Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6)
Christopher R. IngrahamAkira KinoshitaShinji KondoBaoli YangSamin A. SajanKurt J TroutMargaret MalikMartine DunnwaldStephen L GoudyMichael LovettJeffrey C. MurrayBrian C. Schutte
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IRF8
IRF4
IRF7
IRF1
IRF5
GATA6
Limb development
Multiple Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded proteins with potential roles in KSHV-associated neoplasms have been identified. KSHV encodes 4 genes with homology to transcription factors of the interferon (IFN) regulatory factor (IRF) family. Viral IRF3 (vIRF3) is expressed in latently KSHV-infected primary effusion lymphoma (PEL) cells and was recently shown to be essential for the survival of PEL cells. The focus of this study was to determine the mechanism(s) of vIRF3 oncogenic activity contributing to KSHV-associated lymphoma. We report that vIRF3 interacts with the amino-terminal DNA binding domain of human IRF5, leading to a complex manipulation of IRF5 function. vIRF3 associated with both exogenous and endogenous IRF5, thereby inhibiting IRF5-mediated IFN promoter activation and the synthesis of biologically active type I IFNs by blocking its binding to endogenous IFNA promoters. The function of this interaction was not limited to the IFN system as IRF5-mediated cell growth regulation was significantly altered by overexpression of vIRF3 in B cells. vIRF3 prevented IRF5-mediated growth inhibition and G2/M cell cycle arrest. Important, IRF5 was upregulated by the protein kinase C agonist 12-O-tetradecanoyl-phorbol-13-acetate in BCBL1 PEL cells and interaction with vIRF3 was observed at the endogenous p21 promoter in response to 12-O-tetradecanoyl-phorbol-13-acetate, suggesting that these 2 proteins cooperate in the regulation of lytic cycle-induced G1 arrest, which is an important early step for the reactivation of KSHV. In conclusion, cellular IRF5 and vIRF3 interact, leading to the functional modulation of IRF5-mediated type I IFN expression and cell cycle regulation. These findings support an important role for vIRF3 in immune evasion and cell proliferation that likely contribute to the survival of PEL cells.
Evasion (ethics)
Lytic cycle
IRF8
Kaposi's sarcoma-associated herpesvirus
Immune Modulation
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IRF7
IRF8
IRF5
Aeromonas salmonicida
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IRF3
IRF8
IRF4
TLR3
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The Interferon regulatory factors (IRFs) are a family of transcription factors that play pivotal roles in many aspects of the immune response, including immune cell development and differentiation and regulating responses to pathogens. Three family members, IRF3, IRF5 and IRF7, are critical to production of type I interferons downstream of pathogen recognition receptors that detect viral RNA and DNA. A fourth family member, IRF9, regulates interferon-driven gene expression. In addition, IRF4, IRF8 and IRF5 regulate myeloid cell development and phenotype, thus playing important roles in regulating inflammatory responses. Thus understanding how their levels and activity is regulated is of critical importance given that perturbations in either can result in dysregulated immune responses and potential autoimmune disease. This review will focus the role of IRF family members in regulating type I IFN production and responses and myeloid cell development or differentiation, with particular emphasis on how regulation of their levels and activity by ubiquitination and microRNAs may impact autoimmune disease.
IRF5
IRF8
IRF3
IRF7
IRF4
Interferon type I
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CEBPA
GATA2
IRF5
IRF7
GATA3
RUNX1
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Interferon regulatory factor(IRF)members are composed of 10 different proteins, including IRF1 ~ IRF9 and viruses IRF(V-IRF). These IRFs regulate the transcription of type I IFN genes as transcription factors.Systemic lupus erythematosus(SLE)is an autoimmune disease characterized by a large number of autoantibodies and precipitated immune complexes, which can cause the damage of multiple organs and systems.Type I interferon system, especially the IFN-α is an important pathogenic factor in the process of SLE morbidity.SLE patients may have high level of IFN-α, which could affect the activation of the immune system to promote the development of SLE through the regulation of a variety of immune cells′ activation, differentiation and function.Besides IRF3 and IRF7, the transcription factor IRF5 gene has also been shown to be related to the production of type I interferon and is an important regulator of the IFN pathway, and its genetic polymorphism and expression abnormality lead to the susceptibility of SLE.In addition to regulating the expression of type I IFN genes, IRF5 is also associated with other signaling pathways, including B cell transformation of IgG, macrophage polarization and apoptosis, and these signaling pathways in the pathogenesis of SLE also play a very important role.This article reviews the role of IRF5 in the development of SLE disease.
Key words:
SLE; IRF5; Signal pathways
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A number of autoimmune diseases have an increased expression of type I interferon regulated genes in cells from peripheral blood and tissues. This so called interferon signature has been found in patients with SLE, primary Sjögrens syndrome, systemic sclerosis, myositis and a subset of patients with rheumatoid arthritis. The reasons behind the continuous activation of the type I interferon system in patients with these diseases are presence of self-derived inducers of type I interferon production by plasmacytoid dendritic cells (pDCs), lack of proper regulation of cells in the type I interferon system and a genetic predisposition to an enhanced type I interferon response. In fact, a large proportion of the genes predisposing to autoimmunity are involved in the type I interferon signaling pathway, either the production of type I interferon or the response downstream the type I interferon receptor. This has been extensively studied in SLE and among lupus risk genes involved in the production of type I interferon are interferon regulatory factor 5 (IRF5), IRF7 and interleukin-1 receptor associated kinase (IRAK1). SLE susceptibility genes important for the type I interferon response are tyrosine kinase 2 (Tyk2), Signal Transducer and Activator of Transcription 4 (STAT4) and interferon induced with helicase C domain 1 (Ifih1). Several of these genes are in addition risk genes for autoimmune diseases beside SLE. Rare mutations of a number of genes, for instance TREX1 and ACP5, also cause an increased expression of type I interferon stimulated genes and an autoimmune disease resembling SLE. There are several mechanism by which the increased activation of the type I interferon system can contribute to loss of tolerance and an autoimmune disease process. Thus, type I interferon is an immune adjuvant and stimulate cells in both the innate and adaptive immune system, but can also increase the expression of autoantigens. A major challenge in these so called type I interferonopathies is to down regulated the type I interferon system without increasing the risk for severe infections.
Disclosure of Interest
None DeclaredIRF5
IRF7
IRF8
Tyrosine kinase 2
IRF1
Interferon type I
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IRF8
IRF4
IRF7
IRF1
IRF5
GATA6
Limb development
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As a family of transcription factors, the correlations between expression pattern of nine interferon regulatory factor (IRF) family members, the immune invasion pattern, and the associated patient survival rate in endometrial carcinoma (EC) remain to be elucidated. Based on The Cancer Genome Atlas (TCGA), the expression profiles of the high and low IRF mRNA expression groups were analyzed using R (3.6.3) statistical software. Gene annotation and pathway analyses were performed using Metascape. GSEA was performed using the R package clusterProfiler (3.6.3). The single-sample gene set enrichment analysis (ssGSEA) was used to quantify the relative tumor infiltration levels of immune cell types. Immunohistochemistry data provided by HPA database was used to study the expression of the IRF proteins. Using the GEPIA dataset, the correlation between the expression of IRFs and the tumor stage of EC was analyzed. The correlations between the different IRFs were analyzed using cBioPortal. The expression of IRF2, IRF3, IRF5, IRF6, IRF7, IRF8, and IRF9 was different when comparing EC and normal endometrial samples. IRF2, IRF6, IRF7, and IRF8 were indicated to be potential diagnostic markers for EC. In combination with receiver operating characteristic analysis results, IRF2, IRF6, IRF7, and IRF8 were indicated to be potential diagnostic markers for EC. Levels of individual IRFs were associated with alternate outcomes, with the expression of IRF3 being correlated with the stage of EC and high expression of IRF4 being positively correlated with overall survival (OS); conversely, high expression of IRF5 was negatively correlated with OS. Additionally, high expression levels of both IRF2 and IRF4 were positively correlated with the disease-specific survival rate, and high expression of IRF4 was positively correlated with the progression-free interval. These data suggest a role for IRF2, IRF4, and IRF5 in the prognosis of EC. The expression of IRFs is associated with immune infiltration.
IRF7
IRF4
IRF5
IRF8
IRF3
IRF1
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The transcription factor interferon regulatory factor 4 (IRF4) belongs to the IRF family and has several important functions for the adaptive immune response. Mutations affecting IRF family members IRF1, IRF3, IRF7, IRF8, or IRF9 have been described in patients presenting with inborn errors of immunity (IEI) highlighting the importance of these factors for the cellular host defense against mycobacterial and/or viral infections. IRF4 deficiency and haploinsufficiency have been associated with IEI. More recently, two novel IRF4 disease-causing mechanisms have been described due to the characterization of IEI patients presenting with cellular immunodeficiency associated with agammaglobulinemia. Here, we review the phenotypes and physiopathological mechanisms underlying IEI of IRF family members and, in particular, IRF4.
IRF4
Haploinsufficiency
IRF7
IRF8
Primary Immunodeficiency
IRF3
IRF1
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