Herpes Simplex Virus 1 UL2 Inhibits the TNF-alpha-Mediated NF-kappa B Activity by Interacting With p65/p50

Herpes simplex virus 1 (HSV-1) is a large double-stranded DNA virus that encodes at least 80 viral proteins, many of which are involved in the virus-host interaction and are beneficial to the viral survival and reproduction. However, the biological functions of some HSV-1-encoded proteins are not fully understood. Nuclear factor kappa B (NF-kappa B) activation is the major antiviral innate response, which can be triggered by various signals induced by cellular receptors from different pathways. Here, we demonstrated that HSV-1 UL2 protein could antagonize the tumor necrosis factor alpha (TNF-alpha)-mediated NF-kappa B activation. Co-immunoprecipitation assays showed that UL2 could interact with the NF-kappa B subunits p65 and p50, which also revealed the region of amino acids 9 to 17 of UL2 could suppress the NF-kappa B activation and interact with p65 and p50, and UL2 bound to the immunoglobulin-like plexin transcription factor functional domain of p65. However, UL2 did not affect the formation of p65/p50 dimerization and their nuclear localizations. Yet, UL2 was demonstrated to inhibit the NF-kappa B activity by attenuating TNF-alpha-induced p65 phosphorylation at Ser536 and therefore decreasing the expression of downstream inflammatory chemokine interleukin 8. Taken together, the attenuation of NF-kappa B activation by UL2 may contribute to the escape of host's antiviral innate immunity for HSV-1 during its infection.