Negative regulation of toll-like receptor-mediated signaling by Tollip.

Toll-like receptor (TLR)-mediated recognition of pathogens represents one of the most important mechanisms of innate immunity and disease resistance. The adaptor protein Tollip was identified initially as an intermediate in interleukin (IL)-1 signaling. Here we report that Tollip also associates directly with TLR2 and TLR4 and plays an inhibitory role ...
in TLR-mediated cell activation. Inhibition by Tollip is mediated through its ability to potently suppress the activity of IL-1 receptor-associated kinase (IRAK) after TLR activation. In addition, we show for the first time that Tollip is a bona fide substrate for IRAK and is phosphorylated by IRAK upon stimulation with lipopolysaccharide or IL-1. Negative regulation of TLR signaling by Tollip may therefore serve to limit the production of proinflammatory mediators during inflammation and infection.
Mesh Terms:
Carrier Proteins, Cell Line, Dose-Response Relationship, Drug, Drosophila Proteins, Escherichia coli, Humans, Immunoblotting, Interleukin-1, Interleukin-1 Receptor-Associated Kinases, Intracellular Signaling Peptides and Proteins, Lipopolysaccharides, Membrane Glycoproteins, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Protein Kinases, Protein Structure, Tertiary, Receptors, Cell Surface, Signal Transduction, Time Factors, Toll-Like Receptor 2, Toll-Like Receptor 4, Toll-Like Receptors
J. Biol. Chem.
Date: Mar. 01, 2002
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