Interferon regulatory factors

Interferon regulatory factors were discovered as pathogenetic factors for various autoimmune and autoinflammatory diseases (e.g. systemic lupus erythematosus) due to their central role as transcription regulators of the biology of type I interferons (IFN-alpha and -beta).

Interferon regulatory factors are a family of proteins that regulate the transcription of interferons. Interferon regulatory factors regulate many aspects of innate and adaptive immune responses, including the control of antiviral responses to trigger proinflammatory reactions. They also play a regulatory role in the differentiation of immune cells.

The IRFs consist of 9 family members. They exhibit significant homology within their N-terminal DNA-binding domain (DBD) of approximately 120 amino acids, which forms a helix-loop-helix motif that recognizes specific DNA sequences similar to theinterferon stimulated response element(ISRE). The C-terminal domain is more diverse among family members and gives them their unique function by regulating their ability to interact with each other and with proteins outside the IRF family.

In general, the C-terminal domain of each IRF member contains a core export sequence, an autoinhibitory sequence, and an IRF association domain, which in most family members contains serine residues that are phosphorylated to regulate activity. The members of the IRF family can be both homodimeric and heterodimeric. They can form both transcriptionally active and repressive complexes.

Three members of the family, IRF3, IRF5 and IRF7, are crucial for the production of type I interferons (= interferons alpha/beta), which are downstream of pathogen recognition receptors that recognize viral RNA and DNA, for example. A fourth family member, IRF9, regulates interferon-driven gene expression. In addition, IRF4, IRF8 and IRF5 regulate the development and phenotype of myeloid cells and thus play an important role in the regulation of inflammatory reactions.

IRFs are critical regulators of immune responses and immune cell development, and abnormalities in IRF expression and function have been associated with numerous diseases. Because of their critical role in IFN type I activation, IRFs are considered to be important in autoimmune diseases related to activation of the IFN type I system, such as systemic lupus erythematosus (SLE). Furthermore, IRFs appear to play an important role in the regulation of cell reactions in connection with oncogenesis. In addition to autoimmune and tumor diseases, IRFs are also involved in the development of metabolic, cardiovascular and neurological diseases such as hepatic steatosis, diabetes, cardiac hypertrophy, atherosclerosis and stroke.

1. Gao SJ et al.( 1997). KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway. Oncogene 15: 1979-1985.
2. Paun A et al. (2007). The IRF family, revisited. Biochimie 89: 744-53.
3. Santana-de Anda K et al. (2011) Interferon regulatory factors: beyond the antiviral response and their link to the development of autoimmune pathology. Autoimmunity Reviews11: 98-103.
4. Weisz A et al. (1992) Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes. The Journal of Biological Chemistry 267: 25589-25596.
5. Yanai H et al. (2012) The IRF family of transcription factors: Inception, impact and implications in oncogenesis. Oncoimmunology 1: 1376-1386.
6. Zhao GN et al. (2015) Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1852: 365-378.