Yang J, Tian B, Brasier A R
University of Texas Medical Branch, Galveston, TX, United States; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX, United States.
University of Texas Medical Branch, Galveston, TX, United States; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX, United States; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, United States.
Adv Protein Chem Struct Biol. 2017;107:1-36. doi: 10.1016/bs.apcsb.2016.11.001. Epub 2016 Dec 1.
Mucosal surfaces of the human body are lined by a contiguous epithelial cell surface that forms a barrier to aerosolized pathogens. Specialized pattern recognition receptors detect the presence of viral pathogens and initiate protective host responses by triggering activation of the nuclear factor κB (NFκB)/RelA transcription factor and formation of a complex with the positive transcription elongation factor (P-TEFb)/cyclin-dependent kinase (CDK)9 and Bromodomain-containing protein 4 (BRD4) epigenetic reader. The RelA·BRD4·P-TEFb complex produces acute inflammation by regulating transcriptional elongation, which produces a rapid genomic response by inactive genes maintained in an open chromatin configuration engaged with hypophosphorylated RNA polymerase II. We describe recent studies that have linked prolonged activation of the RelA-BRD4 pathway with the epithelial-mesenchymal transition (EMT) by inducing a core of EMT corepressors, stimulating secretion of growth factors promoting airway fibrosis. The mesenchymal state produces rewiring of the kinome and reprogramming of innate responses toward inflammation. In addition, the core regulator Zinc finger E-box homeodomain 1 (ZEB1) silences the expression of the interferon response factor 1 (IRF1), required for type III IFN expression. This epigenetic silencing is mediated by the Enhancer of Zeste 2 (EZH2) histone methyltransferase. Because of their potential applications in cancer and inflammation, small-molecule inhibitors of NFκB/RelA, CDK9, BRD4, and EZH2 have been the targets of medicinal chemistry efforts. We suggest that disruption of the RelA·BRD4·P-TEFb pathway and EZH2 methyltransferase has important implications for reversing fibrosis and restoring normal mucosal immunity in chronic inflammatory diseases.
人体的黏膜表面由连续的上皮细胞表面所覆盖，该表面形成了一道抵御气溶胶化病原体的屏障。专门的模式识别受体可检测病毒病原体的存在，并通过触发核因子κB（NFκB）/RelA转录因子的激活以及与正转录延伸因子（P-TEFb）/细胞周期蛋白依赖性激酶（CDK）9和含溴结构域蛋白4（BRD4）表观遗传阅读器形成复合物来启动保护性宿主反应。RelA·BRD4·P-TEFb复合物通过调节转录延伸产生急性炎症，这会使维持在与低磷酸化RNA聚合酶II结合的开放染色质构型中的无活性基因产生快速的基因组反应。我们描述了最近的研究，这些研究将RelA-BRD4途径的长期激活与上皮-间质转化（EMT）联系起来，方法是诱导EMT共抑制因子的核心，刺激促进气道纤维化的生长因子的分泌。间充质状态会导致激酶组的重新布线以及先天炎症反应的重新编程。此外，核心调节因子锌指E盒同源结构域1（ZEB1）使III型干扰素表达所需的干扰素反应因子1（IRF1）的表达沉默。这种表观遗传沉默由EZH2组蛋白甲基转移酶介导。由于它们在癌症和炎症中的潜在应用，NFκB/RelA、CDK9、BRD4和EZH2的小分子抑制剂一直是药物化学研究的目标。我们认为，破坏RelA·BRD4·P-TEFb途径和EZH2甲基转移酶对于逆转慢性炎症疾病中的纤维化和恢复正常黏膜免疫具有重要意义。
