IRF7: activation, regulation, modification and function

Abstract

Interferon regulatory factor 7 (IRF7) was originally identified in the context of Epstein-Barr virus (EBV) infection, and has since emerged as the crucial regulator of type I interferons (IFNs) against pathogenic infections, which activate IRF7 by triggering signaling cascades from pathogen recognition receptors (PRRs) that recognize pathogenic nucleic acids. Moreover, IRF7 is a multifunctional transcription factor, underscored by the fact that it is associated with EBV latency, in which IRF7 is induced as well as activated by the EBV principal oncoprotein latent membrane protein-1 (LMP1). Aberrant production of type I IFNs is associated with many types of diseases such as cancers and autoimmune disorders. Thus, tight regulation of IRF7 expression and activity is imperative in dictating appropriate type I IFN production for normal IFN-mediated physiological functions. Posttranslational modifications have important roles in regulation of IRF7 activity, exemplified by phosphorylation, which is indicative of its activation. Furthermore, mounting evidence has shed light on the importance of regulatory ubiquitination in activation of IRF7. Albeit these exciting findings have been made in the past decade since its discovery, many questions related to IRF7 remain to be addressed.

Figure 1

Activation of IRFs through signaling pathways triggered by different PRRs. Pathogen-associated molecular patterns (PAMPs) derived from invading pathogens are recognized by distinct PRRs located on the membranes of endosomal compartments and trigger signaling cascades, which lead to activation of IRFs and type I IFN production in the host cell.

Figure 2

Regulation of IRFs in EBV lytic and latent infections. (a) Lytic infection. BGLF4 phosphorylates IRF3, but blocks its DNA-binding activity. Zta inhibits IRF7 transcriptional activity and RTA downregulates expression of IRF7 and -3 through unclear mechanisms. LF2 interacts with IRF7 and therefore blocks its dimerization and transcriptional activity. (b) Latency 3. EBV LMP1 induces expression of IRF7, -4, -5 and A20. LMP1 also activates IRF7 through ubiquitination, but A20 inhibits LMP1-stimulated IRF7 ubiquitination and activity. IRF7 induces expression of LMP1 and TAP2, but inhibits BamH I-A rightward transcript (BART) transcript. EBV also induces expression of TLR7 and its downstream target IRF5, and IRF5 inhibits IRF7 through dimerization with IRF7. EBV also induces IRF2 through unknown mechanism.