Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling.
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.
Yamamoto
Masahiro
M
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Suita, Osaka, Japan.
Sato
Shintaro
S
Mori
Kiyotoshi
K
Hoshino
Katsuaki
K
Takeuchi
Osamu
O
Takeda
Kiyoshi
K
Akira
Shizuo
S
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; C470409:TICAM1 protein, human; C434984:TIRAP protein, human; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495348:TLR7 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D014157:Transcription Factors; D016899:Interferon-beta