Triggering the Interferon Response: The Role of IRF-3 Transcription Factor

Abstract

The interferon (IFN) regulatory factors (IRF) consist of a growing family of related transcription proteins first identified as regulators of the IFN-alpha/beta gene promoters, as well as the IFN-stimulated response element (ISRE) of some IFN-stimulated genes. IRF-3 was originally identified as a member of the IRF family based on homology with other IRF family members and on binding to the ISRE of the IFN-stimulated gene 15 (ISG15) promoter. Several recent studies have focused attention on the unique molecular properties of IRF-3 and its role in the regulation of IFN gene expression. IRF-3 is expressed constitutively in a variety of tissues, and the relative levels of IRF-3 mRNA do not change in virus-infected or IFN-treated cells. Following virus infection, IRF-3 is posttranslationally modified by protein phosphorylation at multiple serine and threonine residues, located in the carboxy-terminus of IRF-3. Phosphorylation causes the cytoplasmic to nuclear translocation of IRF-3, stimulation of DNA binding, and increased transcriptional activation, mediated through the association of IRF-3 with the CBP/p300 coactivator. The purpose of this review is to summarize recent investigations demonstrating the important role of IRF-3 in cytokine gene transcription. These studies provide the framework for a model in which virus-dependent phosphorylation of IRF-3 alters protein conformation to permit nuclear translocation, association with transcriptional partners, and primary activation of IFN and IFN-responsive genes.

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

“…Gene clusters: 1, metabolism; 2, protein synthesis, modification and secretion; 3, ion channels, ion transporters and related proteins; 4, hormones, growth factors and related genes; 5, cytokines, chemokines and related receptors; 6, cytokine signal transduction; 7, MHC and related genes; 8, cell adhesion, cytoskeleton and related genes; 9, transcription factors and related proteins; 10, RNA synthesis, editing and splicing factors; 11, cell cycle; 12, defence/repair; 13, apoptosis and ER stress response and related genes; 14, antiviral response; 15, miscellaneous; 16, hypothetical proteins; 17, not classified viral infection and cytokine treatment (Tables S2 and S3). Activation of TLR-3 usually results in stimulation of IκB-related kinase and TBK-1 (TANK-binding kinase), leading to activation of transcription factors such as immune regulatory factor 3 (IRF-3) (regulated at the post-transcriptional level) [22,23] and NFκB, which in turn results in Fig. 4 Stimulation of genes involved in inflammation (a-c), transcription (d-e), and apoptosis and antiviral effects (f-g) by coxsackievirus B5 (CBV-5) and cytokines, IL-1β+IFN-γ, in human islets.…”

“…IFIT1: 2 and 4 interferon-induced protein with tetratricopeptide repeats 1, 2 and 4 . IFITM1: interferon-induced transmembrane protein 1 (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) . IFNB1: interferon β1, fibroblast .…”

Contribution of Ser386 and Ser396 to Activation of Interferon Regulatory Factor 3

“…1 The pathway leading to expression of IFN-β is guarded by IRF-3, a member of the interferon regulatory factor (IRF) family of transcription factors. 2,3,4 In the absence of infection, IRF-3 is localized in the cytoplasm in an inactive form. Upon infection, cytoplasmic IRF-3 is phosphorylated and translocates into the nucleus, where it interacts with the closely related coactivators, CREB-binding protein (CBP)/p300, to form a nucleoprotein complex at the promoter region of the IFN-β gene.…”

Interferon regulatory factor 3-CL, an isoform of IRF3, antagonizes activity of IRF3

“…[4][5][6] The activated IRF3 associates with the transcriptional cofactors cyclic AMP-responsive elementbinding protein and P300 to bind to the specific DNA targets, thus leading to transcriptional initiation of target genes with other cofactors simultaneously recruited. 7 Accumulating evidence demonstrates that IRF3 plays an essential role in the virus-or bacterium-mediated induction of interferon (IFN)-b and a subset of IFN-stimulated genes through the Toll-like receptors or the cytosolic receptors pathway. [8][9][10] Furthermore, IRF3 has been shown to function as a vital signaling regulator in the innate immune response, development of immune cells and apoptosis.…”