IRF5 gene

The IRF5 gene (IRF5 stands for: Interferon Regulatory Factor 5) is a protein-coding gene located on chromosome 7q32.1. The signaling pathways associated with this gene include the Toll-like receptor 7/8 (TLR7/8) cascade and the Toll-like receptor signaling pathway. The use of alternative promoters and alternative splicing lead to several transcript variants, and a 30-nt indel polymorphism (SNP rs60344245) can result in the loss of a 10-aa segment. An important paralog of this gene is IRF6.

The IRF6 gene encodes a member of the interferon-regulatory factor (IRF) family, a group of transcription factors with diverse functions, including virus-mediated activation of interferon and modulation of cell growth, differentiation, apoptosis and immune system activity. The encoded IRF5 protein is a transcription factor that plays a critical role in innate immunity by regulating the expression of type I interferon (IFN) IFN-alpha and INF-beta as well as inflammatory cytokines downstream of endolysosomal toll-like receptors TLR7, TLR8 and TLR9 (Barnes BJ et al. 2001; Schoenemeyer A et al. 2005). IRF3 and IRF7 genes are activated in response to a variety of viruses or after activation of Toll-like receptors (TLR) 3 and TLR4 by double-stranded RNA and lipopolysaccharide, respectively.

The activation of IRF5 is much more limited. In contrast to IRF3 and IRF7, IRF5 is not a target of the TLR3 signaling pathway, but the gene is activated by TLR7 or TLR8 signals. Activation of IRF5 and IRF7 requires MyD88, interleukin-1 receptor-associated kinase 1 and tumor necrosis factor receptor-associated factor 6.

Ectopic expression of IRF5 enables the production of type I interferons in response to TLR7 signaling, whereas silencing of IRF5 by small interfering RNA reduces the induction of type I interferon in response to the TLR7 ligand R-848. IRF5 and IRF7 have been shown to be important mediators of TLR7 signaling (Schoenemeyer A et al. 2005). Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters. IFR5 is the main transcription factor regulating the IFN response during SARS-CoV-2 infection (Yin X et al. 2021).

Diseases associated with IRF5 include chronic inflammatory bowel disease and systemic lupus erythematosus.

1. Barnes BJ et al. (2001) Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. J Biol Chem 276:23382-23390.
2. Lopez-Pelaez M et al. (2014) Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells. Proc Natl Acad Sci U S A 111:17432-17437.
3. Schoenemeyer A et al. (2005) The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling. J Biol Chem 280:17005-17012.
4. Yin X et al. (2021) MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells. Cell Rep 34:108628.