转化生长因子-β通过依赖于激活诱导胞嘧啶脱氨酶的脱氨基作用触发乙肝病毒共价闭合环状DNA的降解。
TGF-β triggers HBV cccDNA degradation through AID-dependent deamination.
作者信息
Qiao Ying, Han Xiaoxu, Guan Gefei, Wu Na, Sun Jianbo, Pak Vladimir, Liang Guoxin
机构信息
The Core Laboratory for Public Health Science and Practice, The First Affiliated Hospital, China Medical University, Shenyang, China.
Key Laboratory of AIDS Immunology of the National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, China.
出版信息
FEBS Lett. 2016 Feb;590(3):419-27. doi: 10.1002/1873-3468.12058. Epub 2016 Feb 2.
The covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a viral center molecule for HBV infection and persistence. However, the cellular restriction factors of HBV cccDNA are not well understood. Here, we show that TGF-β can induce nuclear viral cccDNA degradation and hypermutation via activation-induced cytidine deaminase (AID) deamination activity in hepatocytes. This suppression by TGF-β is abrogated when AID or the activity of uracil-DNA glycosylase (UNG) is absent, which indicates that AID deamination and the UNG-mediated excision of uracil act in concert to degrade viral cccDNA. Moreover, the HBV core protein promotes the interaction between AID and viral cccDNA. Overall, our results indicate a novel molecular mechanism that allows cytokine TGF-β to restrict viral nuclear cccDNA in innate immunity, thereby suggesting a novel method for potentially eliminating cccDNA.
乙型肝炎病毒（HBV）的共价闭合环状DNA（cccDNA）是HBV感染和持续存在的病毒核心分子。然而，HBV cccDNA的细胞限制因子尚未完全明确。在此，我们发现转化生长因子-β（TGF-β）可通过激活诱导的胞苷脱氨酶（AID）脱氨活性在肝细胞中诱导核内病毒cccDNA降解和超突变。当AID或尿嘧啶-DNA糖基化酶（UNG）活性缺失时，TGF-β的这种抑制作用被消除，这表明AID脱氨和UNG介导的尿嘧啶切除协同作用以降解病毒cccDNA。此外，HBV核心蛋白促进AID与病毒cccDNA之间的相互作用。总体而言，我们的结果表明了一种新的分子机制，即细胞因子TGF-β在固有免疫中限制病毒核cccDNA，从而提示了一种潜在消除cccDNA的新方法。
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