Circular RNAs in Immune Response and Viral Infection

Abstract

Circular RNAs (circRNAs) are a diverse class of RNAs with varying sizes, cellular abundance, and biological functions. Investigations from the past decade have revealed that circRNAs are ubiquitously found in eukaryotes and have defined the different biological roles of circRNAs to illuminate this previously unrecognized class of molecules. In the context of the immune system, immune responses and immune-related diseases alter circRNA expression. More recently, several oncogenic double-stranded DNA viruses have been found to encode circRNAs. In this review, we summarize the current understanding of circRNAs and their emerging functions in immune regulation and autoimmune disorders, and discuss the identification and potential roles of viral circRNAs during infections. Finally, we present promising areas for future investigations in the nascent field of circRNAs.

Keywords: DNA virus; N6-methyladenosine (m(6)A); autoimmune disease; self/non-self; virus-encoded circRNA.

Figure 1 |. CircRNAs in Immune Responses

Under normal conditions, the immune factors NF90/NF110 promote the formation of circRNAs by stabilizing the intronic complementary sequences. After back-splicing, endogenous circRNAs are marked by the m⁶A modification and exported to the cytoplasm where they can be recognized as self to bind immune regulators NF90/NF110 and PKR. Upon viral infection, nuclear NF90/NF110 translocate to the cytoplasm, which decreases circRNA production. Thus, fewer cytoplasmic circRNAs are available to interact with NF90/NF110 and PKR. Meanwhile, double-stranded viral RNAs activate 2’,5’-oligoadenylate synthetase (OAS) to produce 2’−5’-oligoadenylates (2–5A) and stimulate endonuclease RNase L to degrade endogenous circRNAs. Following the release of PKR, the receptor then binds to viral RNA and inhibits virus replication. Exogenous circRNAs without m⁶A modification are recognized by immune receptor RIG-I to trigger an immune response to suppress viral infection.

Figure 2 |. Potential Functions of CircRNAs Encoded by DNA Viruses

DNA viruses, EBV, KSHV, and HPV, encode circRNAs. EBV contains multiple circRNAs from several gene loci of the EBV genome. The EBV circRNAome may function as sponges for host miRNAs to regulate EBV infection and oncogenesis. KSHV generates several circRNAs that can be incorporated into virus particles, which may play a role in virus infection. CircE7 derived from HPV can be translated in a cap-independent manner to produce an oncoprotein that plays an important role in the transformed growth of cancer cells.