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Journal of Virology, June 2006, p. 5156-5167, Vol. 80, No. 11
0022-538X/06/$08.00+0     doi:10.1128/JVI.02349-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Ebola Virus VP24 Binds Karyopherin {alpha}1 and Blocks STAT1 Nuclear Accumulation

St. Patrick Reid,1,{dagger} Lawrence W. Leung,1,{dagger} Amy L. Hartman,2 Osvaldo Martinez,1 Megan L. Shaw,1 Caroline Carbonnelle,3 Viktor E. Volchkov,3 Stuart T. Nichol,2 and Christopher F. Basler1*

Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029,1 Special Pathogens Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, MS G-14, Atlanta, Georgia 30329,2 Filovirus Laboratory, University Claude Bernard Lyon-1, INSERM U412, 69007 Lyon, France3

Received 7 November 2005/ Accepted 15 March 2006

Ebola virus (EBOV) infection blocks cellular production of alpha/beta interferon (IFN-{alpha}/ß) and the ability of cells to respond to IFN-{alpha}/ß or IFN-{gamma}. The EBOV VP35 protein has previously been identified as an EBOV-encoded inhibitor of IFN-{alpha}/ß production. However, the mechanism by which EBOV infection inhibits responses to IFNs has not previously been defined. Here we demonstrate that the EBOV VP24 protein functions as an inhibitor of IFN-{alpha}/ß and IFN-{gamma} signaling. Expression of VP24 results in an inhibition of IFN-induced gene expression and an inability of IFNs to induce an antiviral state. The VP24-mediated inhibition of cellular responses to IFNs correlates with the impaired nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1), a key step in both IFN-{alpha}/ß and IFN-{gamma} signaling. Consistent with this proposed function for VP24, infection of cells with EBOV also confers a block to the IFN-induced nuclear accumulation of PY-STAT1. Further, VP24 is found to specifically interact with karyopherin {alpha}1, the nuclear localization signal receptor for PY-STAT1, but not with karyopherin {alpha}2, {alpha}3, or {alpha}4. Overexpression of VP24 results in a loss of karyopherin {alpha}1-PY-STAT1 interaction, indicating that the VP24-karyopherin {alpha}1 interaction contributes to the block to IFN signaling. These data suggest that VP24 is likely to be an important virulence determinant that allows EBOV to evade the antiviral effects of IFNs.

* Corresponding author. Mailing address: Department of Microbiology, Box 1124, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029. Phone: (212) 241-4847. Fax: (212) 534-1684. E-mail: chris.basler{at}mssm.edu.

{dagger} S.P.R. and L.W.L. contributed equally to this study.

Journal of Virology, June 2006, p. 5156-5167, Vol. 80, No. 11
0022-538X/06/$08.00+0     doi:10.1128/JVI.02349-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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