Circular RNA circDtx1 regulates IRF3-mediated antiviral immune responses through suppression of miR-15a-5p-dependent TRIF downregulation in teleost fish

Circular RNAs (circRNAs) represent a class of widespread and diverse covalently closed circular endogenous RNAs that exert crucial functions in regulating gene expression in mammals. However, the function and regulation mechanism of circRNAs in lower vertebrates are still unknown. Here, we discovered a novel circRNA derived from Deltex E3 ubiquitin ligase 1 (Dtx1) gene, namely, circDtx1, which was related to the antiviral responses in teleost fish. Results indicated that circDtx1 played essential roles in host antiviral immunity and inhibition of SCRV replication. Our study also found a microRNA miR-15a-5p, which could inhibit antiviral immune response and promote viral replication by targeting TRIF. Moreover, we also found that the antiviral effect inhibited by miR-15a-5p could be reversed with the circDtx1. In mechanism, our data revealed that circDtx1 was a competing endogenous RNA (ceRNA) of TRIF by sponging miR-15a-5p, leading to activation of the NF-kappa B/IRF3 pathway, and then enhancing the innate antiviral responses. Our results indicated that circRNAs played a regulatory role in immune responses in teleost fish. Author summary Increasing evidence indicates that circRNAs participate in innate and adaptive immunity. However, the relationship between circRNAs and host antiviral responses remains unknown, particularly in lower vertebrates. Our results provided direct evidence that a circRNA, namely, circDtx1, is related to the antiviral responses in lower vertebrates. In addition, our study also found a microRNA, namely, miR-15a-5p, which could inhibit an antiviral immune response and promote viral replication by targeting TRIF. Moreover, circRNAs can serve as competing endogenous RNAs (ceRNAs) and cross-talk with mRNAs by competing shared miRNAs. Such ceRNAs regulate the distribution of miRNA molecules on their targets and apply an additional level of post-transcriptional regulation. In our study, circDtx1 functions as a ceRNA for miR-15a-5p to control protein abundance of fish TRIF, thereby inhibiting viral replication and promoting antiviral responses. Our study demonstrates the ceRNA regulatory networks existing in lower vertebrates, which can provide new insights into understanding the effects of circRNAs on host-virus interactions.

Automated summary

Our study identified a novel circRNA, circDtx1, in teleost fish that is related to antiviral responses, as well as a microRNA, miR-15a-5p, which inhibits antiviral immune responses and promotes viral replication by targeting TRIF. CircDtx1 acts as a competing endogenous RNA that regulates miR-15a-5p, activating the NF-kappa B/IRF3 pathway and enhancing innate antiviral responses. This study provides insights into the regulatory role of circRNAs in immune responses in lower vertebrates.