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干扰素诱导的持久乙型肝炎病毒 cccDNA 形式的降解依赖于 ISG20。

Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20.

机构信息

Institute of Virology, School of Medicine, Technical University of Munich / Helmholtz Zentrum München, Munich, Germany.

Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.

出版信息

EMBO Rep. 2021 Jun 4;22(6):e49568. doi: 10.15252/embr.201949568. Epub 2021 May 9.

DOI:10.15252/embr.201949568
PMID:33969602
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8183418/
Abstract

Hepatitis B virus (HBV) persists by depositing a covalently closed circular DNA (cccDNA) in the nucleus of infected cells that cannot be targeted by available antivirals. Interferons can diminish HBV cccDNA via APOBEC3-mediated deamination. Here, we show that overexpression of APOBEC3A alone is not sufficient to reduce HBV cccDNA that requires additional treatment of cells with interferon indicating involvement of an interferon-stimulated gene (ISG) in cccDNA degradation. Transcriptome analyses identify ISG20 as the only type I and II interferon-induced, nuclear protein with annotated nuclease activity. ISG20 localizes to nucleoli of interferon-stimulated hepatocytes and is enriched on deoxyuridine-containing single-stranded DNA that mimics transcriptionally active, APOBEC3A-deaminated HBV DNA. ISG20 expression is detected in human livers in acute, self-limiting but not in chronic hepatitis B. ISG20 depletion mitigates the interferon-induced loss of cccDNA, and co-expression with APOBEC3A is sufficient to diminish cccDNA. In conclusion, non-cytolytic HBV cccDNA decline requires the concerted action of a deaminase and a nuclease. Our findings highlight that ISGs may cooperate in their antiviral activity that may be explored for therapeutic targeting.

摘要

乙型肝炎病毒 (HBV) 通过将共价闭合环状 DNA (cccDNA) 沉积在受感染细胞的核内而持续存在，而现有的抗病毒药物无法靶向该 cccDNA。干扰素可以通过 APOBEC3 介导的脱氨作用来减少 HBV cccDNA。在这里，我们表明，单独过表达 APOBEC3A 不足以减少 HBV cccDNA，这需要细胞额外接受干扰素治疗，表明干扰素刺激基因 (ISG) 参与了 cccDNA 的降解。转录组分析鉴定出 ISG20 是唯一一种 I 型和 II 型干扰素诱导的、具有注释核酶活性的核蛋白。ISG20 定位于干扰素刺激的肝细胞的核仁中，并富集于模拟转录活性、APOBEC3A 脱氨的 HBV DNA 的脱氧尿嘧啶单链 DNA 上。ISG20 在急性、自限性但非慢性乙型肝炎的人类肝脏中被检测到。ISG20 的耗竭减轻了干扰素诱导的 cccDNA 丢失，并且与 APOBEC3A 的共表达足以减少 cccDNA。总之，非细胞毒性 HBV cccDNA 的下降需要脱氨酶和核酶的协同作用。我们的研究结果强调了 ISG 可能在其抗病毒活性中合作，这可能会被探索用于治疗靶向。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ba8/8183418/1c06fbf100c5/EMBR-22-e49568-g002.jpg
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