Evidence for licensing of IFN-γ-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program
Evidence for licensing of IFN-γ-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program
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DOI：
10.1073/pnas.0607181103
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发表时间：
2006-10-10
影响因子：
11.1
通讯作者：
Honda, Kenya
中科院分区：
文献类型：
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作者：
Negishi, Hideo;Fujita, Yasuyuki;Honda, Kenya
toll样受体（TLRs）对微生物成分的识别启动信号转导途径，从而触发一系列靶基因的表达。据报道，TLR信号被ifn - γ等细胞因子增强，但这种增强的机制尚不清楚。MyD88接头对于许多tilr的信号传导至关重要，它招募IFN调节因子（IRF）转录因子家族的成员，如IRF5和IRF7，来激活TLR靶基因。在这项研究中，我们证明了由ifn - γ诱导的IRF1也与MyD88相互作用，并在TLR激活后被MyD88激活。我们提供的证据表明，myd88相关的IRF1比非myd88相关的IRF1更有效地迁移到细胞核中，并且该IRF1选择性地参与tlr依赖的基因诱导程序。观察到TLR-MyD88通路下游特定基因亚群的诱导，如ifn - β、诱导型NO合成酶和IL-12p35，在IRF1缺陷细胞中受损，强调了myid88 - clependent“IRF1许可”的关键作用。因此，我们目前的研究将IRF1作为参与MyD88信号传导的额外成员，并提供了ifn - γ增强tilr依赖性基因诱导程序的机制见解。
The recognition of microbial components by Toll-like receptors (TLRs) initiates signal transduction pathways, which trigger the expression of a series of target genes. It has been reported that TLR signaling is enhanced by cytokines such as IFN-gamma, but the mechanisms underlying this enhancement remain unclear. The MyD88 adaptor, which is essential for signaling by many TILRs, recruits members of the IFN regulatory factor (IRF) family of transcription factors, such as IRF5 and IRF7, to evoke the activation of TLR target genes. In this study we demonstrate that IRF1, which is induced by IFN-gamma, also interacts with and is activated by MyD88 upon TLR activation. We provide evidence that MyD88-associated IRF1 migrates into the nucleus more efficiently than non-MyD88-associated IRF1 and that this IRF1 selectively participates in the TLR-dependent gene induction program. The critical role of MyID88-clepenclent "IRF1 licensing" is underscored by the observation that the induction of a specific gene subset downstream of the TLR-MyD88 pathway, such as IFN-beta, inducible NO synthase, and IL-12p35, are impaired in Irf1-deficient cells. Thus, our present study places IRF1 as an additional member participating in MyD88 signaling and provides a mechanistic insight into the enhancement of the TILR-dependent gene induction program by IFN-gamma.