Circular RNAs and Their Emerging Roles in Immune Regulation

Abstract

Circular ribonucleic acid (RNA) molecules (circRNAs) are covalently closed loop RNA molecules with no 5' end caps or 3' poly (A) tails, which are generated by back-splicing. Originally, circRNAs were considered to be byproducts of aberrant splicing. However, in recent years, development of high-throughput sequencing has led to gradual recognition of functional circRNAs, and increasing numbers of studies have elucidated their roles in cancer, neurologic diseases, and cardiovascular disorders. Nevertheless, studies of the functions of circRNAs in the immune system are relatively scarce. In this review, we detail relevant research on the biogenesis and classification of circRNAs, describe their functional mechanisms and approaches to their investigation, and summarize recent studies of circRNA function in the immune system.

Keywords: biogenesis; circRNA; function; immune regulation; research approaches.

Figure 1

Formation and classification of circRNAs and models of circRNA function. circRNAs are formed by back-splicing. There are three major types of circRNA: ecircRNA, ciRNA, and EIciRNA. EcircRNAs function mainly in the cytoplasm through the “microRNA sponge” mechanism, whereas EIciRNA and ciRNA accumulate in the nucleus and facilitate transcription of their parent genes via cis-regulatory effects. In addition, some circRNAs have been reported to act by interacting with or encoding proteins.

Figure 2

CircRNAs in immune responses. Exogenous circRNAs can activate the RIG-1 cellular immune response pathway to suppress viral replication. The immune factor NF90/NF110 can promote circRNA formation by stabilizing the intron complementary sequence. Under viral infection, NF90/NF110 is exported from the nucleus to the cytoplasm to inhibit virus replication. Meanwhile, circRNA expression in the nucleus is decreased. Thus, endogenous circRNAs can be used as “molecular indicators” of antiviral proteins to prompt antiviral immune responses. circRNAs can also function as “microRNA sponges” to increase expression of target proteins involved in antiviral responses or tumor immunity, such as PD-L1. mcircRasGEF1B can help to protect cells from bacterial infection by enhancing the stability of mature ICAM-1 mRNA. In addition, circRNAs can be involved in immune responses by interacting with proteins or their host genes.