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Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor

Nature Cell Biology volume 2, pages 346–351 (2000)Cite this article

Abstract

Interleukin-1 (IL-1) is a proinflammatory cytokine that elicits its pleiotropic effects through activation of the transcription factors NF-κB 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-1β 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-κB activation, we conclude that Tollip is an important constituent of the IL-1R signalling pathway.

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Figure 1: Characterization of Tollip cDNA, mRNA and protein.
Figure 2: Tollip is transiently recruited to the activated IL-1R complex with similar kinetics to those of IRAK.
Figure 3: IRAK and Tollip are preassociated before IL-1 stimulation.
Figure 4: Tollip is sufficient for recruitment of IRAK to IL-1Rs.
Figure 5: Tollip impairs IL-1β-induced activation of NF-κB and JNK.
Figure 6: Model for the function of Tollip in transduction of IL-1signals.

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Acknowledgements

We thank R. MacDonald for EL-4 6.10 cells, M. Muzio for Myc-tagged IRAK-2, J. White for pYTH9, T. Roger for Flag-tagged mTLR2 and mTLR4, H. Kojima for IL-18R, E. Qwarnstrom, C. J. Caunt and O. Micheau for localization studies with Tollip and P. Schneider and R. Budd for critical reading of the manuscript. We also thank R. Brown, S. Farrow, S. Lens, N. Holler and M. Kovacsovics for discussions and for support for this project.

Correspondence and requests for materials should be addressed to J.T. The amino-acid sequences of mouse and human Tollip have been deposited at GenBank under accession numbers AJ242971 and AJ242972, respectively. The amino-acid sequence of human Tollip is a conceptual translation assembled using expressed-sequence tag (EST) accession numbers AA773650, T19084, AA452030, AI126693, AA984561, R22358, AA430274, AA190644, R14385, AI078838, AI391687, D62608, AA49595, AI202790, AA443337, AA188666, AA533680, AL041203, AI434615 and R21855. The amino-acid sequence of C.elegans Tollip is derived from accession number Z79754 using genewise (http://www.sanger.ac.uk/Software/Wise2/Programming).

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  1. Jürg Tschopp and Filippo Volpe: These authors contributed equally to this work

Authors and Affiliations

  1. Institute of Biochemistry, University of Lausanne, BIL Biomedical Research centre, Chemin des Boveresses 155, CH-1066, Epalinges, Switzerland

    Kimberly Burns, Laurence Martin, Fabio Martinon & Jürg Tschopp

  2. Glaxo Wellcome, Gunnels Wood Road, Stevenage, SG1 2NY, UK

    Jonathan Clatworthy, Chris Plumpton, Barbara Maschera, Alan Lewis, Keith Ray & Filippo Volpe

  3. Cell Biology, Gunnels Wood Road, Stevenage, SG1 2NY, UK

    Jonathan Clatworthy, Barbara Maschera & Filippo Volpe

  4. Molecular Pharmacology, Gunnels Wood Road, Stevenage, SG1 2NY, UK

    Chris Plumpton, Alan Lewis, Keith Ray & Filippo Volpe

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  1. Kimberly Burns
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Correspondence to Jürg Tschopp.

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Burns, K., Clatworthy, J., Martin, L. et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nat Cell Biol 2, 346–351 (2000). https://doi.org/10.1038/35014038

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