Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4

Masahiro Yamamoto; Shintaro Sato; Hiroaki Hemmi; Hideki Sanjo; Satoshi Uematsu; Tsuneyasu Kaisho; Katsuaki Hoshino; Osamu Takeuchi; Masaya Kobayashi; Takashi Fujita; Kiyoshi Takeda; Shizuo Akira

doi:10.1038/nature01182

Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4

Nature. 2002 Nov 21;420(6913):324-9. doi: 10.1038/nature01182.

Authors

Masahiro Yamamoto¹, Shintaro Sato, Hiroaki Hemmi, Hideki Sanjo, Satoshi Uematsu, Tsuneyasu Kaisho, Katsuaki Hoshino, Osamu Takeuchi, Masaya Kobayashi, Takashi Fujita, Kiyoshi Takeda, Shizuo Akira

Affiliation

¹ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.

PMID: 12447441
DOI: 10.1038/nature01182

Abstract

Signal transduction through Toll-like receptors (TLRs) originates from their intracellular Toll/interleukin-1 receptor (TIR) domain, which binds to MyD88, a common adaptor protein containing a TIR domain. Although cytokine production is completely abolished in MyD88-deficient mice, some responses to lipopolysaccharide (LPS), including the induction of interferon-inducible genes and the maturation of dendritic cells, are still observed. Another adaptor, TIRAP (also known as Mal), has been cloned as a molecule that specifically associates with TLR4 and thus may be responsible for the MyD88-independent response. Here we report that LPS-induced splenocyte proliferation and cytokine production are abolished in mice lacking TIRAP. As in MyD88-deficient mice, LPS activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases is induced with delayed kinetics in TIRAP-deficient mice. Expression of interferon-inducible genes and the maturation of dendritic cells is observed in these mice; they also show defective response to TLR2 ligands, but not to stimuli that activate TLR3, TLR7 or TLR9. In contrast to previous suggestions, our results show that TIRAP is not specific to TLR4 signalling and does not participate in the MyD88-independent pathway. Instead, TIRAP has a crucial role in the MyD88-dependent signalling pathway shared by TLR2 and TLR4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Antigens, Differentiation / metabolism
Cell Differentiation / drug effects
Cell Division / drug effects
Cells, Cultured
Cytokines / biosynthesis
Dendritic Cells / cytology
Dendritic Cells / drug effects
Dendritic Cells / metabolism
Drosophila Proteins*
Enzyme Activation / drug effects
Gene Deletion
Ligands
Lipopolysaccharides / pharmacology
Macrophages, Peritoneal / drug effects
Macrophages, Peritoneal / enzymology
Macrophages, Peritoneal / metabolism
Membrane Glycoproteins / chemistry
Membrane Glycoproteins / metabolism*
Mice
Mice, Knockout
Mitogen-Activated Protein Kinases / metabolism
Myeloid Differentiation Factor 88
NF-kappa B / metabolism
Receptors, Cell Surface / chemistry
Receptors, Cell Surface / metabolism*
Receptors, Immunologic / metabolism
Receptors, Interleukin-1 / genetics
Receptors, Interleukin-1 / metabolism*
Signal Transduction* / drug effects
Spleen / cytology
Spleen / drug effects
Spleen / metabolism
Substrate Specificity
Toll-Like Receptor 2
Toll-Like Receptor 3
Toll-Like Receptor 4
Toll-Like Receptor 7
Toll-Like Receptors

Substances

Adaptor Proteins, Signal Transducing
Antigens, Differentiation
Cytokines
Drosophila Proteins
Ligands
Lipopolysaccharides
Membrane Glycoproteins
Myd88 protein, mouse
Myeloid Differentiation Factor 88
NF-kappa B
Receptors, Cell Surface
Receptors, Immunologic
Receptors, Interleukin-1
TIRAP protein, mouse
Toll-Like Receptor 2
Toll-Like Receptor 3
Toll-Like Receptor 4
Toll-Like Receptor 7
Toll-Like Receptors
Mitogen-Activated Protein Kinases