IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase
TLDR
IRAK-4 is the closest human homolog to Pelle and depends on its kinase activity to activate NF-κB, suggesting a role of IRAK- 4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAk-1.Abstract:
Toll/IL-1 receptor family members are central components of host defense mechanisms in a variety of species. One well conserved element in their signal transduction is Ser/Thr kinases, which couple early signaling events in a receptor complex at the plasma membrane to larger signalosomes in the cytosol. The fruit fly Drosophila melanogaster has one member of this family of kinases, termed Pelle. The complexity of this pathway is vastly increased in vertebrates, and several Pelle homologs have been described and termed IL-1 receptor-associated kinase (IRAK). Here we report the identification of a novel and distinct member of the IRAK family, IRAK-4. IRAK-4 is the closest human homolog to Pelle. Endogenous IRAK-4 interacts with IRAK-1 and TRAF6 in an IL-1-dependent manner, and overexpression of IRAK-4 can activate NF-κB as well as mitogen-activated protein (MAP) kinase pathways. Most strikingly, and in contrast to the other IRAKs, IRAK-4 depends on its kinase activity to activate NF-κB. In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1.read more
Citations
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Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways.
Alla Zamyatina,Holger Heine +1 more
TL;DR: The LPS-induced TLR4 and caspase-4/11 mediated signaling pathways and their cross-talk are described and specific structural features of the lipid A motif of diverse LPS variants that have been reported to activate caspases or to induced activation of NLRP3 inflammasome are scrutinized.
Journal ArticleDOI
Identification of Critical Residues of the MyD88 Death Domain Involved in the Recruitment of Downstream Kinases
Maria Loiarro,Grazia Gallo,Nicola Fanto,Rita De Santis,Paolo Carminati,Vito Ruggiero,Claudio Sette +6 more
TL;DR: Novel residues of MyD88 are identified that are crucially involved in the recruitment of IRAK1 and IRAK4 and in downstream propagation of Myd88 signaling.
Journal ArticleDOI
The involvement of the interleukin-1 receptor-associated kinases (IRAKs) in cellular signaling networks controlling inflammation.
Lorna Ringwood,Liwu Li +1 more
TL;DR: This review intends to summarize the recent advances regarding the regulations of various IRAK proteins and their cellular functions in mediating inflammatory signaling processes and identify genetic variations in human IRAK genes found to be linked with various human inflammatory diseases.
Journal ArticleDOI
Mal and MyD88: adapter proteins involved in signal transduction by Toll-like receptors.
Luke A. J. O'Neill,Aisling Dunne,Michael Edjeback,Pearl Gray,Caroline A. Jefferies,Claudia Wietek +5 more
TL;DR: Differences between signals generated by TLRs are emerging, with both TLR4 and TLR2 signalling requiring an additional adapter termed MyD88-adapter-like (Mal; also known as TIRAP), which may ultimately provide molecular explanations for specificities in the innate immune response to infection.
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R753Q polymorphism inhibits Toll-like receptor (TLR) 2 tyrosine phosphorylation, dimerization with TLR6, and recruitment of myeloid differentiation primary response protein 88.
TL;DR: The R753Q polymorphism renders TLR2 signaling-incompetent by impairing its tyrosine phosphorylation, dimerization with TLR6, and recruitment of Mal and MyD88, and facilitates design of new therapeutic strategies.
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TL;DR: A protein is described, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome, which is therefore an adapter in TLR-4 signal transduction.
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