Article: article from journal or magazin.
Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor.
Nature Cell Biology
Interleukin-1 (IL-1) is a proinflammatory cytokine that elicits its pleiotropic effects through activation of the transcription factors NF-kappaB and AP-1. Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1beta treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip-IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs). As overexpression of Tollip results in impaired NF-kappaB activation, we conclude that Tollip is an important constituent of the IL-1R signalling pathway.
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Antigens, Differentiation/chemistry, Antigens, Differentiation/genetics, Carrier Proteins/chemistry, Carrier Proteins/genetics, Cell Line, Conserved Sequence/genetics, Enzyme Activation/drug effects, Humans, Interleukin-1/pharmacology, Interleukin-1 Receptor-Associated Kinases, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, Kinetics, Mitogen-Activated Protein Kinases/metabolism, Models, Biological, Molecular Sequence Data, Mutation/genetics, Myeloid Differentiation Factor 88, NF-kappa B/metabolism, Phosphoprotein Phosphatases/metabolism, Phosphorylation/drug effects, Precipitin Tests, Protein Binding/drug effects, Protein Kinases/genetics, Protein Kinases/metabolism, RNA, Messenger/analysis, RNA, Messenger/genetics, Receptors, Immunologic, Receptors, Interleukin-1/genetics, Receptors, Interleukin-1/metabolism, Sequence Alignment, Signal Transduction/drug effects, Two-Hybrid System Techniques
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