Vaccinia Virus Protein A52R Activates p38 Mitogen-activated Protein Kinase and Potentiates Lipopolysaccharide-induced Interleukin-10

• Published in: The Journal of biological chemistry Vol. 280; no. 35; pp. 30838 - 30844
• Main Authors: Maloney, Geraldine, Schröder, Martina, Bowie, Andrew G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.09.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Line; Enzyme Activation; Gene Expression Regulation; Genes, Reporter; Humans; Interleukin-1 Receptor-Associated Kinases; Interleukin-10 - genetics; Interleukin-10 - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; Lipopolysaccharides - metabolism; MAP Kinase Signaling System - physiology; Mice; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Promoter Regions, Genetic; Protein Kinases - genetics; Protein Kinases - metabolism; Protein Structure, Tertiary; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; TNF Receptor-Associated Factor 6 - genetics; TNF Receptor-Associated Factor 6 - metabolism; Transcriptional Activation; Vaccinia virus; Viral Proteins - genetics; Viral Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M501917200

Vaccinia virus (VV) has many mechanisms to suppress and modulate the host immune response. The VV protein A52R was previously shown to act as an intracellular inhibitor of nuclear factor κB (NFκB) signaling by Toll-like receptors (TLRs). Co-immunoprecipitation studies revealed that A52R interacted with both tumor necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 2 (IRAK2). The effect of A52R on signals other than NFκB was not determined. Here, we show that A52R does not inhibit TLR-induced p38 or c-Jun amino N-terminal kinase (JNK) mitogen activating protein (MAP) kinase activation. Rather, A52R could drive activation of these kinases. Two lines of evidence suggested that the A52R/TRAF6 interaction was critical for these effects. First, A52R-induced p38 MAP kinase activation was inhibited by overexpression of the TRAF domain of TRAF6, which sequestered A52R and inhibited its interaction with endogenous TRAF6. Second, a truncated version of A52R, which interacted with IRAK2 and not TRAF6, was unable to activate p38. Because interleukin 10 (IL-10) production is strongly p38-dependent, we examined the effect of A52R on IL-10 gene induction. A52R was found to be capable of inducing the IL-10 promoter through a TRAF6-dependent mechanism. Furthermore, A52R enhanced lipopolysaccharide/TLR4-induced IL-10 production, while inhibiting the TLR-induced NFκB-dependent genes IL-8 and RANTES. These results show that although A52R inhibits NFκB activation by multiple TLRs it can simultaneously activate MAP kinases. A52R-mediated enhancement of TLR-induced IL-10 may be important to virulence, given the role of IL-10 in immunoregulation.