Function, mechanism, signalling pathway
Members of interleukin-1 receptor (Il-1R) and the Toll-like receptor superfamily share an intracytoplasmic Toll-IL-1 receptor (TIR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. The TIR-IRAK signaling pathway appears to be crucial for protective immunity against specific bacteria but is redundant against most other microorganisms. IRAK4 is considered the “master IRAK” in the mammalian IRAK family because it is the only component in the IL-1/TLR signalling pathway that is absolutely crucial to its functioning. When one of these pathways is stimulated, the cell is triggered to release proinflammatory signals and to trigger innate immune actions. The loss of IRAK4, or its intrinsic kinase activity, can entirely stop signalling through these pathways.IRAK4 is involved in signal transduction pathways stimulated by the cellular receptors belonging to the Toll/Interleukin-1 receptor superfamily. The Toll-Like Receptors (TLRs) are stimulated by recognition of pathogen-associated molecular patterns (PAMPS), whereas members of the IL-1R family are stimulated by cytokines. Both play an essential role in the immune response. The ligand binding causes conformational changes to the intracellular domain which allows for the recruitment of scaffolding proteins. One of these proteins, MyD88, uses its death domains to recruit, orient, and activate IRAK4. IRAK2 can then be phosphorylated and joins with IRAK4 and MyD88 to form the myddosome complex, which further phosphorylates and recruits IRAK1. The myddosome complex and IRAK1 recruit and activate TNF receptor-associated factor 6 (TRAF6), a ubiquitin protein ligase.
IRAK-4 (interleukin-1 receptor-associated kinase 4), in the IRAK family, is a protein kinase involved in signaling innate immune responses from Toll-like receptors. It also supports signaling from T-cell receptors. IRAK4 contains domain structures which are similar to those of IRAK1, IRAK2, IRAKM and Pelle. IRAK4 is unique compared to IRAK1, IRAK2 and IRAKM in that it functions upstream of the other IRAKs, but is more similar to Pelle in this trait. IRAK4 has important clinical applications. Animals without IRAK-4 are more susceptible to viruses and bacteria but completely resistant to LPS challenge. History
The first IL-1 receptor-associated kinase (IRAK) was observed in 1994 through experiments with murine T helper cell lines D10N and EL-4. Two years later the first experimental member of this family of kinases, IRAK1, was cloned. In 2002, through database searches at the National Center for Biotechnology Information in an attempt to recognize novel members of the IRAK family, a human cDNA sequence which encoded a peptide sharing significant homology with IRAK1 was identified. This cDNA sequence was found to have five amino acid substitutions compared to IRAK1 and was termed IRAK4.IRAK4 was proposed to be the mammalian homolog of the Pelle gene found in Drosophila melanogaster and was proposed to require its kinase activity in order for it to function in activating NF-κB. It was also proposed by Li et al. that it might function upstream of other IRAKs and possibly cause a cascade of phosphorylation events through its function as an IRAK1 kinase.