Transcriptional Regulation of Antiviral Interferon-Stimulated Genes

Abstract

Interferon-stimulated genes (ISGs) are a group of gene products that coordinately combat pathogen invasions, in particular viral infections. Transcription of ISGs occurs rapidly upon pathogen invasion, and this is classically provoked via activation of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway, mainly by interferons (IFNs). However, a plethora of recent studies have reported a variety of non-canonical mechanisms regulating ISG transcription. These new studies are extremely important for understanding the quantitative and temporal differences in ISG transcription under specific circumstances. Because these canonical and non-canonical regulatory mechanisms are essential for defining the nature of host defense and associated detrimental proinflammatory effects, we comprehensively review the state of this rapidly evolving field and the clinical implications of recently acquired knowledge in this respect.

Keywords: IFN; ISG; transcription.

Figure 1

The Classical Interferon (IFN) Signaling Pathways in Regulating IFN-Stimulated Gene (ISG) Transcription. The three different classes of IFNs signal through their corresponding receptor complexes, leading to phosphorylation of preassociated Janus kinases. For type I and III IFNs, the phosphorylated Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) in turn phosphorylate the receptors at specific intracellular tyrosine residues. This leads to the recruitment and phosphorylation of signal transducers and activators of transcription 1 and 2 (STAT1 and STAT2) at specific tyrosine residues. STAT1 and 2 then recruit IRF9 to form the IFN-stimulated gene factor 3 (ISGF3). For type II IFNs, the phosphorylated JAK1 and JAK2 tyrosine kinases phosphorylate the receptors on tyrosines, leading to homodimerization of STAT1. Both ISGF3 and STAT1 homodimers translocate to the nucleus for further phosphorylation at specific serine residues of STAT1, thereby achieving full activation. Consequently, ISGs are transcriptionally activated by binding of ISGF3 and STAT1 homodimers to IFN-stimulated response elements (ISREs) and γ-activated sequence (GAS) promoter elements, respectively. Conversely, specific phosphatases in the nucleus dephosphorylate STAT1 and STAT2 to avoid excessive and detrimental responses.

Figure 2

Transcriptional Regulation of IFN-Stimulated Genes (ISGs) Involves Chromatin Remodeling and Various Coactivators and Corepressors. Upon IFN stimulation, IFN-stimulated gene factor 3 (ISGF3) or STAT1 homodimers bind to ISG promoter regions, recruiting various chromatin remodeling factors and transcriptional coactivators. These factors include the nucleosome remodeling complexes BAF and PBAF, p300/CBP and GCN5 histone acetyltransferase (HAT), histone deacetylase (HDAC), minichromosome maintenance 3 and 5 (MCM3 and MCM5), N-Myc interactor (NMi), and DRIP150 (a subunit of the multimeric mediator coactivator complex). Consequently, the condensed chromatin transforms into a more relaxed structure to facilitate the transcription of ISGs. Conversely, corepressor factors can inhibit ISG transcription either via the facilitation of a closed chromatin configuration or by interfering with the recruitment of STAT1 or ISGF3 to ISG promoters. Abbreviation: Pol II, RNA polymerase II.

Figure 3

Non-canonical Mechanisms Regulating ISG Transcription. Non-canonical mechanisms both within and outside the IFN–JAK–STAT axis are summarized. Together with canonical mechanisms, they coordinately regulate ISG transcription, thus defining cellular defense status against pathogen invasion.