Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, 100089, China.
Antiviral Res. 2022 Nov;207:105406. doi: 10.1016/j.antiviral.2022.105406. Epub 2022 Sep 7.
Members of the tripartite motif (TRIM) protein family strongly induced by interferons (IFNs) are parts of the innate immune system with antiviral activity. However, it is still unclear which TRIMs could play important roles in hepatitis B virus (HBV) inhibition. Here, we identified that TRIM56 expression responded in IFN-treated HepG2-NTCP cells and HBV-infected liver tissues, which was a potent IFN-inducible inhibitor of HBV replication. Mechanistically, TRIM56 suppressed HBV replication via its Ring and C-terminal domain. C-terminal domain was essential for TRIM56 translocating from cytoplasm to nucleus during HBV infection. Further analysis revealed that TRIM56's Ring domain targeted IκBα for ubiquitination. This modification induced phosphorylation of p65, which subsequently inhibited HBV core promoter activity, resulting in the inhibition of HBV replication. The p65 was found to be necessary for NF-κB signal pathway to inhibit HBV replication. We verified our findings using HepG2-NTCP and primary human hepatocytes. Our findings reveal that TRIM56 is a critical antiviral immune effector and exerts an anti-HBV activity via NF-κB signal pathway, which is essential for inhibiting transcription of HBV covalently closed circular DNA.
干扰素（IFNs）强烈诱导的三聚体基序（TRIM）蛋白家族成员是具有抗病毒活性的先天免疫系统的一部分。然而，目前仍不清楚哪些 TRIM 蛋白可以在乙型肝炎病毒（HBV）抑制中发挥重要作用。在这里，我们发现 TRIM56 在 IFN 处理的 HepG2-NTCP 细胞和 HBV 感染的肝组织中表达，这是一种有效的 IFN 诱导的 HBV 复制抑制剂。在机制上，TRIM56 通过其环和 C 末端结构域抑制 HBV 复制。C 末端结构域对于 TRIM56 在 HBV 感染期间从细胞质向核内转移至关重要。进一步的分析表明，TRIM56 的环结构域靶向 IκBα 进行泛素化。这种修饰诱导 p65 的磷酸化，从而抑制 HBV 核心启动子活性，导致 HBV 复制的抑制。发现 p65 对于 NF-κB 信号通路抑制 HBV 复制是必需的。我们使用 HepG2-NTCP 和原代人肝细胞验证了我们的发现。我们的研究结果表明，TRIM56 是一种关键的抗病毒免疫效应因子，通过 NF-κB 信号通路发挥抗 HBV 活性，这对于抑制 HBV 共价闭合环状 DNA 的转录至关重要。
