Measles virus P protein suppresses Toll-like receptor signal through up-regulation of ubiquitin-modifying enzyme A20.
We recently reported that the activation of NF-kappaB and AP-1 was suppressed in monocytes infected with measles virus, but not in infected epithelial cells. This cell-type-specific suppression of the inflammatory response represents a potential for measles virus to evade host immune system. In the current study, we examined the suppression mechanism of lipopolysaccharide (LPS)-induced, namely Toll-like receptor 4 (TLR4)-mediated, activation of NF-kappaB and AP-1 in measles virus-infected monocytic cells. In the infected cells, LPS treatment failed to induce the formation of active protein kinase complex containing TAK1, TAB2 and tumor necrosis factor receptor-associated factor 6 (TRAF6), dissociate from TLR complexes containing Interleukin-1 receptor-associated kinase 1 (IRAK1). Ubiquitin-modifying enzyme A20, which is a host negative feedback regulator of NF-kappaB, was dramatically up-regulated in infected monocytic cells, but not in infected epithelial cells. Suppression of A20 expression by siRNA restored LPS-induced signaling in infected cells. Measles virus phosphoprotein (P protein) expression was necessary and sufficient for the induction of A20. P protein interacted indirectly with a negative regulatory motif in the A20 gene promoter, and released the suppression of A20 transcription, independent of the activation of NF-kappaB.
Yokota
Shin-ichi
S
Department of Microbiology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
Okabayashi
Tamaki
T
Yokosawa
Noriko
N
Fujii
Nobuhiro
N
D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*; D014764:Viral Proteins / Q000502:physiology*
D017931:DNA Primers; D016328:NF-kappa B; C055859:P protein, Sendai virus; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D025801:Ubiquitin; D014764:Viral Proteins; D011494:Protein Kinases