Interferon‐induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20
| Autor: | Marc Ringelhan, Firat Nebioglu, Christian Urban, Arie Geerlof, Jochen M. Wettengel, Martin Kächele, Maarten van de Klundert, Kristian Unger, Jessica Schneider, Julia Hess, Yuchen Xia, Andreas Oswald, Chunkyu Ko, Alisha N Jones, Felix Lasitschka, Peter Schirmacher, Ralf Bartenschlager, Mathias Heikenwalder, Ulrike Protzer, Daniela Stadler, Wen-Min Chou, Michael Sattler, Sabrina Schreiner, Romina Bester, Andreas Pichlmair |
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| Rok vydání: | 2020 |
| Předmět: |
Hepatitis B virus
Immunology Alpha interferon Biology medicine.disease_cause Virus Replication Biochemistry Antiviral Agents Article 03 medical and health sciences 0302 clinical medicine Interferon Cytidine Deaminase Genetics medicine HBV Humans interferon alpha Interferon gamma chronic hepatitis B Nuclear protein APOBEC3A Molecular Biology 030304 developmental biology 0303 health sciences Nuclease virus diseases Proteins cccDNA Articles Virology Microbiology Virology & Host Pathogen Interaction ddc interferon gamma DNA Viral Exoribonucleases biology.protein Interferons DNA Circular 030217 neurology & neurosurgery Apobec3a Chronic Hepatitis B Hbv Interferon Alpha Interferon Gamma medicine.drug |
| Zdroj: | EMBO Reports EMBO Rep. 22:e49568 (2021) |
| Popis: | 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. Hepatitis B virus deposits a covalently closed circular (ccc)DNA in the nucleus of infected cells to persist. Interferons can purge cccDNA from the nucleus by inducing deaminases and the nuclease ISG20 that modify and subsequently degrade cccDNA. |
| Databáze: | OpenAIRE |
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