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Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p

Suzanne Faure-Dupuy1,2, Tobias Riedl1,3, Maude Rolland4

  • 1Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.

JHEP Reports : Innovation in Hepatology
|October 27, 2021
PubMed

Insights

Immune-mediated APOBEC3B induction, regulated by NF-κB and miR-138-5p, effectively reduces hepatitis B virus cccDNA. Inhibiting miR-138-5p may enhance this antiviral effect for new HBV therapies.

Area of Science:

  • Hepatology and Virology
  • Immunology
  • Molecular Biology

Background:

  • Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) persistence is a major barrier to chronic infection cure.
  • Immune-mediated induction of cytidine deaminase APOBEC3B (A3B) has shown potential in reducing HBV cccDNA.
  • Understanding the regulatory mechanisms of A3B induction is crucial for developing effective antiviral strategies.

Purpose of the Study:

  • To elucidate the signaling pathways and regulatory mechanisms governing A3B induction.
  • To investigate the role of NF-κB and microRNA-138-5p (miR-138-5p) in A3B-mediated HBV control.
  • To evaluate the therapeutic potential of modulating A3B expression for HBV treatment.

Main Methods:

  • Utilized differentiated HepaRG cells and primary human hepatocytes with or without HBV infection.
  • Employed knockdown of NF-κB signaling components, siRNA/miRNA transfections, and treatment with lymphotoxin beta receptor (LTβR)-agonist (BS1).
  • Applied a comprehensive suite of molecular analyses including qPCR, immunoblotting, sequencing, and mass spectrometry.

Main Results:

  • Both canonical and non-canonical NF-κB pathways are essential for A3B induction and anti-HBV activity.
  • A3B expression is post-transcriptionally regulated by miR-138-5p, which promotes A3B mRNA decay; its overexpression reduced A3B levels and antiviral effects.
  • LTβR-agonist treatment significantly reduced cccDNA by 80% without damaging key host genes, independent of cccDNA transcriptional activity.

Conclusions:

  • APOBEC3B is the first described enzyme capable of degrading both transcriptionally active and inactive HBV cccDNA.
  • Inhibiting miR-138-5p should be considered in combination therapies for HBV, particularly when leveraging immune-mediated A3B induction.
  • A3B-mediated cccDNA decay presents a promising therapeutic avenue for chronic HBV infection.
Abstract

Keywords:
A20, tumour necrosis factor alpha-induced protein 3APOBEC3A/A3A, apolipoprotein B mRNA editing catalytic polypeptide-like AAPOBEC3BAPOBEC3B/A3B, apolipoprotein B mRNA editing catalytic polypeptide-like BAPOBEC3G/A3G, apolipoprotein B mRNA editing catalytic polypeptide-like GBCA, bicinchoninic acid assayCHB, chronic hepatitis BCXCL10, C-X-C motif chemokine ligand 10ChIP, chromatin immune precipitationEMSA, electrophoretic mobility-shift assayH3K4Me3, histone 3 lysine 4 trimethylationHBxHepatitis B virusIFNα/γ, interferon alpha/gammaIKKα/β, IκB kinase alpha/betaJMJD8, jumonji domain containing 8LPS, lipopolysaccharideLTβR, lymphotoxin beta receptorMAPK, mitogen-activated protein kinaseNEMO, NF-κB essential modulatorNF-κBNF-κB, nuclear factor kappa BNIK, NF-κB inducing kinaseNT, non-treatedRT-qPCR, reverse transcription-quantitative PCRRelA, NF-κB p65 subunitTNF, tumour necrosis factorUBE2V1, ubiquitin conjugating enzyme E2 V1UTR, untranslated regioncccDNAcccDNA, covalently closed circular DNAd.p.i., days post infectionmiRNAmiRNA, micro RNAsiCTRL, siRNA control

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