Interleukin-1 receptor-associated kinase 3 (IRAK3/IRAK-M) is a negative regulator of MyD88-dependent Toll-like receptor (TLR) signalling []. It is expressed in monocytes/macrophages and lung epithelial cells. Structurally, IRAK3 consists of a kinase domain (KD) flanked by an N-terminal death domain (DD) involved in binding to other IRAK family members and an unstructured C-terminal domain. The kinase domain lacks the critical active site aspartate residue and IRAK-M appears devoid of kinase activity [, ]. IRAK-M may inhibit inflammation through several mechanisms, including stabilization of MKP-1 []and down-regulation of the non-canonical NFkB pathway []. It can also induce NFkB activation to produce inhibitory molecules as a negative feedback for the pathway [].
This entry represents the death Domain (DD) of IRAK3 (also known as IRAK-M). IRAKs are essential components of innate immunity and inflammation in mammals and other vertebrates [, ]. They are involved in signal transduction pathways involving IL-1 and IL-18 receptors, Toll-like receptors(TLRs), nuclear factor-kappaB (NF-kB), and mitogen-activated protein kinases (MAPKs) [, ]. IRAKs contain an N-terminal DD domain and a C-terminal kinase domain. IRAK3 is an inactive kinase present only in macrophages in an inducible manner []. It is a negative regulator of TLR signalling and it contributes to the attenuation of NF-kB activation [].DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signalling pathways and can recruit other proteins into signalling complexes [, , ].
This pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. IRAKs (IL-1R-associated kinases) are involved in Toll-like receptor (TLR) and interleukin-1 (IL-1) signalling pathways, and are thus critical in regulating innate immune responses and inflammation []. IRAKs contain an N-terminal Death domain (DD), a proST region (rich in serines, prolines, and threonines), a central kinase domain (a pseudokinase in the case of IRAK3), and a C-terminal domain; IRAK-4 lacks the C-terminal domain. Vertebrates contain four IRAKs (IRAK-1, -2, -3 (or -M), and -4) that display distinct functions and patterns of expression and subcellular distribution, and can differentially mediate TLR signalling [, ].IRAK3 (or IRAK-M) is the only IRAK that does not show kinase activity. It is found only in monocytes and macrophages in humans, and functions as a negative regulator of TLR signalling including TLR-2 induced p38 activation[]. It also negatively regulates the alternative NFkB pathway in a TLR-2 specific manner []. IRAK3 is downregulated in the monocytes of obese people, and is associated with high SOD2, a marker of mitochondrial oxidative stress. It is an important inhibitor of inflammation in association with obesity and metabolic syndrome []. The IRAK3 subfamily is part of a larger superfamily that includes the catalytic domains of other protein serine/threonine kinases, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase. This entry represents the pseudokinase domain found in IRAK3.
