Journal
EMBO REPORTS
Volume 22, Issue 6, Pages -Publisher
WILEY
DOI: 10.15252/embr.201949568
Keywords
APOBEC3A; chronic hepatitis B; HBV; interferon alpha; interferon gamma
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [272983813-TRR 179, TRR 237]
- ALIOS BioPharma to Technical University of Munich
- Projekt DEAL
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The study demonstrates that ISG20 is a nuclear protein induced by both type I and II interferons with nuclease activity, which works with APOBEC3A to degrade HBV cccDNA. ISG20 is localized in the nucleoli of interferon-stimulated hepatocytes and is expressed in acute, self-limiting hepatitis B but not in chronic infection.
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.
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