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

Daniela Stadler, Martin Kächele, Alisha N. Jones, Julia Hess, Christian Urban, Jessica Schneider, Yuchen Xia, Andreas Oswald, Firat Nebioglu, Romina Bester, Felix Lasitschka, Marc Ringelhan, Chunkyu Ko, Wen Min Chou, Arie Geerlof, Maarten A. van de Klundert, Jochen M. Wettengel, Peter Schirmacher, Mathias Heikenwälder, Sabrina SchreinerRalf Bartenschlager, Andreas Pichlmair, Michael Sattler, Kristian Unger, Ulrike Protzer

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish
Article numbere49568
JournalEMBO Reports
Volume22
Issue number6
DOIs
StatePublished - 4 Jun 2021

Keywords

  • APOBEC3A
  • HBV
  • chronic hepatitis B
  • interferon alpha
  • interferon gamma

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