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Calpain activation by hepatitis C virus proteins inhibits the extrinsic apoptotic signaling pathway

Yannick Simonin1, Olivier Disson, Hervé Lerat

  • 1Centre National de la Recherche Scientifique (CNRS), UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France.

Hepatology (Baltimore, Md.)
|August 28, 2009
PubMed
Abstract

Insights

Hepatitis C virus (HCV) proteins activate calpains, which degrade Bid, a protein crucial for apoptosis. Inhibiting calpains may enhance the immune system's ability to clear HCV-infected cells.

Area of Science:

  • Virology
  • Immunology
  • Cell Biology

Background:

  • Hepatitis C virus (HCV) establishes chronic infections by evading host defenses.
  • Viruses often modulate apoptosis to escape immune surveillance.
  • HCV proteins were previously shown to down-regulate Bid expression in mice, conferring resistance to apoptosis.

Purpose of the Study:

  • To investigate the mechanism by which HCV down-regulates Bid expression in infected cells.
  • To determine if this mechanism is relevant in human HCV infection and associated pathologies.
  • To explore calpain inhibition as a therapeutic strategy.

Main Methods:

  • Analysis of Bid expression in HCV patients and an HCV RNA replicon system.
  • Investigating the role of HCV nonstructural protein NS5A in Bid degradation.
  • Utilizing calpain inhibitors to restore Bid levels and apoptosis sensitivity.
  • Assessing calpain activity in HCV-related tumors and infected mouse hepatocytes.

Main Results:

  • Bid is down-regulated in noncirrhotic HCV-linked tumorigenesis and the HCV RNA replicon system.
  • HCV nonstructural protein NS5A activates calpains, leading to Bid degradation.
  • Calpain inhibitors restore Bid levels and Fas-mediated apoptosis sensitivity.
  • Activated calpains are present in human HCV tumors and HCV transgenic mouse hepatocytes with low Bid.

Conclusions:

  • HCV proteins activate calpains, which degrade Bid, thereby suppressing apoptotic signaling.
  • This mechanism contributes to HCV persistence and pathogenesis, including hepatocellular carcinoma.
  • Inhibiting calpains offers a potential strategy to enhance immune-mediated elimination of HCV-infected cells.

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