title: Herpes simplex virus US3 tegument protein inhibits Toll-like receptor 2 signaling at or before TRAF6 ubiquitination.
abstract: 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-κB signaling, we identified the viral US3 tegument protein as an inhibitor of NF-κB signaling. We found that the US3 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 US3 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 US3-null and US3 kinase-defective mutant viruses, we demonstrate that HSV US3 reduces TRAF6 polyubiquitination and that the kinase activity of US3 is necessary for this effect. Therefore, US3 is necessary and sufficient for inhibiting TLR2 signaling at or before the stage of TRAF6 ubiquitination.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
authors.forename: Jayita
authors.initials: J
authors.lastname: Sen
authors.forename: Xueqiao
authors.initials: X
authors.lastname: Liu
authors.forename: Richard
authors.initials: R
authors.lastname: Roller
authors.forename: David M
authors.initials: DM
authors.lastname: Knipe
mesh_terms: D002460:Cell Line; D018259:Herpesvirus 1, Human / Q000472:pathogenicity*; D006801:Humans; D057131:Immune Evasion; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D054875:Ubiquitination; D014764:Viral Proteins / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D014764:Viral Proteins; D037521:Virulence Factors; D017346:Protein Serine-Threonine Kinases; C095207:US3 protein, Human herpesvirus 1