The measles virus V protein binds to p65 (RelA) to suppress NF-kappaB activity

Nuclear factor κB (NF-κB) transcription factors are involved in controlling numerous cellular processes, including inflammation, innate and adaptive immunity, and cell survival. Here we show that the immunosuppressive measles virus (MV; Morbillivirus genus, Paramyxoviridae) has evolved multiple functions to interfere with canonical NF-κB signaling in epithelial cells. The MV P, V, and C proteins, also involved in preventing host cell interferon responses, were found to individually suppress NF-κB-dependent reporter gene expression in response to activation of the tumor necrosis factor (TNF) receptor, RIG-I-like receptors, or Toll-like receptors. NF-κB activity was most efficiently suppressed in the presence of V, while expression of P or C resulted in moderate inhibition. As indicated by reporter gene assays involving overexpression of the IκB kinase (IKK) complex, which phosphorylates the inhibitor of κB to liberate NF-κB, V protein targets a downstream step in the signaling cascade. Coimmunoprecipitation experiments revealed that V specifically binds to the Rel homology domain of the NF-κB subunit p65 but not of p50. Notably, the short C-terminal domain of the V protein, which is also involved in binding STAT2, IRF7, and MDA5, was sufficient for the interaction and for preventing reporter gene activity. As observed by confocal microscopy, the presence of V abolished nuclear translocation of p65 upon TNF-α stimulation. Thus, MV V appears to prevent NF-κB-dependent gene expression by retaining p65 in the cytoplasm. These findings reveal NF-κB as a key target of MV and stress the importance of the V protein as the major viral immune-modulatory factor.