Measles Virus V Protein Is a Decoy Substrate for IκB Kinase α and Prevents Toll-Like Receptor 7/9-Mediated Interferon Induction

Abstract

ABSTRACT The central role of plasmacytoid dendritic cells (pDC) in activating host immune responses stems from their high capacity to express alpha interferon (IFN-α) 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 IκB kinase α (IKKα), which activates IFN regulatory factor 7 (IRF7) and is independent of the canonical kinases TBK1 and IKKε. 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 IKKα and IRF7 as specific targets of the MV V protein (MV-V). Binding of MV-V to IKKα resulted in phosphorylation of V on the expense of IRF7 phosphorylation by IKKα in vitro and in living cells. This corroborates the role of IKKα as the kinase phosphorylating IRF7. MV-V in addition bound to IRF7 and to phosphomimetic IRF7 and inhibited IRF7 transcriptional activity. Binding to both IKKα 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.