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Journal of Virology, June 2005, p. 6827-6837, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6827-6837.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Cellular Chaperone Heat Shock Protein 90 Facilitates Flock House Virus RNA Replication in Drosophila Cells

Kathryn M. Kampmueller1 and David J. Miller1,2*

Departments of Internal Medicine,1 Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, Michigan 481092

Received 15 December 2004/ Accepted 19 January 2005

The assembly of viral RNA replication complexes on intracellular membranes represents a critical step in the life cycle of positive-strand RNA viruses. We investigated the role of the cellular chaperone heat shock protein 90 (Hsp90) in viral RNA replication complex assembly and function using Flock House virus (FHV), an alphanodavirus whose RNA-dependent RNA polymerase, protein A, is essential for viral RNA replication complex assembly on mitochondrial outer membranes. The Hsp90 chaperone complex transports cellular mitochondrial proteins to the outer mitochondrial membrane import receptors, and thus we hypothesized that Hsp90 may also facilitate FHV RNA replication complex assembly or function. Treatment of FHV-infected Drosophila S2 cells with the Hsp90-specific inhibitor geldanamycin or radicicol potently suppressed the production of infectious virions and the accumulation of protein A and genomic, subgenomic, and template viral RNA. In contrast, geldanamycin did not inhibit the activity of preformed FHV RNA replication complexes. Hsp90 inhibitors also suppressed viral RNA and protein A accumulation in S2 cells expressing an FHV RNA replicon. Furthermore, Hsp90 inhibition with either geldanamycin or RNAi-mediated chaperone downregulation suppressed protein A accumulation in the absence of viral RNA replication. These results identify Hsp90 as a host factor involved in FHV RNA replication and suggest that FHV uses established cellular chaperone pathways to assemble its RNA replication complexes on intracellular membranes.

* Corresponding author. Mailing address: Department of Internal Medicine, Division of Infectious Diseases, 5220E MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0640. Phone: (734) 763-0565. Fax: (734) 764-0101. E-mail: milldavi{at}umich.edu.

Journal of Virology, June 2005, p. 6827-6837, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6827-6837.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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