Nuclear Sensor Interferon-Inducible Protein 16 Inhibits the Function of Hepatitis B Virus Covalently Closed Circular DNA by Integrating Innate Immune Activation and Epigenetic Suppression
Nuclear Sensor Interferon-Inducible Protein 16 Inhibits the Function of Hepatitis B Virus Covalently Closed Circular DNA by Integrating Innate Immune Activation and Epigenetic Suppression
复制标题
核传感器干扰素诱导蛋白 16 通过整合先天免疫激活和表观遗传抑制来抑制乙型肝炎病毒共价闭合环状 DNA 的功能。
DOI：
10.1002/hep.30897
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发表时间：
2019-10-15
期刊：
影响因子：
13.5
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
--
作者：
Yang, Yuanyuan;Zhao, Xinzhuan;Xiong, Sidong
背景与目的B型肝炎病毒（HBV）核定位共价闭合环状DNA（cccDNA）是HBV持续存在的决定因素，也是慢性B型肝炎治愈的关键障碍。然而，目前尚不清楚宿主免疫系统是否以及如何感知HBV cccDNA及其生物学后果。方法和结果在这里，我们证明了干扰素诱导蛋白16（IFI16）可以作为一种独特的先天传感器，识别并结合肝细胞核中的HBV cccDNA，从而抑制cccDNA转录和HBV复制。从机制上讲，我们的数据表明，IFI16通过靶向cccDNA中存在的干扰素刺激反应元件（ISRE）促进HBV cccDNA的表观遗传抑制。令人感兴趣的是，该ISRE也被揭示在IFI16激活的I型干扰素应答中起重要作用。此外，我们的数据显示，HBV可以下调肝细胞中IFI16的表达水平，并且在肝活检组织中IFI16与HBV转录物之间存在负相关性，这表明IFI16在生理条件下抑制cccDNA功能的可能作用。结论核传感器IFI16通过靶向cccDNA的ISRE，整合了先天免疫激活和表观遗传调控，抑制cccDNA的功能，IFI16可能成为抗HBV感染的治疗靶点。
Background and Aims Nuclear-located covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a determining factor for HBV persistence and the key obstacle for a cure of chronic hepatitis B. However, it remains unclear whether and how the host immune system senses HBV cccDNA and its biological consequences. Approach and Results Here, we demonstrated that interferon-inducible protein 16 (IFI16) could serve as a unique innate sensor to recognize and bind to HBV cccDNA in hepatic nuclei, leading to the inhibition of cccDNA transcription and HBV replication. Mechanistically, our data showed that IFI16 promoted the epigenetic suppression of HBV cccDNA by targeting an interferon-stimulated response element (ISRE) present in cccDNA. It is of interest that this ISRE was also revealed to play an important role in IFI16-activated type I interferon responses. Furthermore, our data revealed that HBV could down-regulate the expression level of IFI16 in hepatocytes, and there was a negative correlation between IFI16 and HBV transcripts in liver biopsies, suggesting the possible role of IFI16 in suppressing cccDNA function under physiological conditions. Conclusions The nuclear sensor IFI16 suppresses cccDNA function by integrating innate immune activation and epigenetic regulation by targeting the ISRE of cccDNA, and IFI16 may present as a therapeutic target against HBV infection.