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Journal of Virology, April 2009, p. 3069-3077, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.01875-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Ebola Virus Protein VP35 Impairs the Function of Interferon Regulatory Factor-Activating Kinases IKK{varepsilon} and TBK-1{triangledown}

Kathleen C. Prins,{dagger} Washington B. Cárdenas,{dagger},{ddagger} and Christopher F. Basler*

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

Received 5 September 2008/ Accepted 7 January 2009

The Ebola virus (EBOV) VP35 protein antagonizes the early antiviral alpha/beta interferon (IFN-{alpha}/β) response. We previously demonstrated that VP35 inhibits the virus-induced activation of the IFN-β promoter by blocking the phosphorylation of IFN-regulatory factor 3 (IRF-3), a transcription factor that is crucial for the induction of IFN-{alpha}/β expression. Furthermore, VP35 blocks IFN-β promoter activation induced by any of several components of the retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA-5)-activated signaling pathways including RIG-I, IFN-β promoter stimulator 1 (IPS-1), TANK-binding kinase 1 (TBK-1), and I{kappa}B kinase epsilon (IKK{varepsilon}). These results suggested that VP35 may target the IRF kinases TBK-1 and IKK{varepsilon}. Coimmunoprecipitation experiments now demonstrate physical interactions of VP35 with IKK{varepsilon} and TBK-1, and the use of an IKK{varepsilon} deletion construct further demonstrates that the amino-terminal kinase domain of IKK{varepsilon} is sufficient for interactions with either IRF-3 or VP35. In vitro, either IKK{varepsilon} or TBK-1 phosphorylates not only IRF-3 but also VP35. Moreover, VP35 overexpression impairs IKK{varepsilon}-IRF-3, IKK{varepsilon}-IRF-7, and IKK{varepsilon}-IPS-1 interactions. Finally, lysates from cells overexpressing IKK{varepsilon} contain kinase activity that can phosphorylate IRF-3 in vitro. When VP35 is expressed in the IKK{varepsilon}-expressing cells, this kinase activity is suppressed. These data suggest that VP35 exerts its IFN-antagonist function, at least in part, by blocking necessary interactions between the kinases IKK{varepsilon} and TBK-1 and their normal interaction partners, including their substrates, IRF-3 and IRF-7.

* 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: basler{at}mssm.edu

{triangledown} Published ahead of print on 19 January 2009.

{dagger} K.C.P. and W.B.C. contributed equally.

{ddagger} Present address: Laboratorio de Biomedicina, FIMCM, ESPOL, P.O. Box 09-01-5863, Guayaquil, Ecuador.

Journal of Virology, April 2009, p. 3069-3077, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.01875-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Schumann, M., Gantke, T., Muhlberger, E. (2009). Ebola Virus VP35 Antagonizes PKR Activity through Its C-Terminal Interferon Inhibitory Domain. J. Virol. 83: 8993-8997 [Abstract] [Full Text]  
  • Siu, K.-L., Kok, K.-H., Ng, M.-H. J., Poon, V. K. M., Yuen, K.-Y., Zheng, B.-J., Jin, D.-Y. (2009). Severe Acute Respiratory Syndrome Coronavirus M Protein Inhibits Type I Interferon Production by Impeding the Formation of TRAF3{middle dot}TANK{middle dot}TBK1/IKK{epsilon} Complex. J. Biol. Chem. 284: 16202-16209 [Abstract] [Full Text]  


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