Viruses join the circular RNA world

Abstract

Circular RNAs (circRNAs) are a recently discovered class of noncoding RNAs found in many species across the eukaryotic kingdom. These intriguing RNA species are formed through a unique mechanism that is known as back splicing in which the 5' and 3' termini are covalently joined. Recent research has revealed that viruses also encode a repertoire of circRNAs. Some of these viral circRNAs are abundantly expressed and are reported to play a role in disease pathogenesis. A growing number of studies also indicate that host circRNAs are involved in immune responses against virus infections with either an antiviral or proviral role. In this review, we briefly introduce circRNA, its biogenesis, and mechanism of action. We go on to summarize the latest research on the expression, regulation, and functions of viral and host-encoded circRNAs during the host-virus interaction, with the aim of highlighting the potential of viral and host circRNAs as a suitable target for diagnostic biomarker development and therapeutic treatment of viral-associated diseases. We conclude by discussing the current limitations in knowledge and significance of elucidating the roles of circRNAs in host-virus interactions, as well as future directions for this emerging field.

Keywords: circRNA; circular RNA; miRNA sponge; noncoding RNA; virus.

Fig. 1

Biogenesis of circRNA. Three hypothetical models for circRNA biogenesis mechanisms have been widely accepted, including (1) RBP‐mediated circularization [6, 8, 9]. RBP (e.g., QKI, MBL) is a trans‐factor that regulates circularization through the binding of specific sequence motifs on introns flanking exon(s) to be circularized on a linear pre‐mRNA, and dimerize to facilitate backsplicing; (2) intron pairing‐driven circularization [10, 11]. This model utilizes the presence of inverted complementary sequences in flanking intronic regions (e.g., Alu repeats) that may promote alternative circularization through intron pairing; and (3) Lariat‐driven circularization which starts with canonical splicing, resulting in the production of linear mRNA with skipped exon(s) within a long intron lariat. Subsequently, internal splicing facilitates the removal of flanking intronic sequence, allowing the generation of circRNA [12, 13]. SA, splicing acceptor; SD, splicing donor.

Fig. 2

Biological functions of circRNAs. circRNA (ciRS‐7, cir‐ITCH) acts as a (1) miRNA sponge that may compete with other classes of RNA for miRNA‐binding sites and perturb the complex network of interaction and gene regulation [16, 17, 18, 19, 20]; (2) RBP sponge [9, 21] and protein regulator [23, 24]. circRNAs (e.g., circFoxo3) are able to bind, store, sort, and sequester proteins to particular subcellular locations, and act as dynamic scaffolding molecules that modulate protein–protein interactions; (3) regulates transcription of parental gene in cis‐ or trans‐manners through interacting with U1 snRNP and promote transcription of their parental genes (e.g., circEIF3J and circPAIP2); recruiting TET1 demethylase to induce DNA demethylation of promoter or interacting with DNMT1 promoter that results in DNMT1 silencing (e.g., circFECR1) [12, 22]; (4) mRNA trap (e.g., circMbl) whereby the formation of circRNA competes with linear mRNA production [9]; and (5) template for circRNA translation (e.g., circβ‐catenin) as it contains an open reading frame (ORF) [25, 26, 27].

Fig. 3

Mechanism of actions of viral and host circRNAs during viral infection. DNA viruses (EBV [38, 39, 42, 43], KSHV [39, 40, 47], HPV [49, 50], and HBV [52, 53])—transcribed viral circRNAs contribute to disease pathogenesis by acting as miRNA sponge, oncoprotein producer, and affecting hallmarks of cancer. RNA viruses (HCV [70], DENV [70], H1N1 IAV [69], and MERS‐CoV [71]) regulate host circRNA expression to promote viral replication. Poly(I:C) treatment upregulates host circRNA to trigger TLR3 and RIG‐I signaling pathway through miRNA sponging.

Fig. 4

Regulation of host and viral circRNAs by host immune response during viral infection. In noninfected cells, NF90/NF110 localized to the nuclear to promote circRNA biogenesis [63]. Upon viral infection, NF90/NF110 is exported to the cytoplasm to suppress viral replication by targeting viral mRNA. OAS‐activated RNase L would degrade cellular dsRNA‐containing circRNAs bound to PKR that eventually lead to the release and activation of PKR. Both exogenous (not m⁶A‐modified) and degraded circRNAs are postulated to activate RIG‐I [58, 64]. Activation of PKR and RIG‐1 ultimately leads to innate immune response to eliminate virus in the host. However, it remains inconclusive if exogenous circRNA is immunogenic [57, 58, 61].