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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
Author(s) -
Yang Yuanyuan,
Zhao Xinzhuan,
Wang Ziyu,
Shu Wangqin,
Li Lijie,
Li Yuqi,
Guo Zhiwei,
Gao Bo,
Xiong Sidong
Publication year - 2020
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30897
Subject(s) - cccdna , hepatitis b virus , innate immune system , biology , virology , interferon , epigenetics , hepatitis b virus pre beta , circular dna , immune system , microbiology and biotechnology , virus , immunology , hepatitis b virus dna polymerase , gene , genetics , hbsag , genome
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.