TY  - JOUR
AU  - Faure-Dupuy, Suzanne
AU  - Riedl, Tobias
AU  - Rolland, Maude
AU  - Hizir, Zoheir
AU  - Reisinger, Florian
AU  - Neuhaus, Katharina
AU  - Schuehle, Svenja
AU  - Remouchamps, Caroline
AU  - Gillet, Nicolas
AU  - Schönung, Maximilian
AU  - Stadler, Mira
AU  - Wettengel, Jochen
AU  - Barnault, Romain
AU  - Parent, Romain
AU  - Schuster, Linda Christina
AU  - Farhat, Rayan
AU  - Prokosch, Sandra
AU  - Leuchtenberger, Corinna
AU  - Öllinger, Rupert
AU  - Engleitner, Thomas
AU  - Rippe, Karsten
AU  - Rad, Roland
AU  - Unger, Kristian
AU  - Tscharahganeh, Darjus
AU  - Lipka, Daniel B
AU  - Protzer, Ulrike
AU  - Durantel, David
AU  - Lucifora, Julie
AU  - Dejardin, Emmanuel
AU  - Heikenwälder, Mathias
TI  - Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p.
JO  - JHEP reports
VL  - 3
IS  - 6
SN  - 2589-5559
CY  - Amsterdam
PB  - Elsevier
M1  - DKFZ-2021-02358
SP  - 100354
PY  - 2021
N1  - #EA:F180#LA:F180# / #DKFZ-MOST-Ca197#
AB  - Immune-mediated induction of cytidine deaminase APOBEC3B (A3B) expression leads to HBV covalently closed circular DNA (cccDNA) decay. Here, we aimed to decipher the signalling pathway(s) and regulatory mechanism(s) involved in A3B induction and related HBV control.Differentiated HepaRG cells (dHepaRG) knocked-down for NF-κB signalling components, transfected with siRNA or micro RNAs (miRNA), and primary human hepatocytes ± HBV or HBVΔX or HBV-RFP, were treated with lymphotoxin beta receptor (LTβR)-agonist (BS1). The biological outcomes were analysed by reverse transcriptase-qPCR, immunoblotting, luciferase activity, chromatin immune precipitation, electrophoretic mobility-shift assay, targeted-bisulfite-, miRNA-, RNA-, genome-sequencing, and mass-spectrometry.We found that canonical and non-canonical NF-κB signalling pathways are mandatory for A3B induction and anti-HBV effects. The degree of immune-mediated A3B production is independent of A3B promoter demethylation but is controlled post-transcriptionally by the miRNA 138-5p expression (hsa-miR-138-5p), promoting A3B mRNA decay. Hsa-miR-138-5p over-expression reduced A3B levels and its antiviral effects. Of note, established infection inhibited BS1-induced A3B expression through epigenetic modulation of A3B promoter. Twelve days of treatment with a LTβR-specific agonist BS1 is sufficient to reduce the cccDNA pool by 80
KW  - A20, tumour necrosis factor alpha-induced protein 3 (Other)
KW  - APOBEC3A/A3A, apolipoprotein B mRNA editing catalytic polypeptide-like A (Other)
KW  - APOBEC3B (Other)
KW  - APOBEC3B/A3B, apolipoprotein B mRNA editing catalytic polypeptide-like B (Other)
KW  - APOBEC3G/A3G, apolipoprotein B mRNA editing catalytic polypeptide-like G (Other)
KW  - BCA, bicinchoninic acid assay (Other)
KW  - CHB, chronic hepatitis B (Other)
KW  - CXCL10, C-X-C motif chemokine ligand 10 (Other)
KW  - ChIP, chromatin immune precipitation (Other)
KW  - EMSA, electrophoretic mobility-shift assay (Other)
KW  - H3K4Me3, histone 3 lysine 4 trimethylation (Other)
KW  - HBx (Other)
KW  - Hepatitis B virus (Other)
KW  - IFNα/γ, interferon alpha/gamma (Other)
KW  - IKKα/β, IκB kinase alpha/beta (Other)
KW  - JMJD8, jumonji domain containing 8 (Other)
KW  - LPS, lipopolysaccharide (Other)
KW  - LTβR, lymphotoxin beta receptor (Other)
KW  - MAPK, mitogen-activated protein kinase (Other)
KW  - NEMO, NF-κB essential modulator (Other)
KW  - NF-κB (Other)
KW  - NF-κB, nuclear factor kappa B (Other)
KW  - NIK, NF-κB inducing kinase (Other)
KW  - NT, non-treated (Other)
KW  - RT-qPCR, reverse transcription-quantitative PCR (Other)
KW  - RelA, NF-κB p65 subunit (Other)
KW  - TNF, tumour necrosis factor (Other)
KW  - UBE2V1, ubiquitin conjugating enzyme E2 V1 (Other)
KW  - UTR, untranslated region (Other)
KW  - cccDNA (Other)
KW  - cccDNA, covalently closed circular DNA (Other)
KW  - d.p.i., days post infection (Other)
KW  - miRNA (Other)
KW  - miRNA, micro RNA (Other)
KW  - siCTRL, siRNA control (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34704004
C2  - pmc:PMC8523871
DO  - DOI:10.1016/j.jhepr.2021.100354
UR  - https://inrepo02.dkfz.de/record/177224
ER  -