Disease relevance of IRF5

• We show that, in addition to Newcastle disease virus (NDV) infection, vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) infection activates IRF-5, leading to the induction of IFNA gene subtypes that are distinct from subtypes induced by NDV [1].
• Three very recent reports provide convincing statistical evidence (P < 10(-8)), at a genome-wide level, of the association of common polymorphisms with three different common diseases: systemic lupus erythematosus (IRF5), prostate cancer and type 1 diabetes (IFIH1 region) [2].
• IRF-5 inhibits both in vitro and in vivo B-cell lymphoma tumor growth in the absence of wild-type p53 [3].
• Here we show that ectopic IRF-5 sensitizes p53-proficient and p53-deficient colon cancer cells to DNA damage-induced apoptosis [4].
• Here, the different strategies for targeting the interferon regulatory factor-5 signaling pathway in colorectal cancer are discussed [5].
• Cultured salivary gland epithelial cells from patients carrying the 4R CGGGG IRF5 allele showed a high level of IRF5 mRNA (P = 0.04), which was amplified after reovirus infection (P = 0.026) [6].
• In a multivariate analysis model including the diffuse cutaneous subtype of SSc and positivity for anti-topoisomerase I antibodies, the IRF5 rs2004640 TT genotype remained associated with fibrosing alveolitis (P=0.029, OR 1.92, 95% CI 1.07-3.44) [7].

High impact information on IRF5

• It also shows that the range of IRF-5 immunoregulatory target genes includes members of the cytokine and chemokine superfamilies [1].
• Mutation of these residues from serine to alanine dramatically decreased phosphorylation and resulted in a substantial loss of IRF-5 transactivation in infected cells [1].
• Multiple regulatory domains of IRF-5 control activation, cellular localization, and induction of chemokines that mediate recruitment of T lymphocytes [1].
• By transient- transfection assay, we identified constitutive-activation (amino acids [aa] 410 to 489) and autoinhibitory (aa 490 to 539) domains in the IRF-5 polypeptide [1].
• The combination IFN-beta and irinotecan (CPT-11) cooperatively inhibits cell growth and IRF-5 synergizes with it to further promote apoptosis [4].

Biological context of IRF5

• Finally, transfection of either an IRF5 dominant-negative construct or IRF5 small interfering RNA in these cells resulted in increases in endogenous levels of LMP1 [8].
• CONCLUSION: Our results suggest that the IRF5 functional polymorphisms analyzed do not seem to be implicated in genetic susceptibility to RA [9].
• RESULTS: In the 3 cohorts studied, no statistically significant differences in allele or genotype frequencies of the rs2004640 and rs2280714 IRF5 polymorphisms were observed between RA patients and controls [9].
• Accordingly, haplotype analysis revealed that none of the IRF5 haplotypes was associated with genetic predisposition to RA [9].
• Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death [3].

Anatomical context of IRF5

• In human primary plasmacytoid dendritic cells (PDC), IRF-5 is transcribed into four distinct alternatively spliced isoforms (V1, V2, V3, and V4), whereas in human primary peripheral blood mononuclear cells two additional new isoforms (V5 and V6) were identified [10].

Associations of IRF5 with chemical compounds

• The formation of the IRF-5/IRF-7 heterodimer is dependent on IRF-7 phosphorylation, as shown by the glutathione S-transferase pull-down and immunoprecipitation assays [11].
• Mutation of two leucine residues in the NES motif to alanine, or three adjacent Ser/Thr residues to the phosphomimetic Asp, results in constitutively nuclear IRF-5 and suggests that phosphorylation of adjacent Ser/Thr residues may contribute to IRF-5 nuclear accumulation in virus-induced cells [12].
• Expression of IRF-5 was induced in p53+/+ cells (MCF7 and NHDF), but not inp53-/- cells (H1299) when DNA was damaged by gamma-irradiation, UV-radiation, or adriamycin treatment in a wild-type p53-dependent manner [13].

Regulatory relationships of IRF5

• Interferon regulatory factor-5 (IRF-5) is a mediator of virus-induced immune activation and type I interferon (IFN) gene regulation [10].

Other interactions of IRF5

• Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes [14].
• The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling [15].
• Endogenous IRF5 and IRF7 proteins were shown to physically associate in EBV-positive cells [8].
• We examined the phosphorylation and activation of IRF-5 by TBK1 and IKKepsilon kinases [12].
• Several studies have demonstrated that IRF-3, IRF-5, and IRF-7 specifically contribute to the innate antiviral response to virus infection [12].
• VIRF-3 antagonized IRF-5-mediated activation of the p21 promoter [16].

Analytical, diagnostic and therapeutic context of IRF5

• We have shown previously that IRF-5, like IRF-3 and IRF-7, is a direct transducer of virus-mediated signaling and plays a role in the expression of multiple cytokines/chemokines [11].
• The transcription profiles of infected BJAB cells overexpressing IRF-5 or IRF-7 were determined by using oligonucleotide arrays with probe sets representing about 6800 human genes [17].
• An electrophoretic mobility-shift assay showed that a potential p53 binding site (p53BS) detected in exon 2 of the IRF-5 gene could in fact bind to p53 protein [13].

References