described a patient with a heterozygous STAT2 mutation who suffered from severe viral infections since infancy. Moreover, potential backup systems, including STAT2/IRF9 or IRF1, could be activated under conditions where STAT1 or STAT2 are not fully active.Most of the knowledge about the DNA responsive elements involved in IFN-I and IFN-II signaling dates from early experiments that focused on individual genes and their role in the antiviral response (More recent genome-wide binding approaches (using ChIP-chip or ChIP-seq), monitoring binding of STAT1, STAT2, and IRF1 in response to IFN-I or IFN-II, confirmed this genomic organization and identified many known and novel target genes with varying binding modes to individual or combined ISRE and GAS sites (Closer inspection of the publicly accessible dataset (Presently it is not clear how these ISRE and GAS composite-containing genes are represented within the full spectrum of IFN-I and IFN-II induced ISGs and how they contribute to overall IFN-mediated antiviral activities.At the same time, these genome-wide binding approaches concluded that STAT1, STAT2, and IRF9 bind not only at promoter proximal but also distal ISRE and/or GAS sites suggesting a role of distant enhancers in remote gene regulation (ChIP-chip and ChIP-seq studies also showed that IRF1 binds many distal ISRE-containing enhancers (The function of the majority of distal ISGF3, GAF, and IRF1 binding sites remains largely unknown. In a combinatorial and timely fashion, these complexes mediate prolonged ISG expression and control cellular responsiveness to IFN-I and IFN-II (Figure The exact timely steps that take place during IFN-activated feedback regulation and the control of ISG transcription and long-term cellular responsiveness to IFN-I and IFN-II, are still not clear. It is what allows us to create all these practical circuits, being able to precisely set gains, rates, and other significant parameters with just a few changes of resistor values. In addition, evidence is accumulating for an IFN-independent and -dependent role of unphosphorylated STAT1 and STAT2, with or without IRF9, and IRF1 in basal as well as long-term ISG expression. It “latches” between one of two states, saturated positive or saturated negative. Because positive feedback generates unnecessary distortion; it is not often used in amplifiers. By contrast, IRF1 regulates ISG transcription through homo- or heterodimerization and binding to IRE or ISRE sequences. For example, it was shown that IFN induction of the ISRE-containing genes Collectively, this highly suggested that IRF1 and ISGF3 are not functionally redundant but complement each other and collaborate to ensure the induction of the full range of overlapping target genes which respond to IFN-I and IFN-II (Figure Collaborations between IRF1 and STAT1 in transcriptional regulation of ISRE and GAS-containing ISGs have also been described (Figure In an IFN-independent manner, basal expression of IRF1 can be detected in many cell types. This page compares Negative feedback vs Positive feedback and mentions difference between Negative feedback and Positive feedback in amplifiers. The editor and reviewers' affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review.Interferon (IFN)-I and IFN-II both induce IFN-stimulated gene (ISG) expression through Janus kinase (JAK)-dependent phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT2. JW participated in development of the concept and critically evaluated and edited the manuscript.
Especially, we focus on how this feedback system regulates ISG transcription from the basal to the IFN-induced state at the genome-wide level, how it depends on phosphorylation and expression of ISGF3, IRF1, and GAF components, and how it controls cellular responsiveness to IFN-I and IFN-II in relation to antiviral activity.All IFN-I subtypes bind the IFNAR1 and IFNAR2 subunits of the heterodimeric transmembrane IFNAR receptor to activate the JAK/STAT pathway, used by many cytokines and growth factors.