Viral mimicry of p65/RelA transactivation domain to inhibit NF-κB activation
ABSTRACTThe evolutionary arms race between hosts and their viruses drove the evolution of complex immune systems in mammals and sophisticated immune evasion mechanisms by viruses. Mammalian antiviral defences require sensing of virus infection and stimulation of the expression of interferons and cytokines via the activation of NF-κB and other immune signalling pathways. Viruses antagonise these host antiviral defences by interfering with immune sensing and signal transduction and blocking the actions of interferons and cytokines. Here we show that a viral protein mimics the transcription activation domain of p65, the transcriptionally active subunit of NF-κB. The C terminus of vaccinia virus (VACV) protein F14 (residues 51-73) activates transcription when fused to a DNA-binding domain-containing protein and associates with NF-κB co-activator CBP, disrupting its interaction with p65. Consequently, F14 diminishes CBP-mediated acetylation of p65 and the downstream recruitment of RNA polymerase II processivity factor BRD4 to the promoter of NF-κB-responsive gene CXCL10, thereby inhibiting the expression and secretion of CXCL10 upon stimulation with TNF-α. A VACV strain engineered to lack F14 caused reduced lesions in an intradermal model of infection, showing that F14 contributes to virulence. Our results uncover a mechanism by which viruses disarm the antiviral defences through molecular mimicry of a conserved protein of the host’s immune system.