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A Competent Hepatocyte Model Examining Hepatitis B Virus Entry through Sodium Taurocholate Cotransporting Polypeptide as a Therapeutic Target
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A Competent Hepatocyte Model Examining Hepatitis B Virus Entry through Sodium Taurocholate Cotransporting Polypeptide as a Therapeutic Target

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Ca2+/Calmodulin-Dependent Protein Kinase II Inhibits Hepatitis B Virus Replication from cccDNA via AMPK Activation

Jumi Kim1,2, Hyeonjoong Kwon1,2, Fadia Kalsoom1,2

  • 1Department of Microbiology, Ajou University School of Medicine, Suwon 16499, Korea.

Microorganisms
|March 26, 2022
PubMed

Insights

Hepatitis B virus (HBV) replication suppresses Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. Upregulating CaMKII inhibits HBV replication by activating AMPK and the AKT/mTOR pathway, suggesting CaMKII as a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Virology
  • Cell Signaling

Background:

  • Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates cancer cell functions via calcium signaling.
  • The role of CaMKII in hepatitis B virus (HBV) replication was previously uninvestigated.

Purpose of the Study:

  • To investigate the effect of CaMKII on HBV replication.
  • To elucidate the underlying molecular mechanisms involving the AMPK/AKT/mTOR signaling pathway.

Main Methods:

  • Analysis of CaMKII phosphorylation levels during HBV replication.
  • Overexpression of CaMKII and AMPK in HepG2 cells.
  • Assessment of HBV covalently closed circular DNA (cccDNA), RNA, and replicative intermediate (RI) DNA levels.
  • Investigation in HBx-deficient mutant-transfected cells.

Main Results:

  • Active CaMKII levels decrease during HBV replication.
  • CaMKII overexpression reduces HBV cccDNA, RNAs, and RI DNAs, activating AMPK and inhibiting AKT/mTOR.
  • The CaMKII-mediated pathway is independent of HBx.
  • AMPK overexpression also reduces HBV replication markers via CaMKII activation.
  • A positive feedback loop exists between CaMKII and AMPK.

Conclusions:

  • HBV replication suppresses CaMKII activity.
  • CaMKII upregulation inhibits HBV replication through the AMPK/AKT/mTOR pathway.
  • CaMKII activation represents a potential therapeutic strategy against HBV infection.
Keywords:
AKT/mTOR signaling pathwayAMPKCaMKIIHBV replicationHBxhepatitis B virushepatocellular carcinoma

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