Abstract
The nonstructural protein 3 (NS3) of hepatitis C virus (HCV) inhibits the nuclear transport and the enzymatic activity of the catalytic subunit of protein kinase A. This inhibition is mediated by an arginine-rich domain localized between amino acids 1487-1500 of the HCV polyprotein. The data presented here indicate that the arginine-rich domain, when embedded in recombinant fragments of NS3, interacts with the catalytic site of protein kinase C (PKC) and inhibits the phosphorylation mediated by this enzyme in vitro and in vivo. Furthermore, a direct binding of PKC to the NS3 fragments leads to an inhibition of the free shuttling of the kinase between the cytoplasm and the particulate fraction. In contrast, a peptide corresponding to the arginine-rich domain (HCV (1487-1500)), despite also being a PKC inhibitor, did not influence the PKC shuttling process and was transported to the particulate fraction by the translocating kinase upon activation with tetradecanoylphorbol-13-acetate. Using the tetradecanoylphorbol-13-acetate -stimulated respiratory burst of NS3-introduced neutrophils as a model system, we could demonstrate that NS3 is able to block PKC-mediated functions within intact cells. Our data support the possibility that NS3 disrupts the PKC-mediated signal transduction.
Highlights
In more than 50% of the investigated cases, liver infections with the hepatitis C virus (HCV)1 result in chronic liver disease, which often leads to cirrhosis and hepatocellular carcinoma [1, 2]
Because the entire nonstructural protein 3 (NS3) protein was not found to be readily soluble (Ref. 24 and data not shown), we investigated the interaction between NS3 and protein kinase C (PKC), using the well characterized C- and N-truncated form of the NS3 protein (HCV polyprotein-(1189 –1525)) [5, 8]
As the main result of this study we have shown that the enzymatic activity and the cytosol-to-membrane translocation of PKC is inhibited by the nonstructural protein 3 of hepatitis C virus
Summary
In more than 50% of the investigated cases, liver infections with the hepatitis C virus (HCV)1 result in chronic liver disease, which often leads to cirrhosis and hepatocellular carcinoma [1, 2]. The data presented here indicate that the argininerich domain, when embedded in recombinant fragments of NS3, interacts with the catalytic site of protein kinase C (PKC) and inhibits the phosphorylation mediated by this enzyme in vitro and in vivo. It seems likely that the arginine-rich sequence embedded in a larger fragment of the HCV polyprotein interacts with the catalytic domain of PKC, as observed in the case of PKA in vivo [8].
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