Signaling Systems Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
Signaling Systems Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
Cell Rep. 2018 Oct 2;25(1):95-106.e6. doi: 10.1016/j.celrep.2018.09.002.
Activation of the TLR4 signaling pathway by lipopolysaccharide (LPS) leads to induction of both inflammatory and interferon-stimulated genes, but the mechanisms through which these coordinately activated transcriptional programs are balanced to promote an optimal innate immune response remain poorly understood. In a genome-wide small interfering RNA (siRNA) screen of the LPS-induced tumor necrosis factor α (TNF-α) response in macrophages, we identify the interferon-stimulated protein IFIT1 as a negative regulator of the inflammatory gene program. Transcriptional profiling further identifies a positive regulatory role for IFIT1 in type I interferon expression, implicating IFIT1 as a reciprocal modulator of LPS-induced gene classes. We demonstrate that these effects of IFIT1 are mediated through modulation of a Sin3A-HDAC2 transcriptional regulatory complex at LPS-induced gene loci. Beyond the well-studied role of cytosolic IFIT1 in restricting viral replication, our data demonstrate a function for nuclear IFIT1 in differential transcriptional regulation of separate branches of the LPS-induced gene program.
脂多糖（LPS）激活 TLR4 信号通路会诱导炎症和干扰素刺激基因的表达，但协调激活这些转录程序的机制如何平衡以促进最佳的先天免疫反应仍知之甚少。在对巨噬细胞中 LPS 诱导的肿瘤坏死因子 α（TNF-α）反应进行全基因组小干扰 RNA（siRNA）筛选时，我们发现干扰素刺激蛋白 IFIT1 是炎症基因程序的负调节剂。转录谱分析进一步确定 IFIT1 在 I 型干扰素表达中的正向调节作用，表明 IFIT1 是 LPS 诱导基因类别的相互调节剂。我们证明 IFIT1 的这些作用是通过在 LPS 诱导的基因位点调节 Sin3A-HDAC2 转录调节复合物来介导的。除了细胞质 IFIT1 在限制病毒复制方面的研究较为深入外，我们的数据还表明核 IFIT1 在 LPS 诱导基因程序的不同分支的差异转录调控中具有功能。
