Downloaded from http://cshperspectives.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press The Interferon (IFN) Class of Cytokines and the IFN Regulatory Factor (IRF) Transcription Factor Family Hideo Negishi,1 Tadatsugu Taniguchi,1,2 and Hideyuki Yanai1,2 1Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8505, Japan 2Max Planck-The University of Tokyo Center for Integrative Inflammology, Komaba 4-6-1, Meguro-ku, Tokyo 153-8505, Japan Correspondence: [email protected] 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 follow- ing 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. ll three classes of interferons (IFNs) are so quenced, and formally recognized to comprise a Anamed because of the shared property to related gene family (Knight 1975; Taniguchi interfere with viral replication in the host et al. 1979; Maeda et al. 1980; Rubinstein et al. (Weissmann and Weber 1986; Taniguchi 1988; 1981; Weissmann and Weber 1986; Taniguchi Stark et al. 1998; Levy and Garcia-Sastre 2001; 1988; Stark et al. 1998; Levy and Garcia-Sastre Samuel 2001; Katze et al. 2002; Pestka et al. 2004; 2001; Samuel 2001; Katze et al. 2002; Pestka et al. Platanias 2005; Vilcek 2006). It is perhaps not an 2004; Platanias 2005; Vilcek 2006). Type I IFNs exaggeration to say that the discovery of IFNs are principally expressed by innate immune cells provided the biggest impetus for the study of all (Hervas-Stubbs et al. 2011). Type II IFN, repre- cytokine research. Type I IFNs were initially dis- sented by a single gene product, IFN-γ, was rec- covered as soluble factors that mediated viral ognized for its antiviral activity induced by ac- interference. This is defined as the resistance tivated immune cells, typically by natural killer to virus infection induced by a prior viral infec- (NK) and T cells (Wheelock 1965; Gray et al. tion (Isaacs and Lindenmann 1957; Nagano and 1982). Type III IFNs (also called IFN-λ and ini- Kojima 1958). It was not until after two decades tially also called interleukin [IL]-28 and IL-29) of study that type I IFN genes were cloned, se- are restricted in their tissue distribution (e.g., are Editors: Warren J. Leonard and Robert D. Schreiber Additional Perspectives on Cytokines available at www.cshperspectives.org Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a028423 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a028423 1 Downloaded from http://cshperspectives.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press H. Negishi et al. not highly expressed in hematopoietic cells), ISGF3 (IFN-stimulated gene [ISG] factor 3) and act predominantly at epithelial surfaces that consists of STAT1, STAT2, and IRF9 (Tani- (Sheppard et al. 2003; Iversen and Paludan guchi and Takaoka 2001; Pestka et al. 2004; 2010). Decker et al. 2005; Ivashkiv and Donlin 2014). In this review, we first describe briefly the ISGF3 is a transcriptional activator that on cardinal features of the three types of IFNs in translocation to the nucleus binds IFN-stimulat- the context of the signal transduction pathways ed response elements (ISREs) in gene promoters they trigger and biological activities elicited and of IFN-inducible genes (ISGs) to initiate gene then focus on the regulation of these IFN re- transcription. On the other hand, IRF2, local- sponses by the IFN regulatory factor (IRF) tran- ized in the nucleus, functions as a transcriptional scription factor family. Of particular note, the attenuator of ISGF3-mediated transcriptional discovery of so-called innate immune receptors activation; hence, absence of IRF2 results in ex- beginning with Toll-like receptor 4 (Medzhitov cessive type I IFN signaling (Hida et al. 2000). et al. 1997) has provided the stimulus and con- IFNAR activation also results in the activation of text for understanding the regulatory mecha- STAT1 homodimers that bind and activate γ- nisms of IFNs by the IRF family transcription activated sequence (GAS) (IFN-γ activated se- factors. Because of space limitations, we are un- quence) motifs, leading to the induction of gene able to touch on various biological activities transcription (Decker et al. 2005). Although less manifested by IFNs but instead point the reader well characterized, type I IFN signaling may also to the many excellent reviews on the topic induce signaling of mitogen-activated protein (Pestka et al. 2004; Vilcek 2006; Tamura et al. kinase (MAPK)/c-Jun amino-terminal kinase 2008; Trinchieri 2010). (JNK) pathways (Platanias 2005). Type II IFN or IFN-γ is structurally unre- lated to the other two classes of IFN genes and THREE TYPES OF IFNs: A BRIEF OVERVIEW is best known as a critical cytokine secreted dur- The molecular characterization of IFNs began ing activated NK- and T-cell responses (Whee- when type I IFN genes were recognized to com- lock 1965; Grayet al. 1982). Further, IFN-γ binds prise a gene family (Taniguchi et al. 1980; Pestka a different cell-surface receptor consisting of et al. 2004; Vilcek 2006). The two best-charac- IFNGR1 and IFNGR2 subunits, which in turn terized and most broadly expressed genes of this associate with JAK1 and JAK2, respectively (Fig. subtype are IFN-α, encoded by more than a doz- 1). The activation of these kinases results in en genes, and IFN-β (single gene family) (Deck- STAT1 homodimerization and nuclear translo- er et al. 2005). Other type I IFN subtypes are cation that targets GAS DNA sequences. It is known, namely, IFN-ω, and IFN-τ, but remain worth noting that ISGF3 is also activated by the poorly characterized because of limited tissue IFN-γ signaling, albeit weakly (Takaoka et al. expression, overlapping function with IFN-α 2000). It was also shown that effective IFN-γ and IFN-β, and species-to-species differences signaling is contingent on a weak type I IFN (Pestka et al. 2004; Capobianchi et al. 2015). signaling caused by a low constitutive produc- All type I IFN classes bind to a heterodimeric tion of type I IFNs (Takaoka et al. 2000). receptor composed of two chains, IFNAR1 and Type III IFN or IFN-λs are the least charac- IFNAR2, which signal through recruitment of terized IFN family. Structurally related to type I Janus-activated kinases (JAKs) TYK2 and IFNs and to the IL-10 family (Pestka et al. 2004; JAK1, respectively (Fig. 1) (Taniguchi and Ta- Uze and Monneron 2007; Lazear et al. 2015), kaoka 2001; Pestka et al. 2004; Decker et al. 2005; this family includes IFN-λ1 (IL-28A), IFN-λ2 Ivashkiv and Donlin 2014). Activation of these (IL-28B), and IFN-λ3 (IL-29). IFN-λs bind to JAKs causes tyrosine phosphorylation of signal a heterodimeric cytokine receptor composed transducers and activators of transcription of an IL-28R-binding chain and IL-10R2 that (STAT)1 and STAT2, which in turn leads to is shared with the IL-10 family of cytokines the formation of a trimeric complex, called (Fig. 1) (Uze and Monneron 2007). Similar to 2 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a028423 Downloaded from http://cshperspectives.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press IFNs and the IRF Family Type I IFN Type II IFN Type III IFN IFNGR1 IFNGR2 IFNAR1 IFNAR2 IL10R2 IFNLR1 Cytoplasm JAK1 JAK1 JAK1 TYK2 TYK2 JAK1 JAK2 JAK2 STAT1 STAT1 STAT1 MAPK/JNK P P P P P P pathway P IRF9 P IRF9 STAT2 STAT2 ISGF3 STAT1GAF ISGF3 Nucleus ISRE GAS ISRE IRF2 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-indepe- nent 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 heterotri- meric 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-acti- vated protein kinase (MAPK)/c-Jun amino-terminal kinase (JNK) pathways. Type II IFN binds as a homo- dimer 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.