School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China; Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, Tianjin University, Tianjin 300072, China.
Meizhou People's Hospital, Meizhou 514031, China; Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translation Research of Hakka Population, Meizhou 514031, China.
Biomed Pharmacother. 2022 Mar;147:112622. doi: 10.1016/j.biopha.2022.112622. Epub 2022 Jan 7.
Nucleic acid-mediated interferon signaling plays a pivotal role in defense against microorganisms, especially during viral infection. Receptors sensing exogenous nucleic acid molecules are localized in the cytosol and endosomes. Cytosolic sensors, including cGAS, RIG-I, and MDA5, and endosome-anchored receptors are toll-like receptors (TLR3, TLR7, TLR8, and TLR9). These TLRs share the same domain architecture and have similar structures, facing the interior of endosomes so their binding to nucleic acids of invading pathogens via endocytosis is possible. The correct function of these receptors is crucial for cell homeostasis and effective response against pathogen invasion. A variety of endogenous mechanisms modulates their activities. Nevertheless, naturally occurring mutations lead to aberrant TLR-mediated interferon (IFN) signaling. Furthermore, certain pathogens require a more robust defense against control. Thus, manipulating these TLR activities has a profound impact. High-throughput virtual screening followed by experimental validation led to the discovery of numerous chemicals that can change these TLR-mediated IFN signaling activities. Many of them are unique in selectivity, while others regulate more than one TLR due to commonalities in these receptors. We summarized these nucleic acid-sensing TLR-mediated IFN signaling pathways and the corresponding chemicals activating or deactivating their signaling.
核酸介导的干扰素信号转导在抵御微生物，特别是病毒感染方面发挥着关键作用。识别外源核酸分子的受体位于细胞质和内体中。细胞质传感器包括 cGAS、RIG-I 和 MDA5，以及内体锚定受体 TLR3、TLR7、TLR8 和 TLR9。这些 TLR 具有相同的结构域架构和相似的结构，面向内体内部，因此可以通过内吞作用与入侵病原体的核酸结合。这些受体的正确功能对于细胞内稳态和有效抵御病原体入侵至关重要。多种内源性机制调节它们的活性。然而，自然发生的突变导致异常的 TLR 介导的干扰素 (IFN) 信号转导。此外，某些病原体需要更强大的防御控制。因此，操纵这些 TLR 活性具有深远的影响。高通量虚拟筛选后进行实验验证，发现了许多可以改变这些 TLR 介导的 IFN 信号活性的化学物质。其中许多在选择性方面是独特的，而另一些则由于这些受体的共性而调节不止一种 TLR。我们总结了这些核酸感应 TLR 介导的 IFN 信号通路以及激活或失活其信号通路的相应化学物质。
