2004
DOI: 10.1038/ni1118
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Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6

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… Show more

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Cited by 913 publications
(802 citation statements)
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“…It was not possible to show endogenous phosphorylation of IRF7 by IRAK-1 [59]. It is probable that IRF7 activation by IRAK-1 is independent of TBK1 and IKK-I because plasmacytoid DCs derived from mice deficient in TBK1 or IKK-i show normal responsiveness to TLR9 ligands with respect to induction of IFN-a [54]. However, this study does not exclude the possibility of functional redundancy between TBK1 and IKK-i.…”
Section: Tbk1 and Ikk-i Activate Irf3 And Irf7mentioning
confidence: 64%
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“…It was not possible to show endogenous phosphorylation of IRF7 by IRAK-1 [59]. It is probable that IRF7 activation by IRAK-1 is independent of TBK1 and IKK-I because plasmacytoid DCs derived from mice deficient in TBK1 or IKK-i show normal responsiveness to TLR9 ligands with respect to induction of IFN-a [54]. However, this study does not exclude the possibility of functional redundancy between TBK1 and IKK-i.…”
Section: Tbk1 and Ikk-i Activate Irf3 And Irf7mentioning
confidence: 64%
“…Because the induction of type I IFNs is crucially dependent on the activation of IRFs, this raises the intriguing question of how these TLRs can activate IRFs without the help of TRIF. Plasmacytoid DCs show high levels of constitutive IRF7 expression, relative to monocyte-derived DCs [53], and two concomitant reports showed that Myd88 forms a complex with IRF7 to trigger its activation and induce IFN-a [54,55]. TLR7 and TLR9 are located primarily in the intracellular endosomal compartment [56,57] and the Myd88-IRF7 interaction takes place in the endosomal vesicles of the plasmacytoid DCs [58] (Figure 2).…”
Section: Tbk1 and Ikk-i Activate Irf3 And Irf7mentioning
confidence: 92%
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“…While pDCs deficient of IRF3 normally respond to these TLRs, type I IFN and inflammatory cytokine induction is totally abolished in MyD88-and IRAK4-deficient pDCs. [64][65][66][67] Unlike other types of DCs, pDCs constitutively express high levels of IRF7. 68,69 Furthermore, treatment of pDCs with TLR9 ligands causes nuclear translocation of IRF7, and pDCs derived from IRF7-deficient mice are incapable of producing type I IFN in response to TLR7/8 and TLR9 ligands.…”
Section: Activation Of Irfs By Tlr7/8 and Tlr9mentioning
confidence: 99%
“…68,69 Furthermore, treatment of pDCs with TLR9 ligands causes nuclear translocation of IRF7, and pDCs derived from IRF7-deficient mice are incapable of producing type I IFN in response to TLR7/8 and TLR9 ligands. 64,65 Thus, IRF7 is an essential transcription factor that regulates type I IFN induction in pDCs. Importantly, IRF7 interacts with MyD88, IRAK1 and TRAF6 to form a signaling complex (Figure 3).…”
Section: Activation Of Irfs By Tlr7/8 and Tlr9mentioning
confidence: 99%