title: The measles virus V protein binds to p65 (RelA) to suppress NF-kappaB activity.
abstract: 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.
authors.affiliation: Max von Pettenkofer Institute & Gene Center, Feodor-Lynen-Str. 25, D-81377 Munich, Germany.
authors.forename: Kerstin M
authors.initials: KM
authors.lastname: Schuhmann
authors.forename: Christian K
authors.initials: CK
authors.lastname: Pfaller
authors.forename: Karl-Klaus
authors.initials: KK
authors.lastname: Conzelmann
mesh_terms: D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D017930:Genes, Reporter; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D006801:Humans; D057131:Immune Evasion; D047468:Immunoprecipitation; D008459:Measles virus / Q000276:immunology* / Q000472:pathogenicity*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D051996:Transcription Factor RelA / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D010750:Phosphoproteins; C498143:RELA protein, human; D051996:Transcription Factor RelA; C069181:V protein, measles virus; D014764:Viral Proteins