ADAR脱氨酶能催化双链RNA（dsRNA）底物上的腺苷酸转变为肌苷酸（A-to-I）编辑，从而调节众多生物过程。两种催化活性的ADAR酶之一，ADAR1，在通过抑制RNA感知通路发挥免疫应答的重要作用中，通过ADAR1-dsRNA-MDA5轴进行协调。未编辑的免疫原性dsRNA底物是细胞感应器MDA5的强效配体。一旦激活，MDA5会诱导干扰素的产生，并表达数百个干扰素刺激基因，具有强大的抗病毒活性。这样一来，ADAR1通过在先天性抗病毒应答和自身免疫之间取得微妙平衡，成为RNA感知通路的守门人。ADAR1对免疫原性dsRNA的编辑减少与常见的自身免疫和炎症性疾病的发展密切相关。在病毒感染中，ADAR1发挥抗病毒和促病毒效应。这是通过编辑依赖和编辑非依赖的功能调节的，如PKR拮抗作用。在病毒中已鉴定出几个A-to-I RNA编辑事件，包括在病毒病原体SARS-CoV-2中，这些事件调控病毒的适应性和感染性，并可能在病毒进化中起到一定作用。此外，ADAR1是免疫肿瘤学治疗的理想靶点。在几种人类癌症中观察到ADAR1的过度表达和dsRNA编辑增加。针对特别是对免疫检查点抑制剂难治性癌症，静默ADAR1是肿瘤免疫治疗的有希望的治疗策略，结合表观遗传治疗。对ADAR1的dsRNA编辑和MDA5及PKR对dsRNA的感知机制的认识，具有极大的治疗应用潜力。本文被归类为：RNA加工> RNA编辑和修饰 RNA在疾病和发育中的作用> RNA在疾病中。©2023 Wiley Periodicals LLC.

ADAR deaminases catalyze adenosine-to-inosine (A-to-I) editing on double-stranded RNA (dsRNA) substrates that regulate an umbrella of biological processes. One of the two catalytically active ADAR enzymes, ADAR1, plays a major role in innate immune responses by suppression of RNA sensing pathways which are orchestrated through the ADAR1-dsRNA-MDA5 axis. Unedited immunogenic dsRNA substrates are potent ligands for the cellular sensor MDA5. Upon activation, MDA5 leads to the induction of interferons and expression of hundreds of interferon-stimulated genes with potent antiviral activity. In this way, ADAR1 acts as a gatekeeper of the RNA sensing pathway by striking a fine balance between innate antiviral responses and prevention of autoimmunity. Reduced editing of immunogenic dsRNA by ADAR1 is strongly linked to the development of common autoimmune and inflammatory diseases. In viral infections, ADAR1 exhibits both antiviral and proviral effects. This is modulated by both editing-dependent and editing-independent functions, such as PKR antagonism. Several A-to-I RNA editing events have been identified in viruses, including in the insidious viral pathogen, SARS-CoV-2 which regulates viral fitness and infectivity, and could play a role in shaping viral evolution. Furthermore, ADAR1 is an attractive target for immuno-oncology therapy. Overexpression of ADAR1 and increased dsRNA editing have been observed in several human cancers. Silencing ADAR1, especially in cancers that are refractory to immune checkpoint inhibitors, is a promising therapeutic strategy for cancer immunotherapy in conjunction with epigenetic therapy. The mechanistic understanding of dsRNA editing by ADAR1 and dsRNA sensing by MDA5 and PKR holds great potential for therapeutic applications. This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease.© 2023 Wiley Periodicals LLC.