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Journal of Virology, August 2007, p. 8412-8420, Vol. 81, No. 16
0022-538X/07/$08.00+0     doi:10.1128/JVI.00189-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Functional Heat Shock Protein 90 Chaperone Is Essential for Efficient Flock House Virus RNA Polymerase Synthesis in Drosophila Cells{triangledown}

Kathryn M. Castorena,1 Spencer A. Weeks,2 Kenneth A. Stapleford,3 Amy M. Cadwallader,2 and David J. Miller1,2,3*

Departments of Internal Medicine,1 Microbiology and Immunology,2 Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan 481093

Received 28 January 2007/ Accepted 16 May 2007

The molecular chaperone heat shock protein 90 (Hsp90) is involved in multiple cellular processes including protein maturation, complex assembly and disassembly, and intracellular transport. We have recently shown that a disruption of Hsp90 activity in cultured Drosophila melanogaster cells suppresses Flock House virus (FHV) replication and the accumulation of protein A, the FHV RNA-dependent RNA polymerase. In the present study, we investigated whether the defect in FHV RNA polymerase accumulation induced by Hsp90 suppression was secondary to an effect on protein A synthesis, degradation, or intracellular membrane association. Treatment with the Hsp90-specific inhibitor geldanamycin selectively reduced FHV RNA polymerase synthesis by 80% in Drosophila S2 cells stably transfected with an inducible protein A expression plasmid. The suppressive effect of geldanamycin on protein A synthesis was not attenuated by proteasome inhibition, nor was it sensitive to changes in either the mRNA untranslated regions or protein A intracellular membrane localization. Furthermore, geldanamycin did not promote premature protein A degradation, nor did it alter the extremely rapid kinetics of protein A membrane association. These results identify a novel role for Hsp90 in facilitating viral RNA polymerase synthesis in Drosophila cells and suggest that FHV subverts normal cellular pathways to assemble functional replication complexes.

* 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

{triangledown} Published ahead of print on 23 May 2007.

Journal of Virology, August 2007, p. 8412-8420, Vol. 81, No. 16
0022-538X/07/$08.00+0     doi:10.1128/JVI.00189-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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