CircMYO9A inhibits influenza A virus replication by dampening hemagglutinin cleavage via increasing SERPINE1/PAI-1 expression

Circular RNAs (circRNAs) represent a class of widespread and diverse covalently closed circular endogenous RNAs that play critical roles in regulating gene expression in mammals. However, the roles and regulatory mechanisms of circRNAs during influenza A virus (IAV) infection remain largely unexplored. In this study, we screened the circRNA transcription profiles of WSN-infected cells to identify circRNAs involved in viral replication and identified a novel differentially expressed circular RNA, circMYO9A. Mechanistically, circMYO9A acts as a competing endogenous RNA (ceRNA) for SERPINE1/PAI-1 by sponging miR-6059-3p, thereby increasing SERPINE1/PAI-1 expression, which restricts IAV hemagglutinin cleavage and subsequently reduces the infectivity of progeny viruses. Importantly, our findings demonstrate that circMYO9A significantly inhibits viral replication in the lungs of infected mice, potentially increasing their survival during IAV infection. These results demonstrate that circRNAs play crucial roles in inhibiting IAV replication and provide novel insights into potential therapeutic strategies involving circRNAs.

环状RNA（circular RNAs, circRNAs）是一类广泛分布、种类多样的共价闭合环状内源RNA，在哺乳动物基因表达调控中发挥关键作用。然而，环状RNA在甲型流感病毒（influenza A virus, IAV）感染过程中的功能与调控机制，迄今尚未得到充分解析。本研究通过筛选WSN感染细胞的环状RNA转录谱，鉴定出参与病毒复制的环状RNA，并发现了一种新型差异表达环状RNA circMYO9A。机制上，circMYO9A通过海绵吸附miR-6059-3p，充当SERPINE1/PAI-1的内源竞争RNA（ceRNA），上调SERPINE1/PAI-1的表达；该过程可抑制甲型流感病毒血凝素的裂解，进而降低子代病毒的感染性。值得注意的是，本研究结果显示circMYO9A可显著抑制感染小鼠肺部的病毒复制，有望提升小鼠在甲型流感病毒感染后的存活率。上述研究结果证实，环状RNA在抑制甲型流感病毒复制中发挥关键作用，并为基于环状RNA的潜在治疗策略提供了全新的研究视角。