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
More filters
Journal ArticleDOI
Toll-Like Receptors Are Part of the Innate Immune Defense System of Sponges (Demospongiae: Porifera)
Matthias Wiens,Michael Korzhev,Sanja Perović-Ottstadt,Bérengère J.C. Luthringer,David Brandt,Stefanie Klein,Werner E.G. Müller +6 more
TL;DR: The identification, cloning, and deduced protein sequence from 3 major elements of the poriferan innate response (to bacterial lipopeptides): the TLR, the IL-1 receptor-associated kinase-4-like protein (IRAK-4l), and a novel effector caspase from the demosponge Suberites domuncula show significant sequence similarity with its homologues in higher Metazoa.
Journal ArticleDOI
Variant IRAK-1 Haplotype Is Associated with Increased Nuclear Factor–κB Activation and Worse Outcomes in Sepsis
John Arcaroli,Eliezer Silva,James P. Maloney,Qianbin He,Daiva Svetkauskaite,James Murphy,Edward Abraham +6 more
TL;DR: It is indicated that the IRAK-1 variant haplotype is functionally significant in patients with sepsis, being associated with increased nuclear translocation of NF-kappaB, more severe organ dysfunction, and higher mortality.
Journal ArticleDOI
IRAK-4 inhibitors for inflammation.
TL;DR: The biological function of IRAK-4, the structural characteristics of the Kinase domain, and the development of small molecule inhibitors targeting the kinase activity are reviewed, as well as important features for optimal protein/inhibitor interactions are reviewed.
Journal ArticleDOI
Chemical proteomic map of dimethyl fumarate–sensitive cysteines in primary human T cells
Megan M. Blewett,Ji-Ji Xie,Balyn W. Zaro,Keriann M. Backus,Amnon Altman,John R. Teijaro,Benjamin F. Cravatt +6 more
TL;DR: Cysteines sensitive to DMF, but not MMF, were identified in several proteins with established biochemical or genetic links to T cell function, including protein kinase Cθ (PKCθ), which prevented PKCθ from interacting with the T cell costimulatory receptor CD28 and mediating full T cell activation.
Journal ArticleDOI
Crystal structures of IRAK-4 kinase in complex with inhibitors: a serine/threonine kinase with tyrosine as a gatekeeper.
Zhulun Wang,Jinsong Liu,Athena Sudom,Merrill Ayres,Shyun Li,Holger Wesche,Jay P. Powers,Nigel Walker +7 more
TL;DR: The structures reveal that IRAK-4 has a unique tyrosine gatekeeper residue that interacts with the conserved glutamate from helix alphaC that is "pulled in" to maintain the active orientation and the usual pre-existing hydrophobic back pocket of the ATP-binding site is abolished.
References
More filters
Journal ArticleDOI
Biologic basis for interleukin-1 in disease
TL;DR: This is a lengthy review, with 586 citations chosen to illustrate specific areas of interest rather than a compendium of references, which summarizes what the author considers established or controversial topics linking the biology of IL-1 to mechanisms of disease.
Journal ArticleDOI
TRAF6 is a signal transducer for interleukin-1
TL;DR: The identification of a new TRAF family member is reported, designated TRAF6, which indicates that TRAF proteins may function as signal transducers for distinct receptor families and that TRAf6 participates in IL-1 signalling.
Journal ArticleDOI
MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1.
TL;DR: The findings indicate that NIK participates in an NF-KB-inducing signalling cascade common to receptors of the TNF/NGF family and to the interleukin-1 type-I receptor.
Journal ArticleDOI
Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction
Katherine A. Fitzgerald,Eva M. Palsson-McDermott,Andrew G. Bowie,Andrew G. Bowie,Caroline A. Jefferies,Ashley Mansell,Gerard Brady,Elizabeth Brint,Aisling Dunne,Pearl Gray,Mary T. Harte,Diane McMurray,Dirk E. Smith,John E. Sims,T. A. Bird,Luke A. J. O'Neill +15 more
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.
Journal ArticleDOI
IκB Kinase-β: NF-κB Activation and Complex Formation with IκB Kinase-α and NIK
TL;DR: Overexpression of a catalytically inactive form of IKK-β blocked cytokine-induced NF-κB activation and suggested that an active IκB kinase complex may require three distinct protein kinases.