Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor.
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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Antigens, Differentiation, Carrier Proteins, Cell Line, Conserved Sequence, Enzyme Activation, Humans, Interleukin-1, Interleukin-1 Receptor-Associated Kinases, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, Kinetics, Mitogen-Activated Protein Kinases, Models, Biological, Molecular Sequence Data, Mutation, Myeloid Differentiation Factor 88, NF-kappa B, Phosphoprotein Phosphatases, Phosphorylation, Precipitin Tests, Protein Binding, Protein Kinases, RNA, Messenger, Receptors, Immunologic, Receptors, Interleukin-1, Sequence Alignment, Signal Transduction, Two-Hybrid System Techniques
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Antigens, Differentiation, Carrier Proteins, Cell Line, Conserved Sequence, Enzyme Activation, Humans, Interleukin-1, Interleukin-1 Receptor-Associated Kinases, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, Kinetics, Mitogen-Activated Protein Kinases, Models, Biological, Molecular Sequence Data, Mutation, Myeloid Differentiation Factor 88, NF-kappa B, Phosphoprotein Phosphatases, Phosphorylation, Precipitin Tests, Protein Binding, Protein Kinases, RNA, Messenger, Receptors, Immunologic, Receptors, Interleukin-1, Sequence Alignment, Signal Transduction, Two-Hybrid System Techniques
Nat. Cell Biol.
Date: Jun. 01, 2000
PubMed ID: 10854325
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