Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p
Background & Aims: 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. Methods...
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Elsevier
2021
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oai:doaj.org-article:f8e8591deea845fbbd851f975b52e5742021-11-20T05:11:34ZControl of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p2589-555910.1016/j.jhepr.2021.100354https://doaj.org/article/f8e8591deea845fbbd851f975b52e5742021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589555921001300https://doaj.org/toc/2589-5559Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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. Lay summary: 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.Suzanne Faure-DupuyTobias RiedlMaude RollandZoheir HizirFlorian ReisingerKatharina NeuhausSvenja SchuehleCaroline RemouchampsNicolas GilletMaximilian SchönungMira StadlerJochen WettengelRomain BarnaultRomain ParentLinda Christina SchusterRayan FarhatSandra ProkoschCorinna LeuchtenbergerRupert ÖllingerThomas EngleitnerKarsten RippeRoland RadKristian UngerDarjus TscharahganehDaniel B. LipkaUlrike ProtzerDavid DurantelJulie LuciforaEmmanuel DejardinMathias HeikenwälderElsevierarticleAPOBEC3BHepatitis B virusNF-κBmiRNAcccDNAHBxDiseases of the digestive system. GastroenterologyRC799-869ENJHEP Reports, Vol 3, Iss 6, Pp 100354- (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
APOBEC3B Hepatitis B virus NF-κB miRNA cccDNA HBx Diseases of the digestive system. Gastroenterology RC799-869 |
| spellingShingle |
APOBEC3B Hepatitis B virus NF-κB miRNA cccDNA HBx Diseases of the digestive system. Gastroenterology RC799-869 Suzanne Faure-Dupuy Tobias Riedl Maude Rolland Zoheir Hizir Florian Reisinger Katharina Neuhaus Svenja Schuehle Caroline Remouchamps Nicolas Gillet Maximilian Schönung Mira Stadler Jochen Wettengel Romain Barnault Romain Parent Linda Christina Schuster Rayan Farhat Sandra Prokosch Corinna Leuchtenberger Rupert Öllinger Thomas Engleitner Karsten Rippe Roland Rad Kristian Unger Darjus Tscharahganeh Daniel B. Lipka Ulrike Protzer David Durantel Julie Lucifora Emmanuel Dejardin Mathias Heikenwälder Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p |
| description |
Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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. Lay summary: 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. |
| format |
article |
| author |
Suzanne Faure-Dupuy Tobias Riedl Maude Rolland Zoheir Hizir Florian Reisinger Katharina Neuhaus Svenja Schuehle Caroline Remouchamps Nicolas Gillet Maximilian Schönung Mira Stadler Jochen Wettengel Romain Barnault Romain Parent Linda Christina Schuster Rayan Farhat Sandra Prokosch Corinna Leuchtenberger Rupert Öllinger Thomas Engleitner Karsten Rippe Roland Rad Kristian Unger Darjus Tscharahganeh Daniel B. Lipka Ulrike Protzer David Durantel Julie Lucifora Emmanuel Dejardin Mathias Heikenwälder |
| author_facet |
Suzanne Faure-Dupuy Tobias Riedl Maude Rolland Zoheir Hizir Florian Reisinger Katharina Neuhaus Svenja Schuehle Caroline Remouchamps Nicolas Gillet Maximilian Schönung Mira Stadler Jochen Wettengel Romain Barnault Romain Parent Linda Christina Schuster Rayan Farhat Sandra Prokosch Corinna Leuchtenberger Rupert Öllinger Thomas Engleitner Karsten Rippe Roland Rad Kristian Unger Darjus Tscharahganeh Daniel B. Lipka Ulrike Protzer David Durantel Julie Lucifora Emmanuel Dejardin Mathias Heikenwälder |
| author_sort |
Suzanne Faure-Dupuy |
| title |
Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p |
| title_short |
Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p |
| title_full |
Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p |
| title_fullStr |
Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p |
| title_full_unstemmed |
Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p |
| title_sort |
control of apobec3b induction and cccdna decay by nf-κb and mir-138-5p |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/f8e8591deea845fbbd851f975b52e574 |
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