Direct Inhibition of IRF-Dependent Transcriptional Regulatory Mechanisms Associated With Disease
| Autor: | Agata Michalska, Anna Piaszyk-Borychowska, Aleksandra Antonczyk, Bart Krist, Hans A.R. Bluyssen, Joanna Wesoly, Martyna Plens-Galaska, Malgorzata Sajek |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
lcsh:Immunologic diseases. Allergy Transcription Genetic Immunology Response element Biology Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Transcription (biology) Hypothesis and Theory TLR Transcriptional regulation Animals Humans Immunology and Allergy Protein Interaction Domains and Motifs transcriptional regulation Molecular Targeted Therapy Transcription factor Binding Sites Innate immune system Toll-Like Receptors interferon inhibition Cell biology IRF 030104 developmental biology Gene Expression Regulation Molecular Diagnostic Techniques inflammation Interferon Regulatory Factors Trans-Activators Disease Susceptibility Interferons Protein Multimerization Signal transduction lcsh:RC581-607 Biomarkers Protein Binding Signal Transduction 030215 immunology Binding domain Interferon regulatory factors |
| Zdroj: | Frontiers in Immunology, Vol 10 (2019) Frontiers in Immunology |
| ISSN: | 1664-3224 |
| Popis: | Interferon regulatory factors (IRFs) are a family of homologous proteins that regulate the transcription of interferons (IFNs) and IFN-induced gene expression. As such they are important modulating proteins in the Toll-like receptor (TLR) and IFN signaling pathways, which are vital elements of the innate immune system. IRFs have a multi-domain structure, with the N-terminal part acting as a DNA binding domain (DBD) that recognizes a DNA-binding motif similar to the IFN-stimulated response element (ISRE). The C-terminal part contains the IRF-association domain (IAD), with which they can self-associate, bind to IRF family members or interact with other transcription factors. This complex formation is crucial for DNA binding and the commencing of target-gene expression. IRFs bind DNA and exert their activating potential as homo or heterodimers with other IRFs. Moreover, they can form complexes (e.g., with Signal transducers and activators of transcription, STATs) and collaborate with other co-acting transcription factors such as Nuclear factor-κB (NF-κB) and PU.1. In time, more of these IRF co-activating mechanisms have been discovered, which may play a key role in the pathogenesis of many diseases, such as acute and chronic inflammation, autoimmune diseases, and cancer. Detailed knowledge of IRFs structure and activating mechanisms predisposes IRFs as potential targets for inhibition in therapeutic strategies connected to numerous immune system-originated diseases. Until now only indirect IRF modulation has been studied in terms of antiviral response regulation and cancer treatment, using mainly antisense oligonucleotides and siRNA knockdown strategies. However, none of these approaches so far entered clinical trials. Moreover, no direct IRF-inhibitory strategies have been reported. In this review, we summarize current knowledge of the different IRF-mediated transcriptional regulatory mechanisms and how they reflect the diverse functions of IRFs in homeostasis and in TLR and IFN signaling. Moreover, we present IRFs as promising inhibitory targets and propose a novel direct IRF-modulating strategy employing a pipeline approach that combines comparative in silico docking to the IRF-DBD with in vitro validation of IRF inhibition. We hypothesize that our methodology will enable the efficient identification of IRF-specific and pan-IRF inhibitors that can be used for the treatment of IRF-dependent disorders and malignancies. |
| Databáze: | OpenAIRE |
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