Herpes simplex virus 1 UL2 protein inhibits RIG-I-like receptor pathway-induced IFN-β activity by disrupting IRF3 activation.

Herpes simplex virus 1 (HSV-1) is a member of alphaherpesvirus that can cause some important human diseases, and type I interferon (IFN-I)-mediated antiviral effect plays a vital role in the innate immune response, whereas this reaction can be negatively regulated by some HSV-1 encoded proteins. However, it remains unknown whether additional HSV-1 factors contribute to this process. Here, we found that the HSV-1 encoded uracil-DNA glycosylase, UL2, can inhibit Sendai virus (SeV)-induced IFN-β activity. Mechanically, UL2 interacts with the components of RIG-I-like receptor (RLR) signaling pathway, including TBK1 and activated IRF3. While UL2 does not affect the ubiquitination of TBK1 or IRF3, it rather hinders the SeV-stimulated phosphorylation of IRF3 at Ser396. Simultaneously, UL2 blocks the formation of IRF3 dimer and its nuclear translocation. Therefore, these results suggested a crucial connection between UL2 and IFN-β signaling pathway, which may take considerable role in the HSV-1 evasion of the host antiviral response.