Dual role of neddylation in transcription of hepatitis B virus RNAs from cccDNA and production of viral surface antigen.
DDB1, DNA damage-binding protein 1
HBsAg
HBsAg, hepatitis B virus surface antigen
HBx
HBx, hepatitis B virus X protein
MLN4924
NAE1, NEDD8-activating enzyme E1 subunit 1
NEDD8, neural precursor cell expressed, developmentally downregulated 8
PHHs, primary human hepatocytes
SMC6
SVP, subviral particles
Smc5/6, structural maintenance of chromosomes 5/6
WT, wild-type
cccDNA
cccDNA, covalently closed circular DNA
integrants
neddylation
pgRNA, pregenomic RNA
siRNA, small-interfering RNA
transcription
Journal
JHEP reports : innovation in hepatology
ISSN: 2589-5559
Titre abrégé: JHEP Rep
Pays: Netherlands
ID NLM: 101761237
Informations de publication
Date de publication:
Oct 2022
Oct 2022
Historique:
received:
18
08
2021
revised:
10
07
2022
accepted:
14
07
2022
entrez:
20
9
2022
pubmed:
21
9
2022
medline:
21
9
2022
Statut:
epublish
Résumé
HBV persistence is maintained by both an episomal covalently closed circular (ccc)DNA reservoir and genomic integration of HBV DNA fragments. While cccDNA transcription is regulated by Cullin4A-DDB1-HBx-mediated degradation of the SMC5/6 complex, HBsAg expression from integrants is largely SMC5/6 independent. Inhibiting neddylation of Cullin-RING ubiquitin ligases impairs degradation of substrates. Herein, we show that targeting neddylation pathway components by small-interfering (si)RNAs or the drug MLN4924 (pevonedistat) suppresses expression of HBV proteins from both cccDNA and integrants. An siRNA screen targeting secretory pathway regulators and neddylation genes was performed. Activity of MLN4924 was assessed in infection and integration models. Trans-complementation assays were used to study HBx function in cccDNA-driven expression. siRNA screening uncovered neddylation pathway components ( Neddylation is required both for transcription of a cccDNA reservoir and for the genomic integration of viral DNA. Therefore, blocking neddylation might offer an attractive approach towards functional cure of chronic hepatitis B. Current treatments for chronic hepatitis B are rarely able to induce a functional cure. This is partly because of the presence of a pool of circular viral DNA in the host nucleus, as well as viral DNA fragments that are integrated into the host genome. Herein, we show that a host biological pathway called neddylation could play a key role in infection and viral DNA integration. Inhibiting this pathway could hold therapeutic promise for patients with chronic hepatitis B.
Sections du résumé
Background & Aims
UNASSIGNED
HBV persistence is maintained by both an episomal covalently closed circular (ccc)DNA reservoir and genomic integration of HBV DNA fragments. While cccDNA transcription is regulated by Cullin4A-DDB1-HBx-mediated degradation of the SMC5/6 complex, HBsAg expression from integrants is largely SMC5/6 independent. Inhibiting neddylation of Cullin-RING ubiquitin ligases impairs degradation of substrates. Herein, we show that targeting neddylation pathway components by small-interfering (si)RNAs or the drug MLN4924 (pevonedistat) suppresses expression of HBV proteins from both cccDNA and integrants.
Methods
UNASSIGNED
An siRNA screen targeting secretory pathway regulators and neddylation genes was performed. Activity of MLN4924 was assessed in infection and integration models. Trans-complementation assays were used to study HBx function in cccDNA-driven expression.
Results
UNASSIGNED
siRNA screening uncovered neddylation pathway components (
Conclusions
UNASSIGNED
Neddylation is required both for transcription of a cccDNA reservoir and for the genomic integration of viral DNA. Therefore, blocking neddylation might offer an attractive approach towards functional cure of chronic hepatitis B.
Lay summary
UNASSIGNED
Current treatments for chronic hepatitis B are rarely able to induce a functional cure. This is partly because of the presence of a pool of circular viral DNA in the host nucleus, as well as viral DNA fragments that are integrated into the host genome. Herein, we show that a host biological pathway called neddylation could play a key role in infection and viral DNA integration. Inhibiting this pathway could hold therapeutic promise for patients with chronic hepatitis B.
Identifiants
pubmed: 36124123
doi: 10.1016/j.jhepr.2022.100551
pii: S2589-5559(22)00123-9
pmc: PMC9482114
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100551Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
Stephan Urban is co-inventor and applicant on patents protecting HBV preS1-derived lipopeptides (Myrcludex B/Bulevirtide/Hepcludex). All other authors declare no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details.
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