Newcastle Disease virus (NDV) causes a severe and economically significant disease affecting almost the entire poultry industry worldwide.However, factors that affect NDV replication in host cells are poorly understood.Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and NF-κB signaling known for their functions in the control of immune response as well as tumor invasion and metastasis.In the present study we investigated the consequences of overexpression of host RKIP during viral infection.We demonstrate that NDV infection represses RKIP expression thereby promoting virus replication.Experimental upregulation of RKIP in turn acts as a potential antiviral defense mechanism in host cells that restricts NDV replication by repressing the activation of Raf/MEK/ERK and IκBα/NF-κB signaling pathway.Our results not only extend the concept of linking NDV-host interactions, but even reveal RKIP as a new class of protein-kinase-inhibitor proteins that affects NDV replication with therapeutic potential.Conclusion In summary, we show that NDV infection represses host RKIP expression, which subsequently results in enhanced Raf/MEK/ERK signaling and IκBα/NF-κB pathway activation, since this pathway is usually inhibited by RKIP activity (Fig.3E).NDV replication however requires Raf/MEK/ERK and IκBα/NF-κB signaling, and virus propagation is therefore less efficient if these pathways are obstructed (Fig.3F).Targeted overexpression of RKIP therefore can be exploited as an antiviral defense mechanism and the results of this study could help not only to improve our understanding of NDV host interactions but even more suggests an new avenue for the development of novel antiviral strategies.