Abstract
Toll-like receptors (TLRs) are involved in the recognition of microbial pathogens. A subset of TLRs, TLR7, TLR8 and TLR9, induces antiviral responses by producing interferon-alpha (IFN-alpha). Production of IFN-alpha is dependent on the Toll-interleukin-1 receptor domain-containing adaptor MyD88. Here we show that MyD88 formed a complex with the transcription factor IRF7 but not with IRF3. The death domain of MyD88 interacted with an inhibitory domain of IRF7, and this interaction resulted in activation of the IFN-alpha-dependent promoters. Furthermore, the adaptor molecule TRAF6 also bound and activated IRF7. Ubiquitin ligase activity of TRAF6 was required for IRF7 activation. These results indicate that TLR-mediated IFN-alpha induction requires the formation of a complex consisting of MyD88, TRAF6 and IRF7 as well as TRAF6-dependent ubiquitination.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Differentiation / physiology*
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DNA-Binding Proteins / physiology*
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Humans
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Interferon Regulatory Factor-7
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Interferon-alpha / biosynthesis*
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred C57BL
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Myeloid Differentiation Factor 88
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Proteins / physiology*
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Receptors, Cell Surface / physiology*
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Receptors, Immunologic / physiology*
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TNF Receptor-Associated Factor 6
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Toll-Like Receptor 7
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Toll-Like Receptor 8
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Toll-Like Receptor 9
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Toll-Like Receptors
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Ubiquitin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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DNA-Binding Proteins
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IRF7 protein, human
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Interferon Regulatory Factor-7
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Interferon-alpha
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Irf7 protein, mouse
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MYD88 protein, human
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Proteins
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Receptors, Cell Surface
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Receptors, Immunologic
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TLR7 protein, human
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TLR8 protein, human
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TLR9 protein, human
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TNF Receptor-Associated Factor 6
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Toll-Like Receptor 7
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Toll-Like Receptor 8
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Toll-Like Receptor 9
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Toll-Like Receptors
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Ubiquitin