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The hepatitis C virus core protein contains a BH3 domain that regulates apoptosis through specific interaction with

Nur Khairiah Mohd-Ismail1, Lin Deng, Sunil Kumar Sukumaran

  • 1Collaborative Anti-Viral Research Group, Institute of Molecular and Cell Biology, Singapore.

Journal of Virology
|July 17, 2009
PubMed

Insights

The hepatitis C virus (HCV) core protein acts as a BH3-only protein, inducing apoptosis by interacting with Mcl-1. A specific amino acid difference enhances this proapoptotic function in genotype 1b, impacting viral pathogenesis.

Area of Science:

  • Virology
  • Molecular Biology
  • Cell Biology

Background:

  • The hepatitis C virus (HCV) core protein plays a role in viral replication and pathogenesis by modulating apoptosis.
  • Understanding the mechanisms of HCV-induced apoptosis is crucial for developing antiviral strategies.

Purpose of the Study:

  • To identify and characterize the proapoptotic function of the HCV core protein.
  • To investigate the interaction of the HCV core protein with the Bcl-2 family of proteins.
  • To determine the role of specific amino acid residues in the proapoptotic activity of the HCV core protein.

Main Methods:

  • Coimmunoprecipitation assays to study protein interactions.
  • Overexpression studies to assess the effect of Mcl-1 on apoptosis.
  • Peptide mimetic experiments to analyze cytochrome c release.
  • Site-directed mutagenesis to investigate the role of specific residues.
  • Generation and analysis of a mutant HCV infectious clone.

Main Results:

  • The HCV core protein possesses a Bcl-2 homology 3 (BH3) domain essential for its proapoptotic activity.
  • The core protein specifically interacts with myeloid cell factor 1 (Mcl-1), a prosurvival Bcl-2 family member.
  • Overexpression of Mcl-1 confers protection against core-induced apoptosis.
  • A single amino acid difference (residue 119) between genotypes 1b and 2a significantly affects the proapoptotic potency of the core protein.
  • A mutant virus (J6/JFH-1(V119L)) with the genotype 1b residue at position 119 induced higher apoptosis and showed enhanced Mcl-1 interaction.

Conclusions:

  • The HCV core protein is a novel BH3-only viral homologue that induces apoptosis.
  • The interaction with Mcl-1 and the specific hydrophobic residues within the BH3 domain are critical for the proapoptotic function of the HCV core protein.
  • Variations in the core protein's BH3 domain, such as at residue 119, can influence its ability to induce apoptosis and potentially contribute to HCV pathogenesis.

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