Inborn errors of immunity with loss- and gain-of-function germline mutations in STAT1

Abstract

Signal transducer and activator of transcription 1 (STAT1) is a well-known molecule in the human immune system and was the first STAT to be identified in 1989 [ 1–5]. STAT1 is composed of 7 domains encoded by 25 exons positioned on chromosome 2, and the function of each domain has been well investigated [ 6–8]. STAT proteins have dual functions as signal transducers and activators of transcription [ 4, 9]. STAT1 mediates the signalling of type I (IFN-α, IFN-β), type II (IFN-γ), and type III (IFN-λ) interferons (IFNs) and interleukin-27 (IL-27), thereby playing an essential role in the biological immune defence against various pathogens ( Fig. 1) [ 5, 7, 10]. STAT1 normally exists in the cytoplasm in an inactive form [ 9]. Binding of STAT1-activating ligands to certain receptors activates Janus activating kinases (JAK), which phosphorylate tyrosine residues on the receptors. The phosphorylated receptors then recruit STAT1, which undergoes phosphorylation of tyrosine residues (Y701) by JAK. Phosphorylated STAT1 via type II IFNs or IL-27 forms homodimer called IFN-γ activated factor (GAF). GAF translocates into the nucleus and binds to the IFN-γ activated site (GAS), resulting in the induction of target gene transcription for defence against intra-macrophagic bacteria. Additionally, phosphorylated STAT1 forms a heterotrimer with STAT2 and IRF9, called IFN-stimulated gene factor 3 (ISGF3), upon type I and type III IFN stimulation. After nuclear translocation, ISGF3 binds to IFN-stimulated response element (ISRE) and induces the transcription of its target genes to defend against viruses. After those processes, activated STAT1 is finally dephosphorylated in the nucleus and translocated back to the cytoplasm, where it remains as a monomer or antiparallel unphosphorylated dimer [ 7, 11–13]. Thus, this activation pathway, called the JAK-STAT pathway, is an extensive signalling pathway downstream of several cytokine receptors that plays an indispensable role in the immune defence in humans ( Fig. 1).