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Journal of Virology, December 2007, p. 13469-13477, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01097-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin {alpha} Proteins with Activated STAT1{triangledown}

St. Patrick Reid, Charalampos Valmas, Osvaldo Martinez, Freddy Mauricio Sanchez, and Christopher F. Basler*

Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029

Received 21 May 2007/ Accepted 24 September 2007

The Zaire ebolavirus protein VP24 was previously demonstrated to inhibit alpha/beta interferon (IFN-{alpha}/ß)- and IFN-{gamma}-induced nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1) and to inhibit IFN-{alpha}/ß- and IFN-{gamma}-induced gene expression. These properties correlated with the ability of VP24 to interact with the nuclear localization signal receptor for PY-STAT1, karyopherin {alpha}1. Here, VP24 is demonstrated to interact not only with overexpressed but also with endogenous karyopherin {alpha}1. Mutational analysis demonstrated that VP24 binds within the PY-STAT1 binding region located in the C terminus of karyopherin {alpha}1. In addition, VP24 was found to inhibit PY-STAT1 binding to both overexpressed and endogenous karyopherin {alpha}1. We assessed the binding of both PY-STAT1 and the VP24 proteins from Zaire, mouse-adapted Zaire, and Reston Ebola viruses for interaction with all six members of the human karyopherin {alpha} family. We found, in contrast to previous studies, that PY-STAT1 can interact not only with karyopherin {alpha}1 but also with karyopherins {alpha}5 and {alpha}6, which together comprise the NPI-1 subfamily of karyopherin {alpha}s. Similarly, all three VP24s bound and inhibited PY-STAT1 interaction with karyopherins {alpha}1, {alpha}5, and {alpha}6. Consistent with their ability to inhibit the karyopherin-PY-STAT1 interaction, Zaire, mouse-adapted Zaire, and Reston Ebola virus VP24s displayed similar capacities to inhibit IFN-ß-induced gene expression in human and mouse cells. These findings suggest that VP24 inhibits interaction of PY-STAT1 with karyopherins {alpha}1, {alpha}5, or {alpha}6 by binding within the PY-STAT1 binding region of the karyopherins and that this function is conserved among the VP24 proteins of different Ebola virus species.

* 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

{triangledown} Published ahead of print on 10 October 2007.

Journal of Virology, December 2007, p. 13469-13477, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01097-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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