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Journal of Virology, May 2004, p. 5358-5367, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.5358-5367.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Identification of the Nuclear Export Signal and STAT-Binding Domains of the Nipah Virus V Protein Reveals Mechanisms Underlying Interferon Evasion

Jason J. Rodriguez, Cristian D. Cruz, and Curt M. Horvath*

Immunobiology Center, The Mount Sinai School of Medicine, New York, New York 10029

Received 8 November 2003/ Accepted 19 December 2003

The V proteins of Nipah virus and Hendra virus have been demonstrated to bind to cellular STAT1 and STAT2 proteins to form high-molecular-weight complexes that inhibit interferon (IFN)-induced antiviral transcription by preventing STAT nuclear accumulation. Analysis of the Nipah virus V protein has revealed a region between amino acids 174 and 192 that functions as a CRM1-dependent nuclear export signal (NES). This peptide is sufficient to complement an export-defective human immunodeficiency virus Rev protein, and deletion and substitution mutagenesis revealed that this peptide is necessary for both V protein shuttling and cytoplasmic retention of STAT1 and STAT2 proteins. However, the NES is not required for V-dependent IFN signaling inhibition. IFN signaling is blocked primarily by interaction between Nipah virus V residues 100 to 160 and STAT1 residues 509 to 712. Interaction with STAT2 requires a larger Nipah virus V segment between amino acids 100 and 300, but deletion of residues 230 to 237 greatly reduced STAT2 coprecipitation. Further, V protein interactions with cellular STAT1 is a prerequisite for STAT2 binding, and sequential immunoprecipitations demonstrate that V, STAT1, and STAT2 can form a tripartite complex. These findings characterize essential regions for Henipavirus V proteins that represent potential targets for therapeutic intervention.

* Corresponding author. Mailing address: Immunobiology Center, The Mount Sinai School of Medicine, Box 1630, 1 Gustave L. Levy Pl., New York, NY 10029. Phone: (212) 659-9406. Fax: (212) 849-2525. E-mail: curt.horvath{at}mssm.edu.

Journal of Virology, May 2004, p. 5358-5367, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.5358-5367.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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