Open AccessEvidence for licensing of IFN-γ-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program
Author(s) -
Hideo Negishi,
Yasuyuki Fujita,
Hideyuki Yanai,
Shoji Sakaguchi,
Xinshou Ouyang,
Masahiro Shirakawa,
Hiroshi Takayanagi,
Yusuke Ohba,
Tadatsugu Taniguchi,
Kenya Honda
Publication year - 2006
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0607181103
Subject(s) - irf1 , transcription factor , interferon regulatory factors , signal transduction , irf7 , toll like receptor , biology , microbiology and biotechnology , regulation of gene expression , irf5 , signal transducing adaptor protein , gene , receptor , genetics , innate immune system
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 inIrf1 -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.