STATs and IRFs in Innate Immunity: From Transcriptional Regulators to Therapeutic Targets

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Background

Signal Transducer and Activator of Transcription (STAT) and Interferon Regulatory Factor (IRF) are important transcriptional regulators that modulate crucial aspects of innate and adaptive immunity. Among their activating signals are cytokines and growth factors, including interferons (IFNs), interleukins (ILs) and growth factors such as EGF and PDGF. Also many oncogenic signals and pathogenic responses, dependent on pattern-recognition receptors (PRRs), act as STAT and IRF activators.

STATs facilitate the action of cytokines, growth factors and pathogens, mainly through membrane receptor-associated Janus kinases (JAKs). The STAT family is composed of seven members: STAT1-4, STAT5A, STAT5B and STAT6 and structurally, they share five domains: (i) an amino-terminal domain; (ii) a coiled-coil domain; (iii) a DNA-binding domain; (iv) an SH2 domain and a (v) carboxy-terminal transactivation domain. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine (pTyr) motifs for specific STAT-receptor contacts and STAT dimerization. The active dimers induce gene transcription in the nucleus by binding to a specific DNA-response element (TTCN2-4GAA) within target genes.

IRFs are primarily related to the innate response of the immune system that is dependent on pattern-recognition receptors (PRRs), including Toll-Like Receptors. IRFs are a family of nine homologous proteins (IRF1-9), which contain a conserved DNA binding domain and a IRF association domain (IAD). The DNA binding domain is located at the amino termini of IRFs and consists of a five-tryptophan repeat that recognizes a DNA motif-IFN regulatory element (IRE), or its tandem-repeat form, named the IFN-stimulated response element (ISRE), present in the regulatory regions of IFNs and IFN-inducible genes (ISGs). The C-terminal half contains an IAD, which supports interactions with either (i) IRF family members; (ii) other transcription factors or (iii) self-association, and is crucial during DNA binding. These interactions enable the activity of IRFs to be modulated and allow IRFs bind to a variety of target genes.

Genome-wide transcription profiling and chromatin association studies have identified many STAT and IRF targets, including protein-coding and non-coding genes which encode microRNAs and long non-coding RNAs. In addition, complex transcriptional regulatory mechanisms have been identified that predict co-binding strategies of STATs and IRFs that are the basis of important immuno-regulatory and oncogenic responses. Finally, abnormalities in the activation of STAT- and IRF-dependent pathways as well as genetic mutations appear in many diseases including: viral infections, autoimmune diseases, cardiovascular diseases, asthma, allergies and cancer, consequently rendering these proteins as highly interesting therapeutic targets.

This Research Topic aims to provide a comparative overview of STATs and IRFs in innate immunity, with an emphasis on (i) their function as transcriptional regulators during immuno-regulatory and oncogenic responses; (ii) their pathogenic role in different diseases and (iii) their potential as therapeutic targets. We welcome the submission of articles that cover, but are not limited to, the following sub-topics:

1. The role of STATs and IRFs in cytokine and growth factor signaling.
2. Regulation of IRFs downstream of PRR signaling.
3. The role of STATs and IRFs as genome-wide transcriptional regulators.
4. The role of STATs and IRFs in regulating innate immune responses.
5. The role of STATs and IRFs in diseases.
6. STAT and IRF mutations in human inborn errors of immunity.
7. Viral evasion and STAT/IRF inhibition.
8. Therapeutic strategies targeting STATs and IRFs.

Keywords: STAT, IRF, TLR, PRR, IAD, ISRE

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