Circular RNAs: A novel type of non-coding RNA and their potential implications in antiviral immunity

Abstract

Circular RNAs (circRNAs), a novel type of non-coding RNAs (ncRNAs), are ubiquitously expressed in eukaryotic cells during post-transcriptional processes. Unlike linear RNAs, circRNAs form covalent-closed continuous loops without 5' to 3' polarities and poly (A) tails. With advances in high-throughput sequencing technology, numerous circRNAs have been identified in plants, animals and humans. Notably, circRNAs display cell-type, tissue-type and developmental-stage specific expression patterns in eukaryotic transcriptome, which reveals their significant regulatory functions in gene expression. More importantly, circRNAs serve as microRNA (miRNA) sponges and crucial regulators of gene expression. Additionally, circRNAs modulate pre-mRNA alternative splicing and possess protein-coding capacity. CircRNAs exhibit altered expression under pathological conditions and are strongly associated with the development of various human diseases. Interestingly, circRNAs can also induce antiviral immune responses. A recent study found that the delivery of circRNAs generated in vitro activates RIG-I-mediated innate immune responses and provides protection against viral infection. The antiviral dsRNA-binding proteins, NF90/NF110, act as key regulators in circRNA biogenesis. NF90/NF110 are also functional in inhibiting viral replication through binding to viral mRNAs. In this review, we provide a comprehensive overview on the classification, biogenesis and functions of circRNAs. We also discuss the critical role of circRNAs in eliciting antiviral immunity, providing evidence for the potential implications of circRNAs in antiviral therapies.

Keywords: antiviral immunity; circular RNA; microRNA sponge.

Figure 1

The categories of circRNAs. Pre-mRNA can be processed through either canonical splicing to produce linear RNAs (left) or backsplicing to generate circRNAs (right). CircRNAs are mainly divided into three categories based on their components. Exonic circRNAs (ecircRNAs) are exclusively composed of exons and represent the largest group of circRNAs. ElciRNAs retain intronic sequences between the back-spliced exons (at least two) and predominantly exist in the nucleus. Circular intronic RNAs (ciRNAs) are generated only from intron lariats and constitute a small class of circRNAs.

Figure 2

The functional role of circRNAs in antiviral immunity. The immune factors NF90/NF110 promote circRNA biogenesis via interacting with the introns flanking circRNA-forming exons. Upon viral infection, NF90/NF110 are released from the circRNPs and exported from the nucleus to the cytoplasm, which leads to a decreased level of circRNAs. The released NF90/NF110 suppress viral replication through binding to viral mRNAs. In host cells, endogenous circRNAs generally bind to RNA-binding proteins (RBPs). These RBPs serve to mark 'self' circRNAs, which allows host cells to distinguish 'self' circRNAs from foreign circRNAs. Foreign circRNAs can activate RIG-I-mediated innate immune responses, thereby protecting host cells from viral infection. CircRNAs can also act as miRNA sponges and upregulate the expression of target proteins that are involved in immune-related pathways.