/hBRM-associated factors 200 (BAF200C) was identified. Then, the existence of HBc interactions with BAF200C and full-length BAF200 was confirmed via co-immunoprecipitation assays in 293T, HepG2 and HepG2-NTCP cells. Furthermore, we show that the binding between HBc and BAF200 was of vital importance to HBc mediated downregulation of interferon-induced transmembrane protein 1 (IFITM1) expression, and the mechanisms for the downregulation were disclosed as follows. Basal level of IFITM1 expression depends on BAF200, rather than the JAK-STAT1 pathway. The interaction of HBc with BAF200 disturbs the stability of the polybromo-associated BAF (PBAF) complex and results in the suppression of IFTM1 transcription. Finally, the antiviral effects of IFITM1 on cell proliferation and HBV replication were found to be partially restored when HBc was co-transfected with BAF200. Collectively, our findings indicate that HBc plays a role in HBV resistance against the antiviral activities of IFNα, providing details about HBV evasion of host innate immunity.
人乙型肝炎病毒核心蛋白（HBc）是乙型肝炎病毒（HBV）的结构蛋白，有助于 HBV 调节宿主细胞转录。然而，转录调控的机制仍知之甚少。为了剖析 HBc 的功能，进行了酵母双杂交以鉴定 HBc 结合蛋白，并鉴定出 BRG1/hBRM 相关因子 200 的 C 端（BAF200C）。然后，通过共免疫沉淀实验在 293T、HepG2 和 HepG2-NTCP 细胞中证实了 HBc 与 BAF200C 和全长 BAF200 的相互作用。此外，我们表明，HBc 与 BAF200 的结合对于 HBc 介导的干扰素诱导跨膜蛋白 1（IFITM1）表达下调至关重要，并且揭示了下调的机制如下。IFITM1 表达的基础水平取决于 BAF200，而不是 JAK-STAT1 途径。HBc 与 BAF200 的相互作用扰乱了多溴相关 BAF（PBAF）复合物的稳定性，并导致 IFTM1 转录的抑制。最后，发现当 HBc 与 BAF200 共转染时，IFITM1 对细胞增殖和 HBV 复制的抗病毒作用部分恢复。总之，我们的研究结果表明，HBc 在 HBV 抵抗 IFNα 的抗病毒活性中发挥作用，为 HBV 逃避宿主先天免疫提供了详细信息。
