NONSTRUCTURAL PROTEIN-3 OF HEPATITIS-C VIRUS BLOCKS THE DISTRIBUTION OF THE FREE CATALYTIC SUBUNIT OF CYCLIC-AMP-DEPENDENT PROTEIN-KINASE

Chronic hepatitis resulting from hepatitis C virus (HCV) infection dev elops into cirrhosis in at least half of infected patients and increas es the risk of hepatocellular carcinoma. The pathogenic effects of a n umber of viruses result from the disturbance of intracellular signal c ascades caused by viral antigens, Therefore. we investigated the inter action of nonstructural protein 3 (NS3) of HCV with the cyclic AMP-dep endent signal pathway. We found a similarity between the HCV sequence rg-Gly-Agr-Thr-Gly-Arg-Glu-Arg-Agr-Gly-Ile-Tyr-Arg localized in NS3 an d the general consensus sequence of protein kinase A (PKA). Consequent ly, the catalytic (C) subunit of PKA bound to a bacterially expressed fragment of HCV polyprotein containing amino acid residues 1189 to 152 5. When this fragment was introduced into cells, it inhibited the tran slocation of the C subunit into the nucleus after stimulation with for skolin. The result of this inhibition was significantly reduced histon e phosphorylation. Therefore, the presence of NS3 in the cytoplasm of infected cells may affect a wide range of PKA functions and contribute to the pathogenesis of the diseases caused by HCV.