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Journal of Virology, November 2001, p. 10623-10629, Vol. 75, No. 22
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.22.10623-10629.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Rhabdoviruses and the Cellular Ubiquitin-Proteasome System: a Budding Interaction

Ronald N. Harty,1,* Melissa E. Brown,1 James P. McGettigan,2 Guangli Wang,3,dagger Himangi R. Jayakar,4 Jon M. Huibregtse,3 Michael A. Whitt,4 and Matthias J. Schnell2

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 191041; Department of Biochemistry and Molecular Pharmacology, Center for Human Virology, Thomas Jefferson University, Philadelphia, Pennsylvania 191072; Department of Molecular Genetics and Microbiology, University of Texas at Austin, Austin, Texas 787123; and Department of Molecular Sciences, University of Tennessee-Memphis, Memphis, Tennessee 381634

Received 28 June 2001/Accepted 8 August 2001

The matrix (M) proteins of vesicular stomatitis virus (VSV) and rabies virus (RV) play a key role in both assembly and budding of progeny virions. A PPPY motif (PY motif or late-budding domain) is conserved in the M proteins of VSV and RV. These PY motifs are important for virus budding and for mediating interactions with specific cellular proteins containing WW domains. The PY motif and flanking sequences of the M protein of VSV were used as bait to screen a mouse embryo cDNA library for cellular interactors. The mouse Nedd4 protein, a membrane-localized ubiquitin ligase containing multiple WW domains, was identified from this screen. Ubiquitin ligase Rsp5, the yeast homolog of Nedd4, was able to interact both physically and functionally with full-length VSV M protein in a PY-dependent manner. Indeed, the VSV M protein was multiubiquitinated by Rsp5 in an in vitro ubiquitination assay. To demonstrate further that ubiquitin may be involved in the budding process of rhabdoviruses, proteasome inhibitors (e.g., MG132) were used to decrease the level of free ubiquitin in VSV- and RV-infected cells. Viral titers measured from MG132-treated cells were reproducibly 10- to 20-fold lower than those measured from untreated control cells, suggesting that free ubiquitin is important for efficient virus budding. Last, release of a VSV PY mutant was not inhibited in the presence of MG132, signifying that the functional L domain of VSV is required for the inhibitory effect exhibited by MG132. These data suggest that the cellular ubiquitin-proteasome machinery is involved in the budding process of VSV and RV.

* Corresponding author. Mailing address: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce St., Philadelphia, PA 19104-6049. Phone: (215) 573-4485. Fax: (215) 898-7887. E-mail: rharty{at}vet.upenn.edu.

dagger Present address: Department of Molecular Biology, Princeton University, Princeton, NJ 08544.

Journal of Virology, November 2001, p. 10623-10629, Vol. 75, No. 22
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.22.10623-10629.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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