Abstract
MyD88 is a Toll/IL-1 receptor (TIR) domain-containing adapter common to signaling pathways via Toll-like receptor (TLR) family. However, accumulating evidence demonstrates the existence of a MyD88-independent pathway, which may explain unique biological responses of individual TLRs, particularly TLR3 and TLR4. TIR domain-containing adapter protein (TIRAP)/MyD88 adapter-like, a second adapter harboring the TIR domain, is essential for MyD88-dependent TLR2 and TLR4 signaling pathways, but not for MyD88-independent pathways. Here, we identified a novel TIR domain-containing molecule, named TIR domain-containing adapter inducing IFN-beta (TRIF). As is the case in MyD88 and TIRAP, overexpression of TRIF activated the NF-kappaB-dependent promoter. A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-kappaB activation. Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-beta promoter. Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. TRIF associated with TLR3 and IFN regulatory factor 3. These findings suggest that TRIF is involved in the TLR signaling, particularly in the MyD88-independent pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / isolation & purification*
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Adaptor Proteins, Vesicular Transport / metabolism
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Adaptor Proteins, Vesicular Transport / physiology
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Amino Acid Sequence
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Cell Line
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DNA-Binding Proteins / metabolism
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Drosophila Proteins*
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Gene Expression Regulation / immunology*
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Humans
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Interferon Regulatory Factor-3
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Interferon-beta / antagonists & inhibitors
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Interferon-beta / genetics*
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Interferon-beta / metabolism
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / physiology*
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Molecular Sequence Data
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / physiology
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Promoter Regions, Genetic / immunology*
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Receptors, Cell Surface / antagonists & inhibitors
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Receptors, Cell Surface / metabolism
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Receptors, Cell Surface / physiology*
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Receptors, Immunologic
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Receptors, Interleukin-1 / physiology*
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Signal Transduction / genetics*
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Signal Transduction / immunology*
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Toll-Like Receptor 2
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptor 7
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Toll-Like Receptors
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Transcription Factors / metabolism
Substances
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Adaptor Proteins, Vesicular Transport
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DNA-Binding Proteins
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Drosophila Proteins
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Membrane Glycoproteins
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NF-kappa B
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Receptors, Cell Surface
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Receptors, Immunologic
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Receptors, Interleukin-1
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TICAM1 protein, human
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TIRAP protein, human
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TLR2 protein, human
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TLR3 protein, human
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TLR4 protein, human
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TLR7 protein, human
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Toll-Like Receptor 2
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptor 7
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Toll-Like Receptors
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Transcription Factors
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Interferon-beta