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Journal of Virology, December 2008, p. 12365-12373, Vol. 82, No. 24
0022-538X/08/$08.00+0     doi:10.1128/JVI.01321-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Measles Virus V Protein Is a Decoy Substrate for I{kappa}B Kinase {alpha} and Prevents Toll-Like Receptor 7/9-Mediated Interferon Induction{triangledown}

Christian K. Pfaller and Karl-Klaus Conzelmann*

Max von Pettenkofer-Institute & Gene Center, Ludwig-Maximilians-University Munich, Feodor-Lynen-Str. 25, 81377 Munich, Germany

Received 24 June 2008/ Accepted 3 October 2008

The central role of plasmacytoid dendritic cells (pDC) in activating host immune responses stems from their high capacity to express alpha interferon (IFN-{alpha}) after stimulation of Toll-like receptors 7 and 9 (TLR7 and -9). This involves the adapter MyD88 and the kinases interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, and I{kappa}B kinase {alpha} (IKK{alpha}), which activates IFN regulatory factor 7 (IRF7) and is independent of the canonical kinases TBK1 and IKK{varepsilon}. We have recently shown that the immunosuppressive measles virus (MV) abolishes TLR7/9/MyD88-dependent IFN induction in human pDC (Schlender et al., J. Virol. 79:5507-5515, 2005), but the molecular mechanisms remained elusive. Here, we have reconstituted the pathway in cell lines and identified IKK{alpha} and IRF7 as specific targets of the MV V protein (MV-V). Binding of MV-V to IKK{alpha} resulted in phosphorylation of V on the expense of IRF7 phosphorylation by IKK{alpha} in vitro and in living cells. This corroborates the role of IKK{alpha} as the kinase phosphorylating IRF7. MV-V in addition bound to IRF7 and to phosphomimetic IRF7 and inhibited IRF7 transcriptional activity. Binding to both IKK{alpha} and IRF7 required the 68-amino-acid unique C-terminal domain of V. Inhibition of TLR/MyD88-dependent IFN induction by MV-V is unique among paramyxovirus V proteins and should contribute to the unique immunosuppressive phenotype of measles. The mechanisms employed by MV-V inspire strategies to interfere with immunopathological TLR/MyD88 signaling.

* Corresponding author. Mailing address: Max von Pettenkofer-Institute & Gene Center, Feodor-Lynen-Str. 25, D-81377 Munich, Germany. Phone: 49 89 2180 76851. Fax: 49 89 2180 76899. E-mail: conzelma{at}lmb.uni-muenchen.de

{triangledown} Published ahead of print on 15 October 2008.

Journal of Virology, December 2008, p. 12365-12373, Vol. 82, No. 24
0022-538X/08/$08.00+0     doi:10.1128/JVI.01321-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Manuse, M. J., Parks, G. D. (2009). Role for the Paramyxovirus Genomic Promoter in Limiting Host Cell Antiviral Responses and Cell Killing. J. Virol. 83: 9057-9067 [Abstract] [Full Text]  


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