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Journal of Virology, July 2005, p. 8732-8741, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8732-8741.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Detailed Mapping of the Nuclear Export Signal in the Rous Sarcoma Virus Gag Protein

Lisa Z. Scheifele,1,{dagger} Eileen P. Ryan,1 and Leslie J. Parent1,2*

Departments of Medicine,1 Microbiology and Immunology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 170332

Received 9 February 2005/ Accepted 26 March 2005

The Rous sarcoma virus (RSV) Gag polyprotein undergoes transient nuclear trafficking as an intrinsic part of the virus assembly pathway. Nuclear export of Gag is crucial for the efficient production of viral particles and is accomplished through the action of a leptomycin B (LMB)-dependent nuclear export signal (NES) in the p10 domain (L. Z. Scheifele, R. A. Garbitt, J. D. Rhoads, and L. J. Parent, Proc. Natl. Acad. Sci. USA 99:3944-3949, 2002). We have now mapped the nuclear export activity to the C-terminal portion of the p10 sequence and identified the four hydrophobic amino acids within this region that comprise a leucine-rich NES. Alteration of these hydrophobic residues resulted in the accumulation of Gag proteins within the nucleus and a budding defect greater than that obtained with LMB treatment of cells expressing the wild-type Gag protein (Scheifele et al., Proc. Natl. Acad. Sci. USA 99:3944-3949, 2002). In addition, export of Gag from the nucleus was found to be a rate-limiting step in virus-like particle production. Consistent with a role for the NES sequence in viral replication, this cluster of hydrophobic residues in p10 is conserved across a wide range of avian retroviruses. Furthermore, naturally occurring substitutions within this region in related viruses maintained nuclear export activity and remained sensitive to the activity of LMB. Using gain-of-function approaches, we found that the hydrophobic motif in p10 was sufficient to promote the nuclear export of a heterologous protein and was positionally independent within the Gag polyprotein. Finally, the export pathway was further defined by the ability of specific nucleoporin inhibitors to prevent the egress of Gag from the nucleus, thereby identifying additional cellular mediators of RSV replication.

* Corresponding author. Mailing address: Departments of Medicine and Microbiology and Immunology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033. Phone: (717) 531-3997. Fax: (717) 531-4633. E-mail: lparent{at}psu.edu.

{dagger} Present address: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 320 Broadway Research Building, 733 North Broadway, Baltimore, MD 21205.

Journal of Virology, July 2005, p. 8732-8741, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8732-8741.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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