The Interferon (IFN) Class of Cytokines and the IFN Regulatory Factor (IRF) Transcription Factor Family

Abstract

Interferons (IFNs) are a broad class of cytokines elicited on challenge to the host defense and are essential for mobilizing immune responses to pathogens. Divided into three classes, type I, type II, and type III, all IFNs share in common the ability to evoke antiviral activities initiated by the interaction with their cognate receptors. The nine-member IFN regulatory factor (IRF) family, first discovered in the context of transcriptional regulation of type I IFN genes following viral infection, are pivotal for the regulation of the IFN responses. In this review, we briefly describe cardinal features of the three types of IFNs and then focus on the role of the IRF family members in the regulation of each IFN system.

Figure 1.

Signal transduction by type I, type II, and type III interferon (IFN) receptors. A schematic view of the signal transduction pathways for the three types of IFN is shown. Type I IFN binds IFNAR2, leading to the subsequent recruitment of IFNAR1. IFN-β also forms a stable complex with IFNAR1 in an IFNAR2-indepenent manner, whereas IFN-α does not (de Weerd et al. 2013). The binding of type I IFN induces formation of a receptor complex between IFNAR-1 and IFNAR-2, leading to activation of the receptor-associated TYK2 and JAK1 kinases. This is followed by the tyrosine phosphorylation of signal transducers and activators of transcription (STAT)1 and STAT2 and, on recruitment of IFN regulatory factor (IRF)9, forms the heterotrimeric IFN-stimulated gene factor 3 (ISGF3) transcription factor complex. In addition, a STAT1 homodimer, termed IFN-γ-activated factor (GAF), is also formed. These transcriptional–activator complexes translocate into the nucleus and activate the IFN-stimulated regulatory elements (ISREs) or γ-activated sequences (GASs) promoter elements, for ISGF3, or GAF, respectively. IRF2 functions as a transcriptional attenuator of the ISGF3-mediated transcriptional activation. Type I IFN signaling may also induce signaling of mitogen-activated protein kinase (MAPK)/c-Jun amino-terminal kinase (JNK) pathways. Type II IFN binds as a homodimer and induces dimerization of IFNGR1 subunits and recruitment of IFNGR2 subunits. This association causes the phosphorylation of JAK1 and JAK2 kinases, leading to phosphorylation of STAT1. Phosphorylated STAT1 forms the GAF complex. IFN-γ signaling also activates ISGF3, albeit weakly. Type III IFN receptor signaling cascade causes activation of JAK1 and TYK2, which causes the recruitment of STAT1 and STAT2 to form the ISGF3 transcription factor complex that binds to ISRE elements in gene promoters to induce transcription of IFN-inducible genes (ISGs).

Figure 2.

Schematic view of Toll-like receptor (TLR)-mediated type I interferon (IFN) gene induction by IFN regulatory factors (IRFs). The presence of RNA or double-stranded (ds)DNA in the cytosol triggers host responses via specific cytoplasmic pattern recognition receptors (PRRs). The binding of uncapped 5′-triphosphate RNA or dsRNA to the helicase domain of retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5) induces the interaction between the caspase activation and recruitment domain (CARD) of RIG-I/MDA5 and the CARD-like domain of the adaptor mitochondrial antiviral signaling protein (MAVS), which is located on the mitochondrial membrane. This receptor–adaptor interaction results in the activation of tumor necrosis factor (TNF) receptor-associated factor (TRAF)-associated nuclear factor [NF]-κB activator (TANK)-binding kinase 1 (TBK1) and inhibitor of NF-κB kinase (IKK)ε. Activated TBK1 induces the phosphorylation of the specific serine residues of IRF3 and IRF7. These IRFs then translocate into the nucleus and activate the type I IFN genes. NF-κB is also activated and involved in type I IFN gene induction. In some cases, IRF5 or IRF8 participate in this IFN gene-induction pathway. dsDNA such as B-DNA is recognized by cGAS, IFI16, DDX41, and DAI. The stimulator of IFN genes (STING) adaptor protein on the endoplasmic reticulum membrane signals downstream of these DNA receptors. STING provides a scaffold for recruitment of TBK1, which phosphorylates IRF3 leading to the activation of type I IFN gene expression.

Figure 3.

Schematic illustration of type I interferon (IFN) gene induction by IFN regulatory factors (IRFs) on innate recognition of cytosolic nucleic acids. Type I IFN genes, particularly IFN-β, are induced via TIR domain-containing adaptor, including IFN-β (TRIF) downstream of TLR3 and TLR4 signaling pathways, and via myeloid differentiation primary-response protein 88 (MyD88) downstream of TLR7 and TLR9 signaling pathways. Further, the TRIF pathway signals exclusively to IRF3 to induce IFN-β gene expression. IRF7 may also be involved for TLR3-, but not for retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)4-mediated type I IFN gene induction. In the MyD88 pathway, IRF1, IRF5, and IRF7 form a complex with MyD88. Among MyD88-bound IRFs, IRF7 is critical for the robust induction of type I IFN in plasmacytoid dendritic cells (pDCs). IRF5 is partially involved in type I IFN gene induction in pDCs, whereas IRF1 is important for expression of type I IFNs in conventional DCs (cDCs). In contrast, IRF8 is involved in the expression of type I IFN genes in pDCs, but does not bind to MyD88. IRF3 also does not bind to MyD88, but is involved in Listeria monocytogenes–mediated type I IFN gene induction in pDCs.