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000177224 0247_ $$2doi$$a10.1016/j.jhepr.2021.100354
000177224 0247_ $$2pmid$$apmid:34704004
000177224 0247_ $$2pmc$$apmc:PMC8523871
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000177224 037__ $$aDKFZ-2021-02358
000177224 041__ $$aEnglish
000177224 082__ $$a610
000177224 1001_ $$0P:(DE-He78)cba564af7ad8b1c41cd1f9f8410896e5$$aFaure-Dupuy, Suzanne$$b0$$eFirst author$$udkfz
000177224 245__ $$aControl of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p.
000177224 260__ $$aAmsterdam$$bElsevier$$c2021
000177224 3367_ $$2DRIVER$$aarticle
000177224 3367_ $$2DataCite$$aOutput Types/Journal article
000177224 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1763462963_1939190
000177224 3367_ $$2BibTeX$$aARTICLE
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000177224 500__ $$a#EA:F180#LA:F180# / #DKFZ-MOST-Ca197#
000177224 520__ $$aImmune-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% without inducing significant damages to a subset of cancer-related host genes. Interestingly, the A3B-mediated effect on HBV is independent of the transcriptional activity of cccDNA as well as on rcDNA synthesis.Altogether, A3B represents the only described enzyme to target both transcriptionally active and inactive cccDNA. Thus, inhibiting hsa-miR-138-5p expression should be considered in the combinatorial design of new therapies against HBV, especially in the context of immune-mediated A3B induction.Immune-mediated induction of cytidine deaminase APOBEC3B is transcriptionally regulated by NF-κB signalling and post-transcriptionally downregulated by hsa-miR-138-5p expression, leading to cccDNA decay. Timely controlled APOBEC3B-mediated cccDNA decay occurs independently of cccDNA transcriptional activity and without damage to a subset of cancer-related genes. Thus, APOBEC3B-mediated cccDNA decay could offer an efficient therapeutic alternative to target hepatitis B virus chronic infection.
000177224 536__ $$0G:(DE-HGF)POF4-316$$a316 - Infektionen, Entzündung und Krebs (POF4-316)$$cPOF4-316$$fPOF IV$$x0
000177224 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo01.inet.dkfz-heidelberg.de
000177224 650_7 $$2Other$$aA20, tumour necrosis factor alpha-induced protein 3
000177224 650_7 $$2Other$$aAPOBEC3A/A3A, apolipoprotein B mRNA editing catalytic polypeptide-like A
000177224 650_7 $$2Other$$aAPOBEC3B
000177224 650_7 $$2Other$$aAPOBEC3B/A3B, apolipoprotein B mRNA editing catalytic polypeptide-like B
000177224 650_7 $$2Other$$aAPOBEC3G/A3G, apolipoprotein B mRNA editing catalytic polypeptide-like G
000177224 650_7 $$2Other$$aBCA, bicinchoninic acid assay
000177224 650_7 $$2Other$$aCHB, chronic hepatitis B
000177224 650_7 $$2Other$$aCXCL10, C-X-C motif chemokine ligand 10
000177224 650_7 $$2Other$$aChIP, chromatin immune precipitation
000177224 650_7 $$2Other$$aEMSA, electrophoretic mobility-shift assay
000177224 650_7 $$2Other$$aH3K4Me3, histone 3 lysine 4 trimethylation
000177224 650_7 $$2Other$$aHBx
000177224 650_7 $$2Other$$aHepatitis B virus
000177224 650_7 $$2Other$$aIFNα/γ, interferon alpha/gamma
000177224 650_7 $$2Other$$aIKKα/β, IκB kinase alpha/beta
000177224 650_7 $$2Other$$aJMJD8, jumonji domain containing 8
000177224 650_7 $$2Other$$aLPS, lipopolysaccharide
000177224 650_7 $$2Other$$aLTβR, lymphotoxin beta receptor
000177224 650_7 $$2Other$$aMAPK, mitogen-activated protein kinase
000177224 650_7 $$2Other$$aNEMO, NF-κB essential modulator
000177224 650_7 $$2Other$$aNF-κB
000177224 650_7 $$2Other$$aNF-κB, nuclear factor kappa B
000177224 650_7 $$2Other$$aNIK, NF-κB inducing kinase
000177224 650_7 $$2Other$$aNT, non-treated
000177224 650_7 $$2Other$$aRT-qPCR, reverse transcription-quantitative PCR
000177224 650_7 $$2Other$$aRelA, NF-κB p65 subunit
000177224 650_7 $$2Other$$aTNF, tumour necrosis factor
000177224 650_7 $$2Other$$aUBE2V1, ubiquitin conjugating enzyme E2 V1
000177224 650_7 $$2Other$$aUTR, untranslated region
000177224 650_7 $$2Other$$acccDNA
000177224 650_7 $$2Other$$acccDNA, covalently closed circular DNA
000177224 650_7 $$2Other$$ad.p.i., days post infection
000177224 650_7 $$2Other$$amiRNA
000177224 650_7 $$2Other$$amiRNA, micro RNA
000177224 650_7 $$2Other$$asiCTRL, siRNA control
000177224 7001_ $$0P:(DE-He78)e4d7c2f391da716edc9beec6468f108f$$aRiedl, Tobias$$b1$$udkfz
000177224 7001_ $$aRolland, Maude$$b2
000177224 7001_ $$aHizir, Zoheir$$b3
000177224 7001_ $$0P:(DE-HGF)0$$aReisinger, Florian$$b4
000177224 7001_ $$0P:(DE-HGF)0$$aNeuhaus, Katharina$$b5
000177224 7001_ $$0P:(DE-HGF)0$$aSchuehle, Svenja$$b6
000177224 7001_ $$aRemouchamps, Caroline$$b7
000177224 7001_ $$aGillet, Nicolas$$b8
000177224 7001_ $$0P:(DE-He78)7f52f75aab723501c520280cebdb2c46$$aSchönung, Maximilian$$b9$$udkfz
000177224 7001_ $$0P:(DE-He78)475fbe15f759c77d8668a5031687c5a1$$aStadler, Mira$$b10$$udkfz
000177224 7001_ $$aWettengel, Jochen$$b11
000177224 7001_ $$aBarnault, Romain$$b12
000177224 7001_ $$aParent, Romain$$b13
000177224 7001_ $$0P:(DE-He78)1f11e79165fc6b3e3d0986c574b682a1$$aSchuster, Linda Christina$$b14$$udkfz
000177224 7001_ $$aFarhat, Rayan$$b15
000177224 7001_ $$0P:(DE-He78)3c6157a315192b4a95e0138399b89da9$$aProkosch, Sandra$$b16$$udkfz
000177224 7001_ $$0P:(DE-He78)37436c64e916a3fb91afac3344c5fe67$$aLeuchtenberger, Corinna$$b17$$udkfz
000177224 7001_ $$aÖllinger, Rupert$$b18
000177224 7001_ $$aEngleitner, Thomas$$b19
000177224 7001_ $$0P:(DE-He78)94de5f7413279464b6e738d91dfae1eb$$aRippe, Karsten$$b20$$udkfz
000177224 7001_ $$aRad, Roland$$b21
000177224 7001_ $$aUnger, Kristian$$b22
000177224 7001_ $$0P:(DE-HGF)0$$aTscharahganeh, Darjus$$b23
000177224 7001_ $$0P:(DE-He78)c403a040c97f91902a7d31b93859f9fc$$aLipka, Daniel B$$b24$$udkfz
000177224 7001_ $$aProtzer, Ulrike$$b25
000177224 7001_ $$aDurantel, David$$b26
000177224 7001_ $$aLucifora, Julie$$b27
000177224 7001_ $$aDejardin, Emmanuel$$b28
000177224 7001_ $$0P:(DE-He78)66ed2d4ec9bc11d29b87ac006adf85e5$$aHeikenwälder, Mathias$$b29$$eLast author$$udkfz
000177224 773__ $$0PERI:(DE-600)2972660-8$$a10.1016/j.jhepr.2021.100354$$gVol. 3, no. 6, p. 100354 -$$n6$$p100354$$tJHEP reports$$v3$$x2589-5559$$y2021
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