Department of Microbiology, University of Chicago, Chicago, Illinois, United States of America.
Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, United States of America.
PLoS Pathog. 2020 Sep 8;16(9):e1008842. doi: 10.1371/journal.ppat.1008842. eCollection 2020 Sep.
Signaling through retinoic acid inducible gene I (RIG-I) like receptors (RLRs) is tightly regulated, with activation occurring upon sensing of viral nucleic acids, and suppression mediated by negative regulators. Under homeostatic conditions aberrant activation of melanoma differentiation-associated protein-5 (MDA5) is prevented through editing of endogenous dsRNA by RNA editing enzyme Adenosine Deaminase Acting on RNA (ADAR1). In addition, ADAR1 is postulated to play pro-viral and antiviral roles during viral infections that are dependent or independent of RNA editing activity. Here, we investigated the importance of ADAR1 isoforms in modulating influenza A virus (IAV) replication and revealed the opposing roles for ADAR1 isoforms, with the nuclear p110 isoform restricting versus the cytoplasmic p150 isoform promoting IAV replication. Importantly, we demonstrate that p150 is critical for preventing sustained RIG-I signaling, as p150 deficient cells showed increased IFN-β expression and apoptosis during IAV infection, independent of RNA editing activity. Taken together, the p150 isoform of ADAR1 is important for preventing sustained RIG-I induced IFN-β expression and apoptosis during viral infection.
视黄酸诱导基因 I（RIG-I）样受体（RLRs）的信号传导受到严格调控，在检测到病毒核酸时会发生激活，而负调节因子则介导抑制。在稳态条件下，通过 RNA 编辑酶腺苷脱氨酶作用于 RNA（ADAR1）对内源性 dsRNA 的编辑，防止黑色素瘤分化相关蛋白-5（MDA5）的异常激活。此外，ADAR1 被假定在依赖或不依赖 RNA 编辑活性的病毒感染过程中发挥促病毒和抗病毒作用。在这里，我们研究了 ADAR1 同工型在调节甲型流感病毒（IAV）复制中的重要性，并揭示了 ADAR1 同工型的相反作用，核 p110 同工型限制了细胞质 p150 同工型促进 IAV 复制。重要的是，我们证明 p150 对于防止持续的 RIG-I 信号传导至关重要，因为 p150 缺陷细胞在 IAV 感染期间表现出 IFN-β 表达增加和凋亡，而与 RNA 编辑活性无关。总之，ADAR1 的 p150 同工型对于防止病毒感染期间持续的 RIG-I 诱导的 IFN-β 表达和凋亡很重要。
