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.

Inhibition of interferon gene activation by death-effector domain-containing proteins from the molluscum contagiosum virus

“…Viral protein level expression was verified by immunoblotting to ensure that the lack of inhibition was not due to a lack of protein expression. TBK1 activates IRF7 in addition to IRF3 (51,52). It was shown previously that MC159 does not inhibit IRF7-induced IFN-β enhancer activation (43) when a constitutively active IRF7 is expressed, suggesting that MC159 does not directly interact with IRF7.…”

Interferon regulatory factor 7- (IRF7-) mediated immune response affects Newcastle disease virus replication in chicken embryo fibroblasts

“…Previous studies have shown that human plasmacytoid dendritic cells (pDCs) can express IRF7 constitutively, but this basal expression is rapidly upregulated after the stimulation and is maintained in vitro only in the presence of a stimulant. Further studies have demonstrated that nuclear translocation of IRF7 occurs earlier than IRF7 induction (Au et al, 1998;Sato et al, 1998;Honda et al, 2005;Ning et al, 2011). The characterisation of cellular components involved in viral detection and IRF activation will further delineate this vital mechanism of the innate immune response.…”

“…In recent years, extensive studies of the interferon regulatory factor (IRF) family have confirmed that IRFs have gained great attention due to their diverse roles such as initiating antiviral responses, regulating inflammatory cytokine expression and controlling cell cycle and apoptosis, as well as mediating the development of macrophages, dendritic cells, B and T lymphocytes (Au et al, 1998;Sato et al, 1998;Honda et al, 2005;Ning et al, 2011). As an important transcription mediator, IRF7 has been initially identified to induce the expression of IFNs and IFN-stimulated genes (ISGs) in the hosts, and it plays a critical role in initiating host innate immune responses to viral and bacterial infection (Marie et al, 1998;Smith et al, 2001).…”

The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers

“…Distinct from both KSHV and MHV-68 encoded ORF36 can only bind to phosphorylated IRF3, and inhibits the production of IFN-β (Hwang et al, 2009), EBV encoded ORF36 (namely BGLF4 kinase) could phosphorylates IRF-3 and inhibits the active IRF-3 recruitment to ISREs and thus suppresses the type I IFN response (Wang et al, 2009). Similar to IRF-3, IRF-7 is also phosphorylated by TBK1 and IKKε, which leads to heterodimerize with IRF-3 and fully stimulate type I IFN expression (Ning et al, 2011). It has been shown that although ORF45 of KSHV could inhibit IRF-7 phosphorylation (Zhu et al, 2002;Liang et al, 2012), the latent membrane protein LMP1 induces the phosphorylation and K63-linked ubiquitination of IRF7, resulting in its nuclear translocation and increased transcriptional activity (Ning et al, 2008;Bentz et al, 2012).…”