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J. Biol. Chem., Vol. 280, Issue 35, 30838-30844, September 2, 2005

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

Geraldine Maloney, Martina Schröder, and Andrew G. Bowie

From the Viral Immune Evasion Group, School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland

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 B (NFB) 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 NFB 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 NFB-dependent genes IL-8 and RANTES. These results show that although A52R inhibits NFB 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.

Received for publication, February 22, 2005 , and in revised form, June 14, 2005.

^* This work was supported by the Irish Health Research Board, Enterprise Ireland, and the Science Foundation Ireland Grant 02/IN.1/B192. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry, Trinity College Dublin, Dublin 2, Ireland. Tel.: 353-1-6082435; Fax: 353-1-6772400; E-mail: agbowie{at}tcd.ie.

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