Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling.
Toll-like receptor (TLR) activation is central to immunity, wherein the activation of the TLR9 subfamily members TLR9 and TLR7 results in the robust induction of type I IFNs (IFN-alpha/beta) by means of the MyD88 adaptor protein. However, it remains unknown how the TLR signal "input" can be processed through MyD88 to "output" the induction of the IFN genes. Here, we demonstrate that the transcription factor IRF-7 interacts with MyD88 to form a complex in the cytoplasm. We provide evidence that this complex also involves IRAK4 and TRAF6 and provides the foundation for the TLR9-dependent activation of the IFN genes. The complex defined in this study represents an example of how the coupling of the signaling adaptor and effector kinase molecules together with the transcription factor regulate the processing of an extracellular signal to evoke its versatile downstream transcriptional events in a cell. Thus, we propose that this molecular complex may function as a cytoplasmic transductional-transcriptional processor.
Honda
Kenya
K
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Yanai
Hideyuki
H
Mizutani
Tatsuaki
T
Negishi
Hideo
H
Shimada
Naoya
N
Suzuki
Nobutaka
N
Ohba
Yusuke
Y
Takaoka
Akinori
A
Yeh
Wen-Chen
WC
Taniguchi
Tadatsugu
T
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000502:physiology*; D004735:Energy Transfer; D005453:Fluorescence; D006801:Humans; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014161:Transduction, Genetic
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; C494235:Irf7 protein, mouse; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014157:Transcription Factors