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  • Review Article
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IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors

Nature Reviews Immunology volume 6, pages 644–658 (2006)Cite this article

Key Points

  • In innate immune responses, molecular patterns that are associated with invading pathogens are recognized by two classes of pattern-recognition receptor (PRR): transmembrane PRRs, namely Toll-like receptors (TLRs); and cytosolic PRRs, including retinoic-acid-inducible gene I (RIG-I) and melanoma-differentiation-associated gene 5 (MDA5). Signalling through these PRRs results in the activation of transcription factors that regulate genes encoding chemokines and other cytokines.

  • The interferon (IFN)-regulatory factor (IRF) family of transcription factors is crucial for the regulation of various aspects of immune responses, most notably those mediated by PRRs. The family comprises nine members, each of which contains a well-conserved DNA-binding domain that recognizes IFN-stimulated response elements (ISREs) in the promoters of target genes.

  • The activation of cytosolic PRRs typically elicits expression of type I IFN genes (the genes that encode IFNα and IFNβ). IRF7 functions as the master regulator of induction of these genes, and IRF3 contributes to this induction. Both IRF3 and IRF7 are activated by TBK1 (TANK (tumour-necrosis-factor-receptor-associated factor (TRAF)-family-member-associated nuclear factor (NF-κB) activator)-binding kinase 1), which phosphorylates these IRFs to convert them into an active form.

  • Signalling through TLRs is mainly mediated by two distinct adaptor molecules: MyD88 (myeloid differentiation primary-response protein 88) and TRIF (Toll/interleukin-1 receptor (TIR)-domain-containing adaptor protein inducing IFNβ). In the MyD88-dependent pathway, IRF4, IRF5 and IRF7 directly interact with MyD88 and regulate gene-expression programmes in this way. IRF7 is essential for the robust type I IFN gene induction that is elicited by ligation of TLR7 or TLR9, whereas IRF5 is required for the induction of pro-inflammatory cytokine genes. By contrast, IRF3 has an essential role in the TRIF-dependent pathway of type I IFN gene induction by TLR4.

  • IRFs interact with other transcription factors, such as NF-κB, and these interactions determine the specificity and magnitude of transcriptional events that are induced by PRR activation.

  • The aberrant activation of IRFs by PRRs has been implicated in the development of autoimmune diseases such as systemic lupus erythematosus.

Abstract

The interferon-regulatory factor (IRF) family of transcription factors was initially found to be involved in the induction of genes that encode type I interferons. IRFs have now been shown to have functionally diverse roles in the regulation of the immune system. Recently, the crucial involvement of IRFs in innate and adaptive immune responses has been gaining much attention, particularly with the discovery of their role in immunoregulation by Toll-like receptors and other pattern-recognition receptors.

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Figure 1: Activation of interferon-regulatory factors by cytosolic pattern-recognition receptors.
Figure 2: Interferon-regulatory factors in positive-feedback regulation of type I interferon genes.
Figure 3: Toll-like-receptor-mediated pathways for activation of interferon-regulatory factors.
Figure 4: Interactions between interferon-regulatory factor 3 and nuclear factor-κB.

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Acknowledgements

We thank E. Barsoumian, A. Takaoka, Y. Ohba and H. Yanai for valuable discussion and advice. This work was supported by Kakenhi (Grants-in-Aid for Scientific Research) on the Priority Area 'Integrative Research Toward the Conquest of Cancer', from the Ministry of Education, Culture, Sports, Science and Technology (Japan).

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  1. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan

    Kenya Honda & Tadatsugu Taniguchi

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  1. Kenya Honda
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Glossary

Helix–turn–helix motif

A structural motif that can bind DNA. It comprises two α-helices joined by a short strand of amino acids, and it is found in many proteins that regulate gene expression.

IFN-stimulated response element

(ISRE). A common DNA motif that is found in the promoters of genes that are regulated by type I interferons (IFNs). It is bound by IFN-regulatory factors (IRFs) and was initially known as the IRF enhancer (IRFE). The consensus sequence is GAAANNGAAAG/CT/C, where N denotes any nucleotide.

Type I IFNs

A family of cytokines that includes interferon (IFNα; which is encoded by 13 functional genes in humans and 14 in mice) and IFNβ.

Pathogen-associated molecular patterns

(PAMPs). Molecular patterns that are found in pathogens but not in mammalian cells. Examples include terminally mannosylated and polymannosylated compounds (which bind the mannose receptor) and various microbial components, such as bacterial lipopolysaccharide, hypomethylated DNA, flagellin and double-stranded RNA (all of which bind Toll-like receptors).

Nucleotide-binding oligomerization-domain proteins

(NOD proteins). Members of a family that includes the apoptosis regulator APAF1 (apoptotic-protease-activating factor 1), mammalian NOD-LRR proteins (also known as NACHT-LRR proteins or CATERPILLERs) and plant disease-resistance gene products. Several NOD proteins have been implicated in the induction of nuclear factor-κB activity and in the activation of caspases.

Virus-responsive elements

(VREs). The promoter of the gene that encodes interferon-β (IFNβ) contains at least four regulatory cis elements — positive-regulatory domain I (PRDI), PRDII, PRDIII and PRDIV — which are involved in virus-mediated gene induction. IFN-regulatory factors (IRFs) bind PRDI and PRDIII (which are IFN-stimulated response elements, ISREs), whereas nuclear factor-κB and activator protein 1 (AP1) bind PRDII and PRDIV, respectively. By contrast, the promoters of the genes that encode IFNα contain only IRF-binding elements, and these are known as PRDI-like and PRDIII-like elements (PRD-LEs).

Mouse embryonic fibroblasts

(MEFs). A well-defined cell type that has been widely used to identify the consequences of ablation or ectopic expression of a gene of interest. In addition, MEFs are known to allow infection with various viruses and to express type I IFN genes effectively. They therefore provide a simple model for the study of innate immunity to viral infections.

Latent form

A protein that is inactive in the absence of additional modification(s), such as phosphorylation or ubiquitylation.

Holocomplex

A complex that consists of subunits, each of which cannot carry out a reaction by itself but can carry out the reaction as a complex.

Histone acetyltransferase

A protein that acetylates core histones, resulting in important regulatory effects on chromatin structure and assembly, and on gene transcription.

Immunophilin family

A family of cis–trans peptidylprolyl isomerases that includes cyclophilins and FK506-binding proteins (FKBPs). These proteins were originally discovered as cellular receptors for immunosuppressive drugs, including cyclosporin A and FK506. The complexes that form between immunophilins and their cognate ligands are the functional modules for immunosuppression. Immunophilins are now known to function at the crossroads of protein folding and trafficking, and signal transduction.

RNA-helicase domain

A protein domain that is found in many RNA-binding proteins that are required for mRNA synthesis, pre-mRNA splicing, ribosome biogenesis and RNA decay. This domain can unwind double-stranded RNA using energy derived from the hydrolysis of ATP.

Caspase-recruitment domain

(CARD). A protein domain that is found in certain initiator caspases (for example, mammalian caspase-9) and their adaptor proteins (for example, apoptotic-protease-activating factor 1, APAF1). This domain mediates protein–protein interaction.

B form of DNA

(B-DNA). DNA with a right-handed double helix. This is the conformation that is normally seen in solution and is thought to be the conformation of most DNA in vivo. It also formed the basis of the model described by James Watson and Francis Crick.

Z form of DNA

(Z-DNA). DNA with a left-handed double helix. This conformation occurs as a consequence of methylation. It is found mainly in genes that are undergoing transcription. It is present only transiently, because the cessation of transcription results in rapid conversion of Z-DNA to the B form of DNA (the normal conformation), through the activity of topoisomerases.

Plasmacytoid DCs

(pDCs). A subset of dendritic cells (DCs) that was named 'plasmacytoid' because their appearance under the microscope is similar to that of plasmablasts. In humans, these DCs can be derived from lineage (Lin)- haematopoietic stem cells from the peripheral blood. These DCs are the main producers of type I interferons in response to viral infections.

CpG-A

Also known as D-type CpG. Synthetic oligodeoxynucleotides with the following three features: poly(G) sequences at the 3′ end; a central palindromic sequence; and CG dinucleotides within the palindrome. The poly(G) tails on CpG-A can interact with each other, resulting in the formation of G tetrads and clusters. The structure of CpG-A is interpreted by plasmacytoid DCs as a molecular pattern that indicates infection with a DNA virus, and this recognition elicits robust production of type I interferons. However, identical sequences have not been found in the genomes of DNA viruses.

Death domain

A protein domain that is found in many proteins that are involved in signalling and apoptosis. This domain mediates protein–protein interaction.

Endotoxic shock

A clinical condition that is induced by hyperreactivity of the innate immune system to bacterial lipopolysaccharide (LPS). It is mediated by the inflammatory cytokines interleukin-1 and tumour-necrosis factor, both of which are produced in high amounts following sustained activation of Toll-like receptor 4 by LPS.

CpG-B

Also known as K-type CpG. Synthetic oligodeoxynucleotides that contain a CpG motif(s) on a phosphorothioate backbone. Analogous to bacterial infection, CpG-B triggers the differentiation of both plasmacytoid and conventional DCs, as well as the proliferation and activation of B cells. However, identical sequences have not been found in the genomes of bacteria.

ETS/ISRE composite DNA motif

(ETS/interferon-stimulated-response-element composite DNA motif). A motif found in numerous genes that are essential for the proper function of macrophages and B cells. Interferon-regulatory factor 4 (IRF4) or IRF8 binds this motif following interaction with the transcription factor PU.1. The consensus sequence is GGAAGTGAAA, with the PU.1-binding core motif (at the 5′ end) and the IRF-binding core motif (at the 3′ end) underlined.

REL-homology domain

(RHD). A conserved domain of ∼300 amino acids that is found in the amino-terminal region of nuclear factor-κB (NF-κB)-family members. It contains motifs that are responsible for dimerization, nuclear translocation and binding to NF-κB-binding motifs that are present in DNA.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies specific for DNA, RNA or proteins associated with nucleic acids form immune complexes. These complexes damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B- and T-cell function.

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Honda, K., Taniguchi, T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol 6, 644–658 (2006). https://doi.org/10.1038/nri1900

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