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Ca(2+) /S100 proteins regulate HCV virus NS5A-FKBP8/FKBP38 interaction and HCV virus RNA replication

Joji Tani1, Seiko Shimamoto, Kyoko Mori

  • 1Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa, Japan.

Liver International : Official Journal of the International Association for the Study of the Liver
|March 26, 2013
PubMed
Abstract

Insights

S100 proteins bind FKBP8/FKBP38, inhibiting hepatitis C virus (HCV) replication by disrupting the FKBP8/FKBP38-NS5A interaction. This calcium-dependent mechanism offers a new target for antiviral therapies.

Area of Science:

  • Virology
  • Molecular Biology
  • Biochemistry

Background:

  • FKBP8/FKBP38 is an FK506-binding protein localizing to mitochondrial and ER outer membranes.
  • It possesses a Calmodulin-binding domain and a tetratricopeptide-repeat (TPR) domain, interacting with Hsp90 and Hepatitis C Virus (HCV) NS5A.
  • This interaction is crucial for HCV RNA replication.

Purpose of the Study:

  • To investigate the role of S100 proteins as host factors in regulating the FKBP8/FKBP38-mediated HCV replication complex.
  • To evaluate the inhibitory effect of S100 proteins on the formation of the ternary complex and HCV replication in vitro and in vivo.

Main Methods:

  • Recombinant expression and purification of S100 proteins, FKBP38, FKBP8, HCV NS5A, Hsp90, and calmodulin.
  • In vitro binding assays including GST pull-down, S-tag pull-down, and surface plasmon resonance.
  • Analysis of HCV replication inhibition by Western blotting in an HCV replicon cell line following S100 protein transfection.

Main Results:

  • S100A1, S100A2, S100A6, S100B, and S100P directly interacted with FKBP8/FKBP38 in a calcium-dependent manner.
  • These S100 proteins inhibited the interactions between FKBP8/FKBP38 with Hsp90 and NS5A.
  • Overexpression of S100A1, S100A2, and S100A6 significantly inhibited HCV replication in cultured cells.

Conclusions:

  • S100 proteins associate with FKBP8/FKBP38, modulating HCV replication.
  • This interaction reveals a novel calcium-dependent regulatory mechanism in HCV replication mediated by the NS5A-host protein interaction.
Keywords:
Ca2+-binding proteinsHCV replicon harbouring cellsHsp90ternary complex formationtetratricopeptide repeat

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