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

Stadler, Daniela; Kaechele, Martin; Jones, Alisha N.; Hess, Julia; Urban, Christian; Schneider, Jessica; Xia, Yuchen; Oswald, Andreas; Nebioglu, Firat; Bester, Romina; Lasitschka, Felix; Ringelhan, Marc; Ko, Chunkyu; Chou, Wen-Min; Geerlof, Arie; Klundert, Maarten A. van de; Wettengel, Jochen M.; Schirmacher, Peter; Heikenwaelder, Mathias; Schreiner, Sabrina; Bartenschlager, Ralf; Pichlmair, Andreas; Sattler, Michael; Unger, Kristian and Protzer, Ulrike (2021): Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20. In: EMBO Reports, Vol. 22, No. 6, e49568

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.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1469-221X
• Language: English