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-β (ifnβ) gene a prototype of eukaryotic gene regulation [1]–[6]. Indeed, the compact ∼50 base-pair enhancer region upstream of the ifnβ transcription start site is amongst the best-studied stretches of mammalian DNA, and its function in regulation of ifnβ expression is considered a paradigm of stimulus-activated 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-κB, and ATF-2/c-Jun—downstream of the RIG-I-like receptor (RLR) family of viral RNA sensors [7]–[9]. These transcription factors bind well-defined adjacent sites in the ifnβ enhancer to nucleate formation of an “enhanceosome”. The nascent enhanceosome then recruits chromatin-modifying enzymes and general transcription factors to initiate transcription of ifnβ 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-κB, and ATF-2/c-Jun are all perhaps equally necessary for virus-driven ifnβ expression. Recent findings from our laboratories and other groups, however, suggest an alternate view of NF-κB function in antivirus responses: that NF-κB is indeed required for ifnβ expression, but only before (and very early after) infection. As the infection unfolds, NF-κB is no longer necessary for ifnβ induction, and instead takes on a more general role in the expression of non-IFN innate immune and pro-inflammatory genes; meanwhile, IRFs-3/7 inherit ifnβ expression to propel the type I IFN antiviral system. In this article, we update the enhanceosome paradigm by proposing temporally distinct functions for NF-κB in the RLR-triggered innate immune response.