Suzuki, N. et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416, 750-756.This study showed the crucial role of IRAK4 in LPS-induced septic shock and TLR and IL1 signalling
Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns, and members of the pro-inflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains called Toll/IL-1R/plant R gene homology (TIR) domains. Intracellular signalling mechanisms mediated by TIRs are similar, with MyD88 (refs 5-8) and TRAF6 (refs 9, 10) having critical roles. Signal transduction between MyD88 and TRAF6 is known to involve the serine-threonine kinase IL-1 receptor-associated kinase 1 (IRAK-1) and two homologous proteins, IRAK-2 (ref. 12) and IRAK-M. However, the physiological functions of the IRAK molecules remain unclear, and gene-targeting studies have shown that IRAK-1 is only partially required for IL-1R and TLR signalling. Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs. IRAK-4-deficient animals are completely resistant to a lethal dose of lipopolysaccharide (LPS). In addition, animals lacking IRAK-4 are severely impaired in their responses to viral and bacterial challenges. Our results indicate that IRAK-4 has an essential role in innate immunity.
"Interestingly, overexpression of IRAK4 mutants containing truncations within the N-terminal kinase domain can suppress IL1-inducible recruitment of wild-type IRAK4 to the IL1R complex, and prevent association with IRAK1, whereas enabling sequestration of MyD88 (Medvedev et al, 2005). In contrast to IRAK1-deficient mice, IRAK4 À / À animals display a severe impairment in inflammatory cytokine expression and NF-kB activation upon challenge with TLR ligands or IL1, and are completely resistant to LPS-mediated septic shock (Suzuki et al, 2002). Additionally, IL1-induced JNK and p38 activation is completely defective in cells lacking IRAK4. "
[Show abstract][Hide abstract] ABSTRACT: Innate immune signalling has an essential role in inflammation, and the dysregulation of signalling components of this pathway is increasingly being recognised as an important mediator in cancer initiation and progression. In some malignancies, dysregulation of inflammatory toll-like receptor (TLR) and interleukin-1 receptor (IL1R) signalling is typified by increased NF-κB activity, and it occurs through somatic mutations, chromosomal deletions, and/or transcriptional deregulation. Interleukin-1 receptor-associated kinase (IRAK) family members are mediators of TLR/IL1R superfamily signalling, and mounting evidence implicates these kinases as viable cancer targets. Although there have been previous efforts aimed at the development of IRAK kinase inhibitors, this is currently an area of renewed interest for cancer drug development.British Journal of Cancer advance online publication, 7 October 2014; doi:10.1038/bjc.2014.513 www.bjcancer.com.
British Journal of Cancer 10/2014; 112(2). DOI:10.1038/bjc.2014.513 · 4.84 Impact Factor
"Several studies have shown the involvement of IRAK4 in TLR and IL-1R signaling, particularly in Myd88-dependent TLR signaling14. Severe defects have been observed in cytokine responses in mice lacking IRAK4, and impaired responses have been seen in human IRAK4-deficient cells141516. These studies indicate that, despite the absolute involvement of IRAK4 in TLR signaling, inhibition of IRAK4 activation may cause too broad an impact on TLR/IL-1R signaling pathways. "
[Show abstract][Hide abstract] ABSTRACT: Interleukin-1 receptor-associated kinases (IRAKs) are Ser/Thr protein kinases that play an important role as signaling mediators in the signal transduction facilitated by the Toll-like receptor (TLR) and interleukin-1 receptor families. Among IRAK family members, IRAK4 is one of the drug targets for diseases related to the TLR and IL-1R signaling pathways. Experimental evidence suggests that the IRAK4 kinase domain is phosphorylated in its activation loop at T342, T345, and S346 in the fully activated state. However, the molecular interactions of subdomains within the active and inactive IRAK4 kinase domain are poorly understood. Hence, we employed a long-range molecular dynamics (MD) simulation to compare apo IRAK4 kinase domains (phosphorylated and unphosphorylated) and ATP-bound phosphorylated IRAK4 kinase domains. The MD results strongly suggested that lobe uncoupling occurs in apo unphosphorylated IRAK4 kinase via the disruption of the R334/T345 and R310/T345 interaction. In addition, apo unphosphorylated trajectory result in high mobility, particularly in the N lobe, activation segment, helix αG, and its adjoining loops. The Asp-Phe-Gly (DFG) and His-Arg-Asp (HRD) conserved kinase motif analysis showed the importance of these motifs in IRAK4 kinase activation. This study provides important information on the structural dynamics of IRAK4 kinase, which will aid in inhibitor development.
"The mammalian IRAK-4 differs from DmTube by mainly being involved in immune responses to gram-negative bacterial infections (Swantek et al., 2000; Takeda and Akira, 2005). The bacterial defense function of IRAK-4 has been confirmed in IRAK-4 deficient mice, which showed increased mortality upon a bacterial infection (Suzuki et al., 2002). Recently, in the pacific white shrimp, Litopenaeus vannamei, and the mud crab, Scylla paramamosain, both Gene 541 (2014) 41–50 Abbreviations: DD, death domain; dsRNA, double-stranded RNA; GAPDH, glyceralde- hyde-3-phosphate dehydrogenase; GNBPs, gram-negative binding proteins; LPS, lipopolysaccharides; ORF, open reading frame; PAMPs, pathogen-associated molecular patterns; PG, peptidoglycan; PGRPs, peptidoglycan recognition proteins; PPRs, pattern-recognition receptors; RACE, rapid amplification of cDNA ends; TLRs, Toll-like receptors. "
[Show abstract][Hide abstract] ABSTRACT: As a key component of the Toll signaling pathway, Tube plays central roles in many biological activities, such as survival, development and innate immunity. Tube has been found in shrimps, but has not yet been reported in the crustacean, Eriocheir sinensis. In this study, we cloned the full-length cDNA of the adaptor Tube for the first time from E. sinensis and designated the gene as EsTube. The full-length cDNA of EsTube was 2247-bp with a 1539-bp open reading frame (ORF) encoding a 512-amino acid protein. The protein contained a 116-residue death domain (DD) at its N-terminus and a 272-residue serine/threonine-protein kinase domain (S_TKc) at its C-terminus. Phylogenetic analysis clustered EsTube initially in one group with other invertebrate Tube and Tube-like proteins, and then with the vertebrate IRAK-4 proteins, finally with other invertebrate Pelle proteins. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis results showed that EsTube was highly expressed in the ovary and testis, and moderately expressed in the thoracic ganglia and stomach. EsTube was expressed at all selected stages and was highly expressed in the spermatid stage (October, testis) and the stage III-2 (November, ovary). EsTube was differentially induced after injection of lipopolysaccharides (LPS), peptidoglycan (PG) or zymosan (β-1,3-glucan). Our study indicated that EsTube might possess multiple functions in immunity and development in E. sinensis.
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