Defining Emerging Roles for NF-κB in Antivirus Responses: Revisiting the Interferon-β Enhanceosome Paradigm

Classic studies over the last two decades have made virus-induced activation of the mammalian interferon-b (ifnb) gene a prototype of eukaryotic gene regulation [1–6]. Indeed, the compact ,50 base-pair enhancer region upstream of the ifnb transcription start site is amongst the beststudied stretches of mammalian DNA, and its function in regulation of ifnb expression is considered a paradigm of stimulusactivated mammalian gene regulation. In a widely accepted model, RNA virus infection of most cell types triggers the activation of three classes of transcription factor—interferon regulatory factors (IRFs)-3/7, NF-kB, and ATF-2/c-Jun— downstream of the RIG-I-like receptor (RLR) family of viral RNA sensors [7–9]. These transcription factors bind welldefined adjacent sites in the ifnb enhancer to nucleate formation of an ‘‘enhanceosome’’. The nascent enhanceosome then recruits chromatin-modifying enzymes and general transcription factors to initiate transcription of ifnb and launch the type I IFN antiviral innate immune response [1,2,10]. Implicit in the inherently cooperative nature of enhanceosome formation is the supposition that IRFs-3/7, NF-kB, and ATF-2/c-Jun are all perhaps equally necessary for virus-driven ifnb expression. Recent findings from our laboratories and other groups, however, suggest an alternate view of NF-kB function in antivirus responses: that NF-kB is indeed required for ifnb expression, but only before (and very early after) infection. As the infection unfolds, NF-kB is no longer necessary for ifnb induction, and instead takes on a more general role in the expression of nonIFN innate immune and pro-inflammatory genes; meanwhile, IRFs-3/7 inherit ifnb expression to propel the type I IFN antiviral system. In this article, we update the enhanceosome paradigm by proposing temporally distinct functions for NF-kB in the RLR-triggered innate immune response. Unexpected Results from NF-kB Gene-Targeted Mice