Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20.
APOBEC3A
HBV
chronic hepatitis B
interferon alpha
interferon gamma
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
04 06 2021
04 06 2021
Historique:
revised:
18
03
2021
received:
30
10
2019
accepted:
23
03
2021
pubmed:
11
5
2021
medline:
29
6
2021
entrez:
10
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33969602
doi: 10.15252/embr.201949568
pmc: PMC8183418
doi:
Substances chimiques
Antiviral Agents
0
DNA, Circular
0
DNA, Viral
0
Proteins
0
Interferons
9008-11-1
Exoribonucleases
EC 3.1.-
ISG20 protein, human
EC 3.1.-
APOBEC3A protein, human
EC 3.5.4.5
Cytidine Deaminase
EC 3.5.4.5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e49568Subventions
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 272983813-TRR179
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : TRR237
Organisme : ALIOS BioPharma
Informations de copyright
© 2021 Helmholtz Zentrum Muenchen. Published under the terms of the CC BY NC ND 4.0 license.
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