The IRF family of transcription factors: Inception, impact and implications in oncogenesis

Abstract

Members of the interferon-regulatory factor (IRF) proteins family were originally identified as transcriptional regulators of the Type I interferon system. Thanks to consistent advances made in our understanding of the immunobiology of innate receptors, it is now clear that several IRFs are critical for the elicitation of innate pattern recognition receptors, and-as a consequence-for adaptive immunity. In addition, IRFs have attracted great attentions as they modulate cellular responses that are involved in tumorigenesis. The regulation of oncogenesis by IRFs has important implications for understanding the host susceptibility to several Types of cancers, their progression, as well as the potential for therapeutic interventions.

Figure 1. Schematic illustration of human and viral IRF family members. Nine human IRF family members (IRF1 to IRF9) (upper) and three vIRFs (vIRF1, vIRF2, and vIRF3) (lower), all encoded by Kaposi sarcoma-associated herpesvirus (KSHV) are shown. Length (in amino acid) is reported. IRF family members possess an amino N-terminal DNA-binding domain (DBD) that is characterized by a series of five relatively well conserved tryptophan-rich repeats. All IRF family members, except for IRF1 and IRF2, contain an IRF association domain (IAD1). IRF1 and IRF2 share another IRF association domain (IAD2), which is structurally distinct from IAD1. IRF3 and IRF7 have multiple sites that—upon viral infection—are substrates for phosphorylation by the serine/threonine kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε). Phosphorylation at these sites is required for the nuclear translocation of IRF3 and IRF7. KSHV encodes a cluster of three viral vIRFs, all of which show homology in their N-terminal regions to the DBD of IRFs but lack several tryptophan residues. For this reason, vIRFs are believed to be unable to directly bind DNA. vIRF1 contains an IAD domain which enables vIRF1 to associate with other IRFs, such as IRF1. vIRF3 has an IAD-like domain which shows 32% identity with the IAD of IFR4, although the exact function of this domain remains elusive.