Insights from vaccinia virus into Toll-like receptor signalling proteins and their regulation by ubiquitin: role of IRAK-2.

TLRs (Toll-like receptors) are an important class of pathogen-sensing proteins, which signal the presence of a pathogen by activating transcription factors, such as NF-kappaB (nuclear factor kappaB). The TLR pathway to NF-kappaB activation involves multiple phosphorylation and ubiquitination events. Notably, TRAF-6 [TNF (tumour necrosis factor)-receptor-associated factor-6] Lys(63) polyubiquitination is a critical step in the formation of signalling complexes, which turn on NF-kappaB. Here, the relative role of different IRAKs [IL-1 (interleukin 1)-receptor-associated kinases] in NF-kappaB activation is discussed. Further, I demonstrate how understanding one molecular mechanism whereby vaccinia virus inhibits NF-kappaB activation has led to a revealing of a key role for IRAK-2 in TRAF-6-mediated NF-kappaB activation.