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.
Zhang
Guolong
G
Section of Immunobiology, Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06520, USA.
Ghosh
Sankar
S
D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007375:Interleukin-1 / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D002352:Carrier Proteins; D029721:Drosophila Proteins; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C410602:TOLLIP protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases