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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >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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Evidence for licensing of IFN-γ-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program

机译：MyD88在Toll样受体依赖性基因诱导程序中许可IFN-γ诱导的IFN调节因子1转录因子的证据

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摘要

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-γ, but the mechanisms underlying this enhancement remain unclear. The MyD88 adaptor, which is essential for signaling by many TLRs, 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-γ, 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 MyD88-dependent "IRF1 licensing" is underscored by the observation that the induction of a specific gene subset downstream of the TLR-MyD88 pathway, such as IFN-β, 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 TLR-dependent gene induction program by IFN-γ.
机译：Toll样受体（TLR）对微生物成分的识别会启动信号转导途径，从而触发一系列靶基因的表达。据报道，TLR信号转导被诸如IFN-γ的细胞因子增强，但是这种增强的基础机制仍不清楚。 MyD88衔接子对于许多TLR的信号转导必不可少，它募集转录因子的IFN调节因子（IRF）家族的成员，例如IRF5和IRF7，以唤起TLR靶基因的激活。在这项研究中，我们证明了TLR激活后，由IFN-γ诱导的IRF1也与MyD88相互作用并被MyD88激活。我们提供的证据表明，MyD88相关的IRF1比非MyD88相关的IRF1更有效地迁移到核中，并且该IRF1选择性地参与了TLR依赖性基因诱导程序。观察到的是，依赖MyD88的“ IRF1许可”的关键作用在TLR-MyD88途径下游的特定基因子集（如IFN-β，诱导型NO合酶和IL-12p35）的诱导受损中得到了强调。 Irf1缺陷细胞。因此，我们目前的研究将IRF1作为参与MyD88信号传导的其他成员，并为通过IFN-γ增强TLR依赖性基因诱导程序提供了机械学见识。

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