Degradation of nuclear factor kappa B during foot-and-mouth disease virus infection

We have previously shown that the leader proteinase (L^pro) of foot-and-mouth disease virus (FMDV) interferes with the innate immune response by blocking the translation of interferon (IFN) protein and by reducing the immediate-early induction of beta IFN mRNA and IFN-stimulated genes. Here, we report that L^pro regulates the activity of nuclear factor κB (NF-κB). Analysis of NF-κB-dependent reporter gene expression in BHK-21 cells demonstrated that infection with wild-type (WT) virus has an inhibitory effect compared to infection with a genetically engineered mutant lacking the leader coding region. The expression of endogenous NF-κB-dependent genes tumor necrosis factor alpha and RANTES is also reduced in WT virus-infected primary porcine cells. This inhibitory effect is neither the result of a decrease in the level of the mRNA of p65/RelA, a subunit of NF-κB, nor a block on the nuclear translocation of p65/RelA, but instead appears to be a consequence of the degradation of accumulated p65/RelA. Viral L^pro is localized to the nucleus of infected cells, and there is a correlation between the translocation of L^pro and the decrease in the amount of nuclear p65/RelA. By using a recombinant cardiovirus expressing L^pro, we demonstrate that the disappearance of p65/RelA takes place in the absence of any other FMDV product. The observation that L^pro disrupts the integrity of NF-κB suggests a global mechanism by which FMDV antagonizes the cellular innate immune and inflammatory responses to viral infection.