Circular RNAs (circRNAs) as novel regulatory molecules have been recognized in diverse species, including viruses. The virus-derived circRNAs play various roles in the host biological process and the life cycle of the viruses. This review summarized the circRNAs from the DNA and RNA viruses and discussed the biogenesis of viral and host circRNAs, the potential roles of viral circRNAs, and their future perspective. This review will elaborate on new insights gained on viruses encoded circRNAs during virus infection.
The pathogenesis of Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) infection is unclear, although accumulating evidence indicates that circular RNAs (circRNAs), which act as competing endogenous RNAs or positive regulators, play important roles in regulating gene expression in eukaryotes and, thus, may play a role in BmCPV infections. To explore the expression and biological functions of circRNAs in the silkworm midgut following BmCPV infection, silkworm circRNA expression profiles of normal midgut tissue (control) and BmCPV-infected midgut tissue (test) were determined using high-through sequencing. A total of 9,753 and 7,475circRNAs were detected from the control and test samples, respectively. The two samples shared 6,085 circRNAs, while 646 and 737 circRNAs were expressed specifically in the control and test samples, respectively. A total of 3,638 circRNAs were shown to be differentially expressed, and 400 circRNAs were substantially differentially expressed with a fold-change ≥ 2.0 (p< 0.05 and a false discover rate < 0.05), of which 294 were up-regulated and 106 were down-regulated following infection. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted to determine the principal functions of the substantially differentially regulated genes. circRNA-miRNA interaction networks were constructed based on a correlation analysis between the differentially expressed circRNAs and the nature of their microRNA (miRNA) binding sites. The network inferred that 13 miRNAs interacting with 193 circRNAs were among the 300 most abundant relationships. bmo-miR-3389-5p, bmo-miR-745-3p, and bmo-miR-3262 were related to 30, 34, and 34 circRNAs, respectively. circRNA_8115, circRNA_9444, circRNA_4553, circRNA_0827, and circRNA_6649 contained six, five, four, four, and four miRNA binding sites, respectively. We further found that alternative circularization of circRNAs is a common feature in silkworms and that the junction sites of many silkworm circRNAs are flanked by canonical GT/AG splicing signals. Our study is the first to show the circRNA response to virus infection. Thus, it provides a novel perspective on circRNA-miRNA interactions during BmCPV pathogenesis, and it lays the foundation for future research of the potential roles of circRNAs in BmCPV pathogenesis.
Our previous study has confirmed that HBV_circ_1, a circular RNA derived from HBV pgRNA/pcRNA with two junction sites (junction A and junction B), prohibitin 2 (PHB2) is a candidate interaction protein of HBV_circ_1 and hepatocellular carcinoma (HCC) progression can be promoted by HBV_circ_1. However, it is still unknown how HBV_circ_1 is formed and how it functions. In this study, we indicated that the junction site A of HBV_circ_1 was formed by joining the two ends of pgRNA/pcRNA after removing the non-repeating sequence located at the 5' and 3' terminals and one of the repeating units, which was driven by the repeated sequences at the 3′- and 5′-terminal of pgRNA/ pcRNA. HBV_circ_1 inhibited autophagy in tumor cells, but HBV_ circ_ 1 did not affect the expression of key genes related to the autophagy initiation complex. Furthermore, HBV_circ_1 interacted with PHB2 and blocked the binding of PHB2 to LC3, resulting in the blockage of autophagy. Mutation of HBV_circ_1 failed to block the binding of PHB2 to LC3 and lost the ability to inhibit autophagy. In vivo experiment showed that the mice injected with cells overexpressing mutated HBV_circ_1 formed smaller tumors, and had lower p62 expression level in the tumor formed by the mutated HBV_circ_1 compared with that overexpressing HBV_circ_1, suggesting HBV-related HCC progression can be promoted by blocking mitophagy through competitively binding of HBV_circ_1 to PHB2 with LC3. These studies provide a new perspective for understanding the carcinogenesis of HBV_circ_1, and HBV_circ_1 may be a target in HBV-related HCC treatment.Funding: This work was supported by the China Postdoctoral Science Foundation (2021M702397), the Jiangsu Higher Education Institutions of China (grant no.19KJB320005), a project funded by the Priority Academic Program of Development of Jiangsu Higher Education Institutions.Declaration of Interest: The authors declare no competing interests.Ethical Approval: The procedures for care and use of animals were approved by the Ethics Committee of Soochow University and all applicable institutional and governmental regulations concerning the ethical use of animals were followed.
Bombyx mori cypovirus (BmCPV), a member of the Reoviridae, specifically infects silkworms and causes extensive economic losses to the sericulture industry. To date, the entry mechanism of BmCPV into cells is unclear. Here we used electron microscopy to study the route of entry of BmCPV into cells, and the results demonstrated that the entry of BmCPV into BmN cells was mediated by endocytosis. Blocking the entry pathway with four endocytosis inhibitors, including dansylcadaverine, chlorpromazine, genistein, and PP2, significantly decreased the infectivity of BmCPV. This indicates that BmCPV enters BmN cells via endocytosis, and that clathrin-mediated sorting is the predominant entry method. After the relative expression levels of clathrin heavy chain (clathrin, GenBank accession No. NM_001142971.1) and the adaptor protein complex-1 gamma subunit AP-1 (AP-1, GenBank accession No. JQ824201.1), which are involved in clathrin-mediated endocytosis, were inhibited by RNA interference or abolishing the functions of clathrin and AP-1 with their corresponding antibodies, the infectivity of BmCPV was reduced significantly, which suggests that clathrin-mediated endocytosis contributed to the entry of BmCPV into cells. Our findings suggest that the clathrin-mediated endocytosis pathway is a candidate for the development of therapeutics for silkworm cytoplasmic polyhedrosis.
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