Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Wiley Interdiscip Rev RNA. 2011 Jan-Feb;2(1):58-78. doi: 10.1002/wrna.32. Epub 2010 Aug 24.
In mammals the type 1 interferon (IFN) system functions as the primary innate antiviral defense and more broadly as a stress response and regulator of diverse homeostatic mechanisms. RNA plays a central role in the induction of IFN and in its biologic activities. Cellular toll-like receptors (TLR), RIG-I-like receptors (RLR), and nucleotide organization domain-like receptors (NLR) sense pathogen- and danger-associated RNAs as nonself based on structural features and subcellular location that distinguish them from ubiquitous host RNAs. Detection of nonself RNAs activates signaling pathways to induce IFN transcription and secretion. In turn, IFN binds cell surface receptors to initiate signaling that results in the induction of IFN-stimulated genes (ISGs) that mediate its biologic activities. RNA also plays a critical role in this effector phase of the IFN system, serving as an activator of enzyme activity for protein kinase RNA-dependent (PKR) and oligoadenylate synthetase (OAS), and as a substrate for 2('), 5(') -linked oligoadenylate dependant-endoribonuclease (RNase-L). In contrast to the transcriptional response induced by RNA receptors, these key ISGs mediate their activities primarily through post transcriptional mechanisms to regulate the translation and stability of host and microbial RNAs. Together RNA-sensing and RNA-effector molecules comprise a network of coordinately regulated proteins with integrated feedback and feed-forward loops that tightly regulate the cellular response to RNA. This stringent regulation is essential to prevent deleterious effects of uncontrolled IFN expression and effector activation. In light of this extensive crosstalk, targeting key mediators of the cellular response to RNA represents a viable strategy for therapeutic modulation of immune function and treatment of diseases in which this response is dysregulated (e.g., cancer).
在哺乳动物中，I 型干扰素 (IFN) 系统作为主要的先天抗病毒防御机制，更广泛地作为应激反应和多种体内平衡机制的调节剂发挥作用。RNA 在诱导 IFN 及其生物学活性中发挥核心作用。细胞 Toll 样受体 (TLR)、RIG-I 样受体 (RLR) 和核苷酸结合寡聚化结构域样受体 (NLR) 根据结构特征和亚细胞定位感知病原体和危险相关 RNA，将其识别为非自身，从而将其与普遍存在的宿主 RNA 区分开来。非自身 RNA 的检测激活信号通路，诱导 IFN 转录和分泌。反过来，IFN 结合细胞表面受体启动信号转导，导致诱导 IFN 刺激基因 (ISG)，介导其生物学活性。RNA 在 IFN 系统的这个效应阶段也起着至关重要的作用，作为蛋白激酶 RNA 依赖性 (PKR) 和寡聚腺苷酸合成酶 (OAS) 的酶活性激活剂，以及 2'，5' - 连接寡聚腺苷酸依赖性内切核糖核酸酶 (RNase-L) 的底物。与 RNA 受体诱导的转录反应不同，这些关键的 ISG 通过主要通过转录后机制调节宿主和微生物 RNA 的翻译和稳定性来发挥其活性。RNA 感应和 RNA 效应分子共同构成了一个协调调节的蛋白质网络，具有集成的反馈和前馈环，可紧密调节细胞对 RNA 的反应。这种严格的调控对于防止不受控制的 IFN 表达和效应子激活的有害影响至关重要。鉴于这种广泛的串扰，针对细胞对 RNA 反应的关键介质代表了一种可行的治疗策略，可用于调节免疫功能和治疗其中反应失调的疾病（例如癌症）。
