How Does The K1 Protein From Vaccinia Virus Inhibit NF-κB Activation?

Inflammation is an innate immune response to injury or microbial infection.  When acute inflammation occurs, leukocytes migrate to the damaged region to aid in clearing bacteria and viruses, repairing tissue, and initiating healing. Nuclear Factor kappa B (NF-κB) is a transcription factor that stimulates the inflammatory response by up-regulating the expression of pro-inflammatory cytokines such as TNF, IL-8 and IL-1β. Vaccinia virus, a member of the poxvirus family, encodes several proteins that inhibit NF-κB activation. One such protein is K1. Recently, our lab demonstrated that the K1 protein inhibits virus induced NF-κB activation by inhibiting PKR, an upstream activator of NF-κB. In this PKR-mediated pathway, the K1 protein inhibits the degradation of IκBα, the inhibitor of NF-κB. Our current data suggest that the K1 protein possesses a second NF-kB inhibitory mechanism. First, we ectopically-expressed K1 in PKR^-/- cells and observed that the K1 protein still inhibited PMA and TNF induced NF-κB activation via dual reporter luciferase assay. Second, preliminary data suggests that the K1 protein does not inhibit IκBα degradation in this second mechanism. Third, we observed that the K1 protein co-associates with the p65 subunit of NF-κB by performing co-immunoprecipitations. We hypothesize that the K1 protein binds to the p65 subunit of NF-κB to either block NF-κB nuclear translocation, NF-κB-DNA binding or post-translational modifications required for full transcriptional activity. The K1 protein provides an example of how a single viral protein has evolved multiple mechanisms to evade host immune responses triggered early during infection.