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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)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
ISSN (print) / ISBN 1469-221X
e-ISSN 1469-3178
Zeitschrift EMBO Reports
Quellenangaben Band: 22, Heft: 6, Seiten: , Artikelnummer: e49568 Supplement: ,
Verlag EMBO Press
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
Institute of Structural Biology (STB)
Translational Metabolic Oncology (TMO)
Förderungen Projekt DEAL
ALIOS BioPharma to Technical University of Munich
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)
ALIOS BioPharma
Deutsche Forschungsgemeinschaft (DFG)