Regulation of interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88

Details

Serval ID
serval:BIB_8B259CBDE414
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Regulation of interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88
Journal
Current Biology
Author(s)
Janssens  S., Burns  K., Tschopp  J., Beyaert  R.
ISSN
0960-9822 (Print)
Publication state
Published
Issued date
03/2002
Volume
12
Number
6
Pages
467-71
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Mar 19
Abstract
MyD88 is an adaptor protein that is involved in interleukin-1 receptor (IL-1R)- and Toll-like receptor (TLR)-induced activation of NF-kappaB. It is composed of a C-terminal Toll/IL-1R homology (TIR) domain and an N-terminal death domain (DD), which mediate the interaction of MyD88 with the IL-1R/TLR and the IL-1R-associated kinase (IRAK), respectively. The interaction of MyD88 with IRAK triggers IRAK phosphorylation, which is essential for its activation and downstream signaling ability. Both domains of MyD88 are separated by a small intermediate domain (ID) of unknown function. Here, we report the identification of a splice variant of MyD88, termed MyD88(S), which encodes for a protein lacking the ID. MyD88(S) is mainly expressed in the spleen and can be induced in monocytes upon LPS treatment. Although MyD88(S) still binds the IL-1R and IRAK, it is defective in its ability to induce IRAK phosphorylation and NF-kappaB activation. In contrast, MyD88(S) behaves as a dominant-negative inhibitor of IL-1- and LPS-, but not TNF-induced, NF-kappaB activation. These results implicate the ID of MyD88 in the phosphorylation of IRAK. Moreover, the regulated expression and antagonistic activity of MyD88(S) suggest an important role for alternative splicing of MyD88 in the regulation of the cellular response to IL-1 and LPS.
Keywords
Adaptor Proteins, Signal Transducing *Alternative Splicing Animals Antigens, Differentiation/*genetics/metabolism Cells, Cultured Humans Interleukin-1/metabolism/*pharmacology Interleukin-1 Receptor-Associated Kinases Lipopolysaccharides/*pharmacology Mice Mice, Inbred BALB C Myeloid Differentiation Factor 88 NF-kappa B/drug effects/*metabolism Protein Kinases/metabolism Receptors, Immunologic/*genetics/metabolism Receptors, Interleukin-1/metabolism Signal Transduction Tumor Necrosis Factor-alpha/pharmacology
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 15:19
Last modification date
20/08/2019 14:49
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