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Stadler, D. ; Kächele, M. ; Jones, A. ; Hess J. ; Urban, C. ; Schneider, J. ; Xia, Y. ; Oswald, A. ; Nebioglu, F.* ; Bester, R. ; Lasitschka, F.* ; Ringelhan, M. ; Ko, C. ; Chou, W.M. ; Geerlof, A. ; van de Klundert, M. ; Wettengel, J.M. ; Schirmacher, P.* ; Heikenwälder, M.* ; Schreiner, S. ; Bartenschlager, R.* ; Pichlmair, A. ; Sattler, M. ; Unger, K. ; Protzer, U.

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

EMBO Rep. 22:e49568 (2021)
Publ. Version/Full Text DOI PMC
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Apobec3a ; Chronic Hepatitis B ; Hbv ; Interferon Alpha ; Interferon Gamma; Closed Circular Dna; Apobec3 Proteins; Computational Platform; Molecular-cloning; Immune-responses; Genomic Analysis; Humanized Mice; Host Response; X Protein; Replication
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 1469-221X
e-ISSN 1469-3178
Journal EMBO Reports
Quellenangaben Volume: 22, Issue: 6, Pages: , Article Number: e49568 Supplement: ,
Publisher EMBO Press
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
Institute of Structural Biology (STB)
Translational Metabolic Oncology (IDC-TMO)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
Enabling and Novel Technologies
Radiation Sciences
PSP Element(s) G-502700-003
G-503000-001
G-501000-001
G-502700-007
Grants Projekt DEAL
ALIOS BioPharma to Technical University of Munich
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)
ALIOS BioPharma
Deutsche Forschungsgemeinschaft (DFG)
DOI 10.15252/embr.201949568
WOS ID WOS:000648511600001
Scopus ID 85105379341
PubMed ID 33969602
Erfassungsdatum 2021-06-21
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