IRF and STAT Transcription Factors - From Basic Biology to Roles in Infection, Protective Immunity, and Primary Immunodeficiencies

Abstract

The induction and action of type I interferon (IFN) is of fundamental importance in human immune defenses toward microbial pathogens, particularly viruses. Basic discoveries within the molecular and cellular signaling pathways regulating type I IFN induction and downstream actions have shown the essential role of the IFN regulatory factor (IRF) and the signal transducer and activator of transcription (STAT) families, respectively. However, the exact biological and immunological functions of these factors have been most clearly revealed through the study of inborn errors of immunity and the resultant infectious phenotypes in humans. The spectrum of human inborn errors of immunity caused by mutations in IRFs and STATs has proven very diverse. These diseases encompass herpes simplex encephalitis (HSE) and severe influenza in IRF3- and IRF7/IRF9 deficiency, respectively. They also include Mendelian susceptibility to mycobacterial infection (MSMD) in STAT1 deficiency, through disseminated measles infection associated with STAT2 deficiency, and finally staphylococcal abscesses and chronic mucocutaneous candidiasis (CMC) classically described with Hyper-IgE syndrome (HIES) in the case of STAT3 deficiency. More recently, increasing focus has been on aspects of autoimmunity and autoinflammation playing an important part in many primary immunodeficiency diseases (PID)s, as exemplified by STAT1 gain-of-function causing CMC and autoimmune thyroiditis, as well as a recently described autoinflammatory syndrome with hypogammaglobulinemia and lymphoproliferation as a result of STAT3 gain-of-function. Here I review the infectious, inflammatory, and autoimmune disorders arising from mutations in IRF and STAT transcription factors in humans, highlightning the underlying molecular mechanisms and immunopathogenesis as well as the clinical/therapeutic perspectives of these new insights.

Keywords: IRF; STAT; antiviral; genetics; interferon; primary immunodeficiency; proinflammatory.

Figure 1

Induction of type I interferon (IFN) and signaling by the type I IFN receptor. The presence of microbial or self-nucleic acid in the cytosol or within the endosomal compartment activates pattern recognition receptors (PRR)s. RNA activates retinoic acid-inducible receptor (RIG)-I in the cytosol and Toll-like receptor (TLR)3 and TLR7 in the endosomal compartment, whereas DNA is sensed by cyclic GMP-AMP synthase (cGAS) in the cytosol and by TLR9 within endosomes. These events trigger signaling pathways through the adaptor molecules stimulator of IFN genes (STING), mitochondrial antiviral signaling protein (MAVS), TIR-domain-containing adapter-inducing interferon-β (TRIF), and Myeloid differentiation primary response (MyD)88 leading to phosphorylation and activation of the TANK binding kinase (TBK)1, which in turn phosphorylates the transcription factors IFN regulatory factor (IRF)3 and IRF7. Whereas IRF3 is constitutively present, IRF7 is expressed at low levels but may be secondarily induced by type I IFN. Phosphorylation of IRF3 and IRF7 leads to homodimerization, nuclear translocation, and expression of type I IFNs (IFNα and IFNβ) acting on neighboring cells with type I IFN receptors. Type I IFN binds to IFNα/β receptor (IFNAR)2 leading to recruitment of IFNAR1 and formation of a complex that activates the receptor-associated Janus-associated kinase (JAK)1 and tyrosine kinase (TYK)2 and subsequent tyrosine phosphorylation of STAT1 and STAT2. These activated transcription factors together with IRF9 form the heterotrimeric transcription factor IFN-stimulated gene factor (ISGF)3 complex which binds to IFN-stimulated regulatory elements (ISRE) in DNA. In addition, STAT1 homodimers form the IFN-γ-activated factor (GAF) complex which binds to IFNg-activated sequences (GAS). Altogether, these transcription factors induce a broad spectrum of IFN-stimulated genes (ISG)s that mediate the complex “antiviral state” of IFNs.

Figure 2

A wide range of cytokines, including interleukin (IL)6, IL10, IL21, IL22, IL23, IFNγ, and growth factors activate receptors utilizing different combinations of the tyrosine kinases janus activated kinase (JAK)1, JAK2, and tyrosine kinase (TYK)2 which trigger signaling pathways involving signal transducer and activator of transcription (STAT)1, STAT3, STAT4, and STAT5A/B. Phosphorylated STAT3 can homo- or heterodimerize with other STAT3 molecules or STAT1 or STAT5, respectively. STAT complexes modulate transcription of various genes, including increased IL6, IL10, IL17A/17F, IL22, transforming growth factor (TGF)β, and monocytic chemotactic protein (MCP)1 production, as well as decreased tumor necrosis factor (TNF)α, IL12, and IFNγ synthesis. SBE, STAT binding element. GAS, γ-IFN-activated sequence.

Figure 3

Inborn errors of immunity in interferon (IFN) regulatory factors (IRF)s and signal transducers and activators of transcription (STAT)s may lead to either loss-of-function (LOF) (red asterisk) or gain-of-function (GOF) (green asterisk) of the molecule and result in different primary immunodeficiencies (PID)s and infectious phenotypes. Within the IFN inducing signaling pathways defects in IRF3, IRF7, IRF9, and IRF8 result in herpes simplex encephalitis (HSE), severe influenza, and Mendelian susceptibility to mycobacterial disease (MSMD), respectively. Defects downstream of the type I IFN receptor in STAT1, STAT2 or IRF9 cause MSMD, susceptibility to measles, and severe influenza, respectively. In contrast, STAT1 GOF causes chronic mucocutaneous candidiasis (CMC). ISRE, IFN stimulated response element; GAS, γ-IFN-activated sequence.

Figure 4

Defects downstream of various receptors utilizing signal transcducer and activator of transcription (STAT)1, STAT3, or STAT5B cause Mendelian susceptibility to mycobacterial disease (MSMD), hyper-IgE syndrome (HIES) and growth hormone insensitivity syndrome (GHIS), respectively. In contrast, STAT1 GOF causes chronic mucocutaneous candidiasis (CMC), whereas, STAT3 GOF leads to an autoinflammatory condition with hypogammaglobulinemia, lymphoproliferation, and a broad infectious phenotype. SBE, STAT bindinf element; GAS, γ-IFN-activated sequence.