Roles of circRNAs in viral pathogenesis

Abstract

Circular RNAs (circRNAs) are a class of non-coding RNAs with a covalently closed circular structure, lacking 5'-caps or 3'-poly(A) tails. They are relatively conserved, highly stable, and often exhibit tissue- or cell-specific production in eukaryotic cells. Based on the advances in sequencing technologies and bioinformatics, multiple reports have suggested that viruses and other microorganisms may encode circRNA-like molecules, providing new insights into the physiological and pathological roles of circRNAs. The innate immune system functions as the body's primary defense mechanism against viral infections. It detects pathogen-associated molecular patterns (PAMPs) and activates signaling pathways to suppress viral replication and limit their spread. CircRNAs are involved in regulation of the host innate immune signaling pathways and play essential roles in viral pathogenesis. It has been shown that circRNAs can regulate gene expression by acting as miRNA sponges or protein sponges, or encoding small proteins in specific cases. For example, previous studies have revealed that circRNAs participate in the host antiviral immune response through the competitive endogenous RNA (ceRNA) network by acting as miRNA sponges. This review highlights research progress in the regulation and functions of host- and virus-encoded circRNAs in host-virus interactions, as well as their potential as diagnostic biomarkers and therapeutic targets in clinical applications.

Keywords: CircRNAs; host-virus interaction; influenza; oncogenic virus; virus infection.

Figure 1

Roles of circRNAs in virus-host interaction. (A) As miRNA sponges, host-encoded circRNAs regulate viral infection by affecting antiviral responses, impacting autophagy, modulating cell migration and invasion, and promoting viral replication. For example, ZIKV infection inhibits the binding of hsa_circ_0007321 to miR-492, increasing the availability of miR-492 to bind to NFKBID mRNA. This activates the NF-κB pathway and upregulates IL-6 and IL-8 expression (Kang et al., 2023b). SVA infection upregulates circ_8521, preventing the binding of miR-324 to LC3A mRNA and enhancing LC3A expression (Yang et al., 2024). KSHV induces the expression of vIRF1, which binds to Lef1 and promotes the interaction between circARFGEF1 and miR-125a-3p while reducing the interaction between miR-125a-3p and GLRX3 mRNA. This increases GLRX3 expression, promoting cell migration and invasion (Yao et al., 2021). HBV upregulates circBACH1, which reduces the interaction between miR-200a-3p and MAP3K2 mRNA, leading to increased MAP3K2 expression and enhance HBV replication (Du et al., 2022a). (B) KSHV, EBV, and CMV promote circ_0001400 expression, which induces G2 cell cycle arrest and inhibits apoptosis through the PI3K/AKT/mTOR pathway (Tagawa et al., 2023). (C) IAV upregulates circVAMP3, which acts as a decoy by binding to NS1, leading to increased IFN-β expression (Min et al., 2023). Created with BioRender.com (accessed on 22 February 2025).