The expression, function and potential mechanism of long non-coding RNA in the context of influenza virus infection

Abstract

Influenza virus leads to contagious respiratory-related diseases, posing threats to public health. The molecular interplay between viruses and host cells determines the progression of influenza virus infection. Robust cellular reactions are triggered during influenza virus infection to activate and synthesize antiviral molecules that target influenza virus replication in multiple stages; meanwhile, host molecules can also be exploited to facilitate virus infection. As a deeper understanding of virus-host interaction has been gained during recent years, diverse types of novel molecules that play a crucial role in influenza virus infection have been discovered. Long non-coding RNAs (lncRNAs) is a class of RNA transcripts that is encoded from non-coding genes with limited protein-coding capacity, showing its significance in influenza virus infection. However, the understanding of lncRNAs in influenza virus infection remains preliminary. This study revealed the profile landscape of lncRNAs and identified lncRNAs candidates that are universally differentially expressed in influenza virus infection. Moreover, the study unveiled Interferon Sensitive Response Element (ISRE)-dependent lncRNAs, lncRNAs carrying ISRE-like motifs in the promoter region, may act as a vital regulator in influenza virus-induced immune responses. To study the biological effect of lncRNAs, two lncRNA candidates were investigated in detail. USP30-AS1 was identified as a universally differentially expressed ISRE-dependent lncRNA in influenza virus infection. Knocking out of USP30-AS1 enhanced influenza virus replication via promoting viral protein synthesis without affecting viral RNA transcription and replication. The activation of USP30-AS1 was JAK-STAT signaling pathway dependent and USP30-AS1 was engaged in the regulation of inflammatory response. Loss of USP30-AS1 switches a balanced immune response into acute inflammatory reaction. Furthermore, BCAR4 was identified as another highly universally differentially expressed lncRNA that carries out its biological activity through an immune-independent manner during influenza virus infection. Deletion of BCAR4 inhibited influenza virus replication via suppressing viral RNA transcription and replication, as well as subsequent viral protein synthesis. The activation of BCAR4 was achieved through a potential promoter-enhancer interaction in response to influenza virus infection and was associated with impeded spliceosomes function. This study reveals the profile signatures of lncRNAs in influenza virus infection and identifies novel ISRE-dependent lncRNAs, providing more information and laying a solid foundation for further studies. Elaborate study in USP30-AS1 reveals that influenza virus infection triggers immune effectors, as well as immune regulators, which plays an equally critical role to maintain a fine-tuned immune response. Moreover, the study of USP30-AS1 provides an possible explanation for tissue damage caused by HPAIs induced acute inflammatory response, implying USP30-AS1 may serve as a potential therapeutic target for attenuating severe inflammation induced by HPAIs infection. The study of BCAR4 gains key clues that influenza virus may trigger BCAR4-dependent emergency splicing working mode in cells by inducing cell stresses and that this BCAR4-dependent splicing machinery is required for influenza virus replication. The study also indicates that USP30-AS1 and BCAR4 is universally triggered under different biological processes during influenza virus infection and highlights that the potential value of USP30-AS1 and BCAR4 for prospective clinical application.