A Novel Intronic Circular RNA Antagonizes Influenza Virus by Absorbing a MicroRNA That Degrades CREBBP and Accelerating IFN-β Production

Virus-host interactions are complicated processes, and multiple cellular proteins promote or inhibit viral replication through different mechanisms. Recent progress has implicated circular RNAs (circRNAs) in cancer biology and progression; however, the role of circRNAs in viral infection remains largely unclear. Here, we detected 11,620 circRNAs in A549 cells and found that 411 of them were differentially expressed in influenza virus-infected A549 cells. We characterized a novel intronic circRNA, AIVR, that was upregulated in influenza virus-infected A549 cells and found that silencing of AIVR significantly promoted influenza virus replication in A549 cells. We further found that AIVR predominantly localizes in the cytoplasm and works as a microRNA (miRNA) sponge. One of the miRNAs absorbed by AIVR binds the mRNA of CREBBP, which is an important component of the large nucleoprotein complex interferon beta (IFN-β) enhanceosome that accelerates IFN-β production. AIVR overexpression significantly increased the mRNA and protein levels of IFN-β in the influenza virus-infected A549 cells. Therefore, the upregulation of AIVR is a cellular antiviral strategy, with AIVR exerting its antiviral effect by absorbing miRNA and promoting the expression of CREBBP to facilitate IFN-β production. Our study provides new insights into the roles of circRNAs in the cellular innate antiviral response. Circular RNAs (circRNAs) are new members of the long noncoding RNA families and have been identified in a variety of organisms, including plants, animals, and humans. Accumulating data indicate that circRNAs perform multiple functions in a variety of cellular processes associated with human diseases, such as Alzheimer's disease and cancer; however, the roles of circRNAs in virus infection have been largely uninvestigated. In this study, we investigated the cellular circRNA response upon influenza virus infection and found that 411 circRNAs were differentially expressed in the virus-infected cells. We identified a novel human intronic circRNA (we named AIVR) that antagonizes influenza virus replication. Upregulated circRNA AIVR absorbs an miRNA that binds the mRNA of CREBBP, leading to an increase in the cellular expression of CREBBP and then accelerating IFN-β production. This study advances the understanding of the roles of circRNAs in the cellular innate antiviral response.