Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor (original) (raw)
- Article
- Published: 10 May 2000
- Jonathan Clatworthy2,3,
- Laurence Martin1,
- Fabio Martinon1,
- Chris Plumpton2,4,
- Barbara Maschera2,3,
- Alan Lewis2,4,
- Keith Ray2,4,
- Jürg Tschopp1 na1 &
- …
- Filippo Volpe2,3,4 na1
Nature Cell Biology volume 2, pages 346–351 (2000)Cite this article
- 2757 Accesses
- 440 Citations
- 12 Altmetric
- Metrics details
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
- Hoffmann, J. A., Kafatos, F. C., Janeway, C. A. & Ezekowitz, R. A. Phylogenetic perspectives in innate immunity. Science 284, 1313–1318 (1999).
Article CAS Google Scholar - Wilson, I., Vogel, J. & Somerville, S. Signalling pathways: a common theme in plants and animals? Curr. Biol. 7, R175–R178 (1997).
Article CAS Google Scholar - Wesche, H., Henzel, W. J., Shillinglaw, W., Li, S. & Cao, Z. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7, 837–847 (1997).
Article CAS Google Scholar - Burns, K. et al. MyD88, an adapter protein involved in interleukin-1 signaling. J. Biol. Chem. 273, 12203–12209 (1998).
Article CAS Google Scholar - Muzio, M., Ni, J., Feng, P. & Dixit, V. M. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278, 1612–1615 (1997).
Article CAS Google Scholar - Wesche, H. et al. The interleukin-1 receptor accessory protein (IL-1RAcP) is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP kinases). J. Biol. Chem. 272, 7727–7731 (1997).
Article CAS Google Scholar - Cao, Z., Henzel, W. J. & Gao, X. IRAK: a kinase associated with the interleukin-1 receptor. Science 271, 1128–1131 (1996).
Article CAS Google Scholar - Wesche, H. et al. IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. J. Biol. Chem. 274, 19403–19410 (1999).
Article CAS Google Scholar - Yamin, T. T. & Miller, D. K. The interleukin-1 receptor-associated kinase is degraded by proteasomes following its phosphorylation. J. Biol. Chem. 272, 21540–21547 (1997).
Article CAS Google Scholar - Cao, Z., Xiong, J., Takeuchi, M., Kurama, T. & Goeddel, D. V. TRAF6 is a signal transducer for interleukin-1. Nature 383, 443–446 (1996).
Article CAS Google Scholar - Song, H. Y., Regnier, C. H., Kirschning, C. J., Goeddel, D. V. & Rothe, M. Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-kappaB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2. Proc. Natl Acad. Sci. USA 94, 9792–9796 (1997).
Article CAS Google Scholar - Baud, V. et al. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev. 13, 1297–1308 (1999).
Article CAS Google Scholar - Nalefski, E. A. & Falke, J. J. The C2 domain calcium-binding motif: structural and functional diversity. Protein Sci. 5, 2375–2390 (1996).
Article CAS Google Scholar - Huang, J., Gao, X., Li, S. & Cao, Z. Recruitment of IRAK to the interleukin-1 receptor complex requires interleukin-1 receptor accessory protein. Proc. Natl Acad. Sci. USA 94, 12829–12832 (1997).
Article CAS Google Scholar - Volpe, F. et al. The IL-1 receptor accessory protein is responsible for the recruitment of the interleukin-1 receptor associated kinase to the IL-1/IL-1 receptor I complex. FEBS Lett. 419, 41–44 (1997).
Article CAS Google Scholar - Maschera, B., Ray, K., Burns, K. & Volpe, F. Overexpression of an enzymically inactive interleukin-1-receptor-associated kinase activates nuclear factor-kappaB. Biochem. J. 339, 227–231 (1999).
Article CAS Google Scholar - Li, X. et al. Mutant cells that do not respond to interleukin-1 (IL-1) reveal a novel role for IL-1 receptor-associated kinase. Mol Cell Biol 19, 4643–4652 (1999).
Article CAS Google Scholar - Shen, B. & Manley, J. L. Phosphorylation modulates direct interactions between the Toll receptor, Pelle kinase and Tube. Development 125, 4719–4728 (1998).
CAS PubMed Google Scholar - Kojima, H. et al. Interleukin-18 activates the IRAK–TRAF6 pathway in mouse EL-4 cells. Biochem. Biophys. Res. Commun. 244, 183–186 (1998).
Article CAS Google Scholar
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).
Author information
Author notes
- Jürg Tschopp and Filippo Volpe: These authors contributed equally to this work
Authors and Affiliations
- 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 - Glaxo Wellcome, Gunnels Wood Road, Stevenage, SG1 2NY, UK
Jonathan Clatworthy, Chris Plumpton, Barbara Maschera, Alan Lewis, Keith Ray & Filippo Volpe - Cell Biology, Gunnels Wood Road, Stevenage, SG1 2NY, UK
Jonathan Clatworthy, Barbara Maschera & Filippo Volpe - Molecular Pharmacology, Gunnels Wood Road, Stevenage, SG1 2NY, UK
Chris Plumpton, Alan Lewis, Keith Ray & Filippo Volpe
Authors
- Kimberly Burns
You can also search for this author inPubMed Google Scholar - Jonathan Clatworthy
You can also search for this author inPubMed Google Scholar - Laurence Martin
You can also search for this author inPubMed Google Scholar - Fabio Martinon
You can also search for this author inPubMed Google Scholar - Chris Plumpton
You can also search for this author inPubMed Google Scholar - Barbara Maschera
You can also search for this author inPubMed Google Scholar - Alan Lewis
You can also search for this author inPubMed Google Scholar - Keith Ray
You can also search for this author inPubMed Google Scholar - Jürg Tschopp
You can also search for this author inPubMed Google Scholar - Filippo Volpe
You can also search for this author inPubMed Google Scholar
Corresponding author
Correspondence toJürg Tschopp.
Rights and permissions
About this article
Cite this article
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
- Received: 10 February 2000
- Revised: 08 March 2000
- Accepted: 07 April 2000
- Published: 10 May 2000
- Issue Date: June 2000
- DOI: https://doi.org/10.1038/35014038