Prenylation of the hepatitis delta virus large antigen: a new target for farnesyltransferase inhibitors
The hepatitis delta virus large antigen (IHDAg) is a virally encoded protein that contains a prenylation signal sequence at its carboxyl terminus consisting of the tetrapeptide Cys-Arg-Pro-Gln. The prenylation of IHDAg was examined in vitro using a fusion protein between glutathione-S-transferase and the C-terminal 117 amino acids of IHDAg (GST-lHDAg). When recombinant GST-lHDAg was incubated with bovine brain cytosol in the presence of either farnesyl diphosphate or geranylgeranyl diphosphate, GST-lHDAg was preferentially farnesylated. Using purified recombinant protein prenyltransferases, GST-lHDAg was found to be an excellent substrate for protein farnesyltransferase (FTase), while modification by protein geranylgeranyltransferase-I was not detected. Consistent with our observations on the in vitro prenylation of the GST-lHDAg fusion protein, isoprenoid analysis of authentic IHDAg expressed in COS cells demonstrated that the protein was farnesylated. Geranylgeranylation of IHDAg expressed in COS cells was not observed. Thus, IHDAg is exclusively a substrate for FTase. As prenylation of IHDAg is required for the assembly of the hepatitis delta viral particle, these results suggest that inhibitors of FTase may be useful therapeutic agents for treatment of delta virus infection. We are currently examining the effects of farnesyltransferase inhibitors on hepatitis delta viral assembly events in a human hepatoma cell line.
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Related Subject Headings
- Biochemistry & Molecular Biology
- 3208 Medical physiology
- 3101 Biochemistry and cell biology
- 1116 Medical Physiology
- 0606 Physiology
- 0601 Biochemistry and Cell Biology
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Published In
ISSN
Publication Date
Volume
Issue
Related Subject Headings
- Biochemistry & Molecular Biology
- 3208 Medical physiology
- 3101 Biochemistry and cell biology
- 1116 Medical Physiology
- 0606 Physiology
- 0601 Biochemistry and Cell Biology