The Journal of Experimental Medicine
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Published online 13 January 2003 doi:10.1084/jem.20021790
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© Rockefeller University Press, 0022-1007/2003/1/263 $5.00
The Journal of Experimental Medicine, Volume 197, Number 2, 263-268

Brief Definitive Report

 Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4

Kimberly Burns1, Sophie Janssens2, Brian Brissoni1, Natalia Olivos1, Rudi Beyaert2 and Jürg Tschopp1

1 Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, CH-1066 Epalinges, Switzerland
2 Department of Molecular Biology, Unit of Molecular Signal Transduction in Inflammation, Gent University, B-9000 Gent, Belgium

Address correspondence to Jürg Tschopp, Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland. Phone: 41-21-6925743; Fax: 41-21-6925605; E-mail: jurg.tschopp{at}ib.unil.ch

Toll-like receptors (TLRs) and members of the proinflammatory interleukin 1 receptor (IL-1R) family are dependent on the presence of MyD88 for efficient signal transduction. The bipartite nature of MyD88 (N-terminal death domain [DD] and COOH-terminal Toll/IL-1 receptor [TIR] domain) allows it to link the TIR domain of IL-1R/TLR with the DD of the Ser/Thr kinase termed IL-1R–associated kinase (IRAK)-1. This triggers IRAK-1 phosphorylation and in turn the activation of multiple signaling cascades such as activation of the transcription factor nuclear factor (NF)-{kappa}B. In contrast, expression of MyD88 short (MyD88s), an alternatively spliced form of MyD88 that lacks only the short intermediate domain separating the DD and TIR domains, leads to a shutdown of IL-1/lipopolysaccharide-induced NF-{kappa}B activation. Here, we provide the molecular explanation for this difference. MyD88 but not MyD88s strongly interacts with IRAK-4, a newly identified kinase essential for IL-1R/TLR signaling. In the presence of MyD88s, IRAK-1 is not phosphorylated and neither activates NF-{kappa}B nor is ubiquitinated. Thus, MyD88s acts as a negative regulator of IL-1R/TLR/MyD88-triggered signals, leading to a transcriptionally controlled negative regulation of innate immune responses.

Key Words: MyD88 • IL-1R • TLR • NF-{kappa}B • IRAK


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