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

K Burns, S Janssens, B Brissoni, N Olivos… - The Journal of …, 2003 - rupress.org
K Burns, S Janssens, B Brissoni, N Olivos, R Beyaert, J Tschopp
The Journal of experimental medicine, 2003rupress.org
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 …
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)-κB. 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-κB 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-κB 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.
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