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.
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)-kappaB. 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-kappaB 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-kappaB 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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Alternative Splicing, Animals, Antigens, Differentiation, Cells, Cultured, Drosophila Proteins, Interleukin-1 Receptor-Associated Kinases, Membrane Glycoproteins, Mice, Models, Biological, Myeloid Differentiation Factor 88, NF-kappa B, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Structure, Tertiary, Receptors, Cell Surface, Receptors, Immunologic, Receptors, Interleukin-1, Recombinant Proteins, Signal Transduction, Toll-Like Receptors
Adaptor Proteins, Signal Transducing, Alternative Splicing, Animals, Antigens, Differentiation, Cells, Cultured, Drosophila Proteins, Interleukin-1 Receptor-Associated Kinases, Membrane Glycoproteins, Mice, Models, Biological, Myeloid Differentiation Factor 88, NF-kappa B, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Structure, Tertiary, Receptors, Cell Surface, Receptors, Immunologic, Receptors, Interleukin-1, Recombinant Proteins, Signal Transduction, Toll-Like Receptors
J. Exp. Med.
Date: Jan. 20, 2003
PubMed ID: 12538665
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