IKKε and TBK1 are essential components of the IRF3 signaling pathway

Abstract

The transcription factors interferon regulatory factor 3 (IRF3) and NF-kappaB are required for the expression of many genes involved in the innate immune response. Viral infection, or the binding of double-stranded RNA to Toll-like receptor 3, results in the coordinate activation of IRF3 and NF-kappaB. Activation of IRF3 requires signal-dependent phosphorylation, but little is known about the signaling pathway or kinases involved. Here we report that the noncanonical IkappaB kinase homologs, IkappaB kinase-epsilon (IKKepsilon) and TANK-binding kinase-1 (TBK1), which were previously implicated in NF-kappaB activation, are also essential components of the IRF3 signaling pathway. Thus, IKKepsilon and TBK1 have a pivotal role in coordinating the activation of IRF3 and NF-kappaB in the innate immune response.

RIP kinases: key decision makers in cell death and innate immunity

“…105 In addition to activation of NFkB, TRIF can also stimulate the TBK1 and IKKi/IKKe kinases to activate interferon regulatory factor (IRF) transcription factors that drive expression of anti-viral type I interferons (IFNs) 99,106 (Figure 3). Interestingly, RIP1 is not used by TRIF in its activation of IRFs.…”

Transcriptional regulation via the NF-κB signaling module

“…A less complex but apparently widespread phenomenon is the synergistic function of IRF-3 and RelA dimers. IRF-3 activation through phosphorylation by upstream kinases (Fitzgerald et al, 2003;Sharma et al, 2003) occurs in response to the LPS responsetransducing TLR4, but not in response to many other NF-kB-inducing signaling pathways (Doyle et al, 2002). Not only is IRF-3 required for the induction of a subset of NF-kB-dependent LPS response genes, but the direct interaction between RelA and IRF-3 is required: hormone-bound glucocorticoid receptor was shown to disrupt the interaction, thereby mediating transrepression of a subset of NF-kB target genes (Ogawa et al, 2005).…”

TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway

“…An intense research effort culminated in key reports identifying two kinases responsible for this phosphorylation [34,35]. Both kinases are related to the IKK kinases and are inducible IKK (IKK-i) (also known as IKK3) and TRAF family member-associated NF-kB activator (TANK)-binding kinase 1 (TBK1) [also called NF-kB-activating kinase (NAK) or TRAF-2-associated kinase (T2K)].…”