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

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Serval ID
serval:BIB_188BA5D2FA2D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
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
Journal
Journal of Experimental Medicine
Author(s)
Burns  K., Janssens  S., Brissoni  B., Olivos  N., Beyaert  R., Tschopp  J.
ISSN
0022-1007 (Print)
Publication state
Published
Issued date
01/2003
Volume
197
Number
2
Pages
263-8
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jan 20
Abstract
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.
Keywords
Adaptor Proteins, Signal Transducing Alternative Splicing Animals Antigens, Differentiation/chemistry/genetics/*metabolism Cells, Cultured *Drosophila Proteins Interleukin-1 Receptor-Associated Kinases Membrane Glycoproteins/chemistry/*metabolism Mice Models, Biological Myeloid Differentiation Factor 88 NF-kappa B/metabolism Phosphorylation Phosphotransferases (Alcohol Group Acceptor)/*metabolism Protein Structure, Tertiary Receptors, Cell Surface/chemistry/*metabolism Receptors, Immunologic/chemistry/genetics/*metabolism Receptors, Interleukin-1/chemistry/*metabolism Recombinant Proteins/chemistry/genetics/metabolism Signal Transduction Toll-Like Receptors
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 15:18
Last modification date
20/08/2019 12:49
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