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.
Mesh Terms:
Base Sequence, Cell Line, DNA Primers, Humans, NF-kappa B, Phosphoproteins, Promoter Regions, Genetic, Protein Kinases, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, TNF Receptor-Associated Factor 6, Toll-Like Receptor 4, Transcription Factor AP-1, Transcriptional Activation, Ubiquitin, Up-Regulation, Viral Proteins
FASEB J.
Date: Jan. 01, 2008
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