Interleukin-1 receptor-associated kinases (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, nuclear factor-kappaB (NF-kB), and mitogen-activated protein kinases (MAPKs). IRAKs contain an N-terminal death domain (DD) and a C-terminal kinase domain [, , , ].IRAK1 is an active kinase and also plays adaptor functions. It binds to the MyD88-IRAK4 complex via its DD, which facilitates its phosphorylation by IRAK4, activating it for further auto-phosphorylation []. Hyper-phosphorylated IRAK1 forms a cytosolic complex with TRAF6, leading to the activation of NF-kB and MAPK pathways. IRAK1 is involved in autoimmunity and may be associated with lupus pathogenesis [].
This entry represents Interleukin-1 receptor-associated kinase 4 (IRAK4) (). IRAK4 is required for the efficient recruitment of IRAK1 to the interleukin-1 (IL-1) receptor complex following IL-1 engagement, triggering intracellular signalling cascades leading to transcriptional up-regulation and mRNA stabilisation [, ]. IRAK4 phosphorylates IRAK1. Pellino-2 may be a substrate for both IRAK1 and IRAK4 []. Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) []. Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Defects in IRAK4 are also the cause of IRAK4 deficiency []. IRAK4 deficiency causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children.
IRAK4 is a serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens []. It is required for the efficient recruitment of IRAK1 to the interleukin-1 (IL-1) receptor complex following IL-1 engagement, triggering intracellular signalling cascades leading to transcriptional up-regulation and mRNA stabilisation [, ]. IRAK4 phosphorylates IRAK1. Pellino-2 may be a substrate for both IRAK1 and IRAK4 [].This entry represents the Death domain of IRAK4.DDs (Death domains) 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 signaling pathways and can recruit other proteins into signaling complexes [, ].
TRAF-interacting protein with a forkhead-associated domain (TIFA), also called T2BP, is an adapter protein which mediates the IRAK1 and TRAF6 interaction following IL-1 stimulation, resulting in the downstream activation of NF-kappa-B and c-Jun amino-terminal kinase (JNK) []. TIFA has been shown to induce the oligomerization and polyubiquitination of TRAF6, which in turn activates transforming growth factor-activated kinase (TAK1) and IkappaB kinase (IKK) []. TIFA contains a phosphothreonine and phosphoserine-binding FHA domain []and a consensus TRAF6-binding motif [].
This entry represents the death domain found in interleukin-1 receptor-associated kinase-like 2 (IRAK2) []. IRAK2 is an essential component of several signaling pathways, including NF-kappaB and the IL-1 signaling pathways. It is an inactive kinase that participates in septic shock mediated by TLR4 and TLR9 []. It plays a redundant role with IRAK1 in early NF-kB and MAPK responses, and remains present at later stages whereas IRAK1 disappears [, ].Interleukin-1 receptor-associated kinases (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, nuclear factor-kappaB (NF-kB), and mitogen-activated protein kinases (MAPKs). IRAKs contain an N-terminal death domain (DD) and a C-terminal kinase domain [, , , ].Death domains (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 signaling pathways and can recruit other proteins into signaling complexes [].
Interleukin-1 receptor-associated kinases (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, nuclear factor-kappaB (NF-kB), and mitogen-activated protein kinases (MAPKs). IRAKs contain an N-terminal death domain (DD) and a C-terminal kinase domain [, , , ].IRAK1 is an active kinase and also plays adaptor functions. It binds to the MyD88-IRAK4 complex via its DD, which facilitates its phosphorylation by IRAK4, activating it for further auto-phosphorylation []. Hyper-phosphorylated IRAK1 forms a cytosolic complex with TRAF6, leading to the activation of NF-kB and MAPK pathways. IRAK1 is involved in autoimmunity and may be associated with lupus pathogenesis [].Death domains (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 signaling pathways and can recruit other proteins into signaling complexes [].
