Review: ICSBP/IRF-8 Transactivation: A Tale of Protein-Protein Interaction

Levi, Ben‐Zion; Hashmueli, Sharon; Gleit‐Kielmanowicz, Merav; Azriel, Aviva; Meraro, David

doi:10.1089/107999002753452764

Cited by 70 publications

(82 citation statements)

References 54 publications

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“…The exon 6 indel was located in a proline-, glutamic acid-, serineand threonine-rich (PEST) domain of IRF5, a motif previously implicated in protein stability and function in the IRF family of proteins. 97 As described above, we observed that rs2070197 confers the third genetic risk of IRF5 for SLE, but we could not see any relevant functional importance in this as well as any other SNPs in the neighboring region. Therefore, we re-analyzed the genetic data based on the hypothesis that rs2070197 is tagging other functional variation; most likely exon 6 indel because of its potential function and relatively close location to it (B1.6 kb upstream).…”

Section: Exon 6 Indel Variation Was the Third Genetic Risk Factor Formentioning

confidence: 45%

A compass that points to lupus: genetic studies on type I interferon pathway

Kyogoku

Tsuchiya

2007

Genes Immun

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It was more than 20 years ago that patients with systemic lupus erythematosus (SLE) were first reported to display elevated serum levels of type I interferon (IFN). Since then, extensive studies revealed a crucial role for type I IFN in SLE pathogenesis. The current model proposes that small increase of type I IFN production by plasmacytoid dendritic cells (pDCs) is sufficient to induce unabated activation of immature peripheral DCs. IFN-matured DCs select and activate autoreactive T cells and B cells, rather than deleting them, resulting in peripheral tolerance breakdown, a characteristic feature of SLE. Furthermore, immune complexes provide an amplification loop to pDCs for further IFN production. In the past 5 years, high-throughput technologies such as expression profiling and single-nucleotide polymorphism (SNP) typing established the role of altered type I IFN system in SLE, and a detailed picture of its molecular mechanisms is beginning to emerge. In this review, we discuss two major lines of genetics studies on type I IFN pathway related to human SLE: (1) expression profiling of IFN-responsive genes and (2) disease-associated SNPs of IFN-related genes, especially IRF5 (IFN-regulatory factor 5). Lastly, we discuss how such genetic alterations in type I IFN pathway fit in the current model of SLE pathogenesis.

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Section: Exon 6 Indel Variation Was the Third Genetic Risk Factor Formentioning

confidence: 45%

A compass that points to lupus: genetic studies on type I interferon pathway

Kyogoku

Tsuchiya

2007

Genes Immun

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“…This suggests this band represents a complex composed of IRF-1, IRF-8, and PU.1, which is characteristic of macrophage-specific promoters (for review see Ref. 3).…”

Section: Irf-8 Is Essential For the Expression Of Specific Pml Isoformentioning

confidence: 99%

Interferon Regulatory Factor-8 Is Indispensable for the Expression of Promyelocytic Leukemia and the Formation of Nuclear Bodies in Myeloid Cells

Dror

Rave-Harel

Burchert

et al. 2007

Journal of Biological Chemistry

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Interferon (IFN) regulatory factor-8 (IRF-8), previously known as ICSBP, is a myeloid cell essential transcription factor. Mice with null mutation in IRF-8 are defective in the ability of myeloid progenitor cells to mature toward macrophage lineage. Accordingly, these mice develop chronic myelogenous leukemia (CML). We demonstrate here that IRF-8 is an obligatory regulator of the promyelocytic leukemia (PML) gene in activated macrophages, leading to the expression of the PML-I isoform. This regulation is most effective together with two other transcription factors, IRF-1 and PU.1. PML is a tumor suppressor gene that serves as a scaffold protein for nuclear bodies. IRF-8 is not only essential for the IFN-␥-induced expression of PML in activated macrophages but also for the formation of nuclear bodies. Reduced IRF-8 transcript levels were reported in CML patients, and a recovery to normal levels was observed in patients in remission following treatment with IFN-␣. We demonstrate a significant correlation between the levels of IRF-8 and PML in these CML patients. Together, our results indicate that some of the myeloleukemia suppressor activities of IRF-8 are mediated through the regulation of PML. When IRF-8 levels are compromised, the reduced PML expression may lead to genome instability and eventually to the leukemic phenotype.

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“…Without IRF8, Tot2 cells remain undifferentiated and grow continuously. IRF8 interacts with partner proteins, PU.1 and IRF1, to regulate target gene expression (20)(21)(22). By interacting with PU.1, IRF8 can bind to the EICE (Ets͞IRF composite element) in vitro; interaction with IRF1 allows IRF8 to bind to the IFN-stimulated response element.…”

Section: Together Irf8 -Chromatin Interaction Is Dynamic In Live Macmentioning

confidence: 99%

“…By interacting with PU.1, IRF8 can bind to the EICE (Ets͞IRF composite element) in vitro; interaction with IRF1 allows IRF8 to bind to the IFN-stimulated response element. Both interactions require the C-terminal IRF association domain (IAD) and the DNA-binding domain (DBD) of IRF8 (20,23). PU.1 also binds to IRF4, a factor structurally similar to IRF8 (24)(25)(26).…”

Section: Together Irf8 -Chromatin Interaction Is Dynamic In Live Macmentioning

confidence: 99%

Partner-regulated interaction of IFN regulatory factor 8 with chromatin visualized in live macrophages

Laricchia-Robbio

Tamura

Karpova

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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IFN regulatory factor (IRF) 8 is a transcription factor that directs macrophage differentiation. By fluorescence recovery after photobleaching, we visualized the movement of IRF8-GFP in differentiating macrophages. Recovery data fitted to mathematical models revealed two binding states for IRF8. The majority of IRF8 was highly mobile and transiently interacted with chromatin, whereas a small fraction of IRF8 bound to chromatin more stably. IRF8 mutants that did not stimulate macrophage differentiation showed a faster recovery, revealing little interaction with chromatin. A macrophage activation signal by IFN-␥͞LPS led to a global slowdown of IRF8 movement, leading to increased chromatin binding. In fibroblasts where IRF8 has no known function, WT IRF8 moved as fast as the mutants, indicating that IRF8 does not interact with chromatin in these cells. However, upon introduction of IRF8 binding partners, PU.1 and͞or IRF1, the mobility of IRF8 was markedly reduced, producing a more stably bound component. Together, IRF8 -chromatin interaction is dynamic in live macrophages and influenced by partner proteins and immunological stimuli.real-time mobility ͉ transcription factor ͉ fluorescence recovery after photobleaching G ene expression in immune cells is controlled by binding of transcription factors to chromatin targets. A classic view is that active transcription factors stably bind to the chromatinized promoter to drive transcription, a view mostly derived from biochemical studies in vitro. With the advent of live cell technologies, the views on the behavior of transcription factors are changing. Studies by fluorescence recovery after photobleaching (FRAP) of many nuclear proteins show that they are highly mobile and only transiently interact with chromatin (1, 2). Proteins showing rapid mobility include general transcription factors, chromatin modifiers, and DNA replication factors (3-9). Some DNA-specific transcription factors, such as nuclear hormone receptors, are also highly mobile in live nuclei (10-12). In addition, Stat1 (signal transducer and activator of transcription 1), a transcription factor that regulates IFN responses, is shown to be mobile before and after translocation into the nucleus (13), although E2F and retinoblastoma protein appear to be more stationary (14). In contrast, core histones, stable components of chromatin, are essentially immobile, showing little recovery after photobleaching (15). A consensus emerging from these studies is that FRAP recovery primarily reflects interactions of nuclear proteins with chromatin and the surrounding genomic DNA (hereafter referred to as chromatin) (16). Nevertheless, photobleaching technologies are still in their early phase of application, and mechanisms regulating FRAP mobility are not fully understood. FRAP mobility might reflect an intrinsic chromatin-binding property of a protein. However, the mobility may be influenced by other factors, such as soluble molecular constituents and structural components of the nucleus. In addition, most transcripti...

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Review: ICSBP/IRF-8 Transactivation: A Tale of Protein-Protein Interaction

Cited by 70 publications

References 54 publications

A compass that points to lupus: genetic studies on type I interferon pathway

A compass that points to lupus: genetic studies on type I interferon pathway

Interferon Regulatory Factor-8 Is Indispensable for the Expression of Promyelocytic Leukemia and the Formation of Nuclear Bodies in Myeloid Cells

Partner-regulated interaction of IFN regulatory factor 8 with chromatin visualized in live macrophages

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