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A Protocol for Analyzing Hepatitis C Virus Replication
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TRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis

Sayaka Aizawa1, Toru Okamoto1, Yukari Sugiyama1

  • 1Department of Molecular Virology, Osaka University, Osaka, 565-0871 Japan.

Nature Communications
|May 5, 2016
PubMed

Insights

Signal-peptide peptidase (SPP) inhibition reduces hepatitis C virus (HCV) production and disease. SPP inhibition targets immature HCV core protein for degradation, mitigating liver issues and ER stress.

Area of Science:

  • Virology
  • Molecular Biology
  • Hepatology

Background:

  • Signal-peptide peptidase (SPP) is an intramembrane protease.
  • SPP plays a role in the maturation of hepatitis C virus (HCV) core protein.

Purpose of the Study:

  • To investigate the role of SPP in HCV production and pathogenesis.
  • To explore the therapeutic potential of SPP inhibition in HCV infection.

Main Methods:

  • Utilized SPP knockout cells and SPP inhibitors.
  • Administered SPP inhibitor orally to transgenic mice expressing HCV core protein (CoreTg).
  • Investigated the involvement of the ubiquitin-proteasome pathway and E3 ubiquitin ligase TRC8.

Main Results:

  • SPP inhibition reduced infectious HCV particle production and pathogenesis.
  • Immature HCV core protein was degraded via the ubiquitin-proteasome pathway upon SPP inhibition.
  • Oral SPP inhibitor treatment in CoreTg mice decreased core protein expression, ameliorated insulin resistance and liver steatosis.
  • SPP haploinsufficiency in CoreTg mice showed similar beneficial effects.
  • TRC8 E3 ubiquitin ligase was essential for immature core protein degradation.
  • HCV core protein expression induced ER stress in SPP/TRC8 double-knockout cells.

Conclusions:

  • HCV utilizes SPP cleavage to evade host cell ER stress induction.
  • SPP is a potential therapeutic target for reducing HCV pathogenesis and associated metabolic disorders.

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