Abstract
The type I interferon (IFN) response is a principal component of our immune system that allows to counter a viral attack immediately upon viral entry into host cells. Upon engagement of aberrantly localised nucleic acids, germline-encoded pattern recognition receptors convey their find via a signalling cascade to prompt kinase-mediated activation of a specific set of five transcription factors. Within the nucleus, the coordinated interaction of these dimeric transcription factors with coactivators and the basal RNA transcription machinery is required to access the gene encoding the type I IFN IFNβ (IFNB1). Virus-induced release of IFNβ then induces the antiviral state of the system and mediates further mechanisms for defence. Due to its key role during the induction of the initial IFN response, the activity of the transcription factor interferon regulatory factor 3 (IRF3) is tightly regulated by the host and fiercely targeted by viral proteins at all conceivable levels. In this review, we will revisit the steps enabling the trans-activating potential of IRF3 after its activation and the subsequent assembly of the multi-protein complex at the IFNβ enhancer that controls gene expression. Further, we will inspect the regulatory mechanisms of these steps imposed by the host cell and present the manifold strategies viruses have evolved to intervene with IFNβ transcription downstream of IRF3 activation in order to secure establishment of a productive infection.
Highlights
The crucial role of interferon regulatory factor 3 (IRF3) and the posttranslational changes it undergoes upon viral infection first reported more than 20 years ago: Upon stimulation, IRF3 gets phosphorylated and accumulates in were first reported more than 20 years ago: Upon stimulation, IRF3 gets phosphorylated and the nucleus where it interacts with the coactivators CREB-binding protein (CBP)/p300 to bind accumulates in the nucleus where it interacts with the coactivators CREB-binding protein to virus-inducible enhancer elements and exerts transcriptional activation of the IFNB1 gene [21,36,37,38]
Due to these discrepancies we suggest to differentiate between phosphorylated IRF3 that is relieved of the auto-inhibition and can “actively” participate in subsequent steps and IRF3 in the holocomplex that can exercise its trans-activation potential as a transcription factor to “actively” induce IFNB1 expression
This aligns with the kinetics of the IFNβ response we will briefly revisit below, wherein only a part of the IFNB1 alleles are engaged in the early response
Summary
The interferon (IFN) system provides mammalian cells with a potent framework to fend off intruding pathogens. More than a dozen genes encoding IFNα subtypes and a single IFNB1 gene give rise to the majority of type I IFNs in humans They are the first messenger molecules released upon detection of a pathogen by infected cells and by bystanders to initiate the intrinsic defence mechanisms and to further involve dedicated cells of the immune system (recently reviewed in [2,3]). Essential to the induction of type I IFN transcription is the activation of two specific members of the interferon regulatory factor (IRF) family, a class of nine transcription factors (reviewed in [8]). In parallel to IRF3/7, nucleic acid-mediated stimulation of the different signalling modules activates nuclear factor “kappa-light-chain-enhancer” of activated B-cells (NF-κB) by inducing dissociation from its inhibitory complex (reviewed in [15]) and activator protein 1 (AP-1) by mitogen-activated protein kinases (MAPKs) [16].
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