Herpes simplex virus US3 tegument protein inhibits Toll-like receptor 2 signaling at or before TRAF6 ubiquitination

Herpes simplex virus (HSV) has evolved multiple strategies to modulate host immune responses. In a screen of HSV open reading frames to identify additional HSV-encoded proteins that affect NF-kappa B signaling, we identified the viral U(S)3 tegument protein as an inhibitor of NF-kappa B signaling. We found that the U(S)3 protein is required for inhibition of TLR2 signaling induced by viral infection and that this inhibition occurs at very early times post-infection. Expression of U(S)3 in transfected cells inhibits TLR2 signaling induced by Zymosan, and this inhibition occurs at or downstream of MyD88 and upstream of p65. Polyubiquitination of TRAF6 is critical for its function in TLR2 signaling. Using U(S)3-null and U(S)3 kinase-defective mutant viruses, we demonstrate that HSV U(S)3 reduces TRAF6 polyubiquitination and that the kinase activity of U(S)3 is necessary for this effect. Therefore, U(S)3 is necessary and sufficient for inhibiting TLR2 signaling at or before the stage of TRAF6 ubiquitination. (C) 2013 Elsevier Inc. All rights reserved.