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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: Di...

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Autores principales: Faure-Dupuy, Suzanne, Riedl, Tobias, Rolland, Maude, Hizir, Zoheir, Reisinger, Florian, Neuhaus, Katharina, Schuehle, Svenja, Remouchamps, Caroline, Gillet, Nicolas, Schönung, Maximilian, Stadler, Mira, Wettengel, Jochen, Barnault, Romain, Parent, Romain, Schuster, Linda Christina, Farhat, Rayan, Prokosch, Sandra, Leuchtenberger, Corinna, Öllinger, Rupert, Engleitner, Thomas, Rippe, Karsten, Rad, Roland, Unger, Kristian, Tscharahganeh, Darjus, Lipka, Daniel B., Protzer, Ulrike, Durantel, David, Lucifora, Julie, Dejardin, Emmanuel, Heikenwälder, Mathias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523871/
https://www.ncbi.nlm.nih.gov/pubmed/34704004
http://dx.doi.org/10.1016/j.jhepr.2021.100354
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author Faure-Dupuy, Suzanne
Riedl, Tobias
Rolland, Maude
Hizir, Zoheir
Reisinger, Florian
Neuhaus, Katharina
Schuehle, Svenja
Remouchamps, Caroline
Gillet, Nicolas
Schönung, Maximilian
Stadler, Mira
Wettengel, Jochen
Barnault, Romain
Parent, Romain
Schuster, Linda Christina
Farhat, Rayan
Prokosch, Sandra
Leuchtenberger, Corinna
Öllinger, Rupert
Engleitner, Thomas
Rippe, Karsten
Rad, Roland
Unger, Kristian
Tscharahganeh, Darjus
Lipka, Daniel B.
Protzer, Ulrike
Durantel, David
Lucifora, Julie
Dejardin, Emmanuel
Heikenwälder, Mathias
author_facet Faure-Dupuy, Suzanne
Riedl, Tobias
Rolland, Maude
Hizir, Zoheir
Reisinger, Florian
Neuhaus, Katharina
Schuehle, Svenja
Remouchamps, Caroline
Gillet, Nicolas
Schönung, Maximilian
Stadler, Mira
Wettengel, Jochen
Barnault, Romain
Parent, Romain
Schuster, Linda Christina
Farhat, Rayan
Prokosch, Sandra
Leuchtenberger, Corinna
Öllinger, Rupert
Engleitner, Thomas
Rippe, Karsten
Rad, Roland
Unger, Kristian
Tscharahganeh, Darjus
Lipka, Daniel B.
Protzer, Ulrike
Durantel, David
Lucifora, Julie
Dejardin, Emmanuel
Heikenwälder, Mathias
author_sort Faure-Dupuy, Suzanne
collection PubMed
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.
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spelling pubmed-85238712021-10-25 Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p Faure-Dupuy, Suzanne Riedl, Tobias Rolland, Maude Hizir, Zoheir Reisinger, Florian Neuhaus, Katharina Schuehle, Svenja Remouchamps, Caroline Gillet, Nicolas Schönung, Maximilian Stadler, Mira Wettengel, Jochen Barnault, Romain Parent, Romain Schuster, Linda Christina Farhat, Rayan Prokosch, Sandra Leuchtenberger, Corinna Öllinger, Rupert Engleitner, Thomas Rippe, Karsten Rad, Roland Unger, Kristian Tscharahganeh, Darjus Lipka, Daniel B. Protzer, Ulrike Durantel, David Lucifora, Julie Dejardin, Emmanuel Heikenwälder, Mathias JHEP Rep Research Article 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. Elsevier 2021-08-25 /pmc/articles/PMC8523871/ /pubmed/34704004 http://dx.doi.org/10.1016/j.jhepr.2021.100354 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Faure-Dupuy, Suzanne
Riedl, Tobias
Rolland, Maude
Hizir, Zoheir
Reisinger, Florian
Neuhaus, Katharina
Schuehle, Svenja
Remouchamps, Caroline
Gillet, Nicolas
Schönung, Maximilian
Stadler, Mira
Wettengel, Jochen
Barnault, Romain
Parent, Romain
Schuster, Linda Christina
Farhat, Rayan
Prokosch, Sandra
Leuchtenberger, Corinna
Öllinger, Rupert
Engleitner, Thomas
Rippe, Karsten
Rad, Roland
Unger, Kristian
Tscharahganeh, Darjus
Lipka, Daniel B.
Protzer, Ulrike
Durantel, David
Lucifora, Julie
Dejardin, Emmanuel
Heikenwälder, Mathias
Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p
title 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_short 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523871/
https://www.ncbi.nlm.nih.gov/pubmed/34704004
http://dx.doi.org/10.1016/j.jhepr.2021.100354
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