Host Cell Factor Requirement for Hepatitis C Virus Enzyme Maturation

The cellular chaperone, HSP90, is identified here as an essential factor for the activity of NS2/3 protease of hepatitis C virus. The cleavage activity of NS2/3 protease synthesized in reticulocyte lysate is ATP-dependent, as evidenced by ATP depletion experiments and inhibition with nonhydrolyzable...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-11, Vol.98 (24), p.13931-13935
Main Authors: Waxman, Lloyd, Whitney, Michael, Pollok, Brian A., Kuo, Lawrence C., Darke, Paul L.
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Antibodies
Benzoquinones
Biological Sciences
Cysteine Endopeptidases - genetics
Cysteine Endopeptidases - metabolism
Enzymes
Gels
Hepacivirus
Hepacivirus - enzymology
Hepatitis
Hepatitis C
Hepatitis C virus
HSP90 Heat-Shock Proteins - antagonists & inhibitors
HSP90 Heat-Shock Proteins - metabolism
Hsp90 protein
Humans
Inhibitory concentration 50
Jurkat Cells
Lactams, Macrocyclic
Lactones - pharmacology
Low molecular weights
Macrolides
NS2/3 protein
Plasmids
Protein Processing, Post-Translational
Proteins
Quinones - metabolism
Quinones - pharmacology
RNA
Ubiquitins
Viruses
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Summary:The cellular chaperone, HSP90, is identified here as an essential factor for the activity of NS2/3 protease of hepatitis C virus. The cleavage activity of NS2/3 protease synthesized in reticulocyte lysate is ATP-dependent, as evidenced by ATP depletion experiments and inhibition with nonhydrolyzable ATP analogs. Geldanamycin and radicicol, ATP-competitive inhibitors of the chaperone HSP90, also inhibit the cleavage of in vitro-synthesized NS2/3. Furthermore, these HSP90 inhibitors prevent NS2/3 cleavage when the protease is expressed in mammalian cells. The physical association of NS2/3 with HSP90 is demonstrated by immunoprecipitation. Thus, by way of a chaperone/folding activity, an HSP90-containing complex is required for maturation of the polyprotein that encodes the enzymes essential for hepatitis C virus replication.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.241510898