Of Keeping and Tipping the Balance: Host Regulation and Viral Modulation of IRF3-Dependent IFNB1 Expression

Abstract

<jats:p>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.</jats:p>

Ribosome-Profiling Reveals Restricted Post Transcriptional Expression of Antiviral Cytokines and Transcription Factors during SARS-CoV-2 Infection

“…In addition to the abovementioned antiviral cytokines, we show that select transcription factors are restricted at the posttranscriptional level, with JUN, ZBTB20, ATF3, HIVEP2 and EGR1 showing the greatest restriction when accounting for the increase in substrate mRNA while REL and CREB5 were significantly upregulated by RNA-seq but not Ribo-seq when analysis was performed on un-normalized Ribo-seq reads. JUN regulates transcription of IFNB1 mRNA as part of the enhanceosome, encompassing ATF2, JUN, IRF3, p50, p65, CBP and p300 [ 42 ]. Post-transcriptional restriction of JUN could limit enhanceosome formation and IFN induction.…”

Shared and Unique Features of Human Interferon-Beta and Interferon-Alpha Subtypes

“…Thus, in most cells, viral PAMPs trigger activation of IRF3, which homodimerizes to complete the functional enhanceosome and initiate transcription of IFNβ. Subsequently, autocrine/paracrine IFNβ increases expression of IRF7 (a robust ISG) in infected and bystander cells—a well-documented critical step in a forward feedback loop for IFNβ to enhance its own expression ( 41 ).…”

“…The critical importance of IRF3 toward initiating IFN expression is emphasized by the number of pathogens with gene products that antagonize its activation ( 41 ) and by reports that cells from IRF3-deficient patients express little or no IFNβ ( 42 , 43 ). The critical importance of the IRF7-mediated forward feedback loop is supported by an in vitro study in which the percentage of IFNβ-expressing cells after viral infection was dependent on cell density, and secretion of IFNβ ( 44 ), and reports that IRF7 deficient patients poorly express IFNβ ( 45 , 46 ).…”

Ribosome-profiling reveals restricted post transcriptional expression of antiviral cytokines and transcription factors during SARS-CoV-2 infection

“…In addition to the abovementioned antiviral cytokines, we show that select transcription factors are restricted at the posttranscriptional level, with JUN, ZBTB20, ATF3, HIVEP2 and EGR1 showing the greatest restriction when accounting for the increase in substrate mRNA while REL and CREB5 were significantly upregulated by RNA-seq but not Ribo-seq when analysis was performed on un-normalized Ribo-seq reads. JUN regulates transcription of IFNB1 mRNA as part of the enhanceosome, encompassing ATF2, JUN, IRF3, p50, p65, CBP and p300 [41]. Post-transcriptional restriction of JUN could limit enhanceosome formation and IFN induction.…”