Abstract
Viruses subvert macromolecular pathways in infected host cells to aid in viral gene amplification or to counteract innate immune responses. Roles for host-encoded, noncoding RNAs, including microRNAs, have been found to provide pro- and anti-viral functions. Recently, circular RNAs (circRNAs), that are generated by a nuclear back-splicing mechanism of pre-mRNAs, have been implicated to have roles in DNA virus-infected cells. This study examines the circular RNA landscape in uninfected and hepatitis C virus (HCV)-infected liver cells. Results showed that the abundances of distinct classes of circRNAs were up-regulated or down-regulated in infected cells. Identified circRNAs displayed pro-viral effects. One particular up-regulated circRNA, circPSD3, displayed a very pronounced effect on viral RNA abundances in both hepatitis C virus- and Dengue virus-infected cells. Though circPSD3 has been shown to bind factor eIF4A3 that modulates the cellular nonsense-mediated decay (NMD) pathway, circPSD3 regulates RNA amplification in a pro-viral manner at a post-translational step, while eIF4A3 exhibits the anti-viral property of the NMD pathway. Findings from the global analyses of the circular RNA landscape argue that pro-, and likely, anti-viral functions are executed by circRNAs that modulate viral gene expression as well as host pathways. Because of their long half-lives, circRNAs likely play hitherto unknown, important roles in viral pathogenesis.
Highlights
IntroductionCircular RNAs (circRNAs) were first detected in plant viral RNA pathogens, termed viroids [1]
Circular RNAs were first detected in plant viral RNA pathogens, termed viroids [1]
Host-derived circular RNA molecules have recently been discovered in the cytoplasm of cells, as-of yet, few functions
Summary
Circular RNAs (circRNAs) were first detected in plant viral RNA pathogens, termed viroids [1]. It has shown that eukaryotic cells express circRNAs as well [2, 3]. Some circRNAs contain scrambled exons, which are produced by an abnormal splicing mechanism [4]. An abundance of thousands of circular RNAs were identified by their distinct 3’-to-5’ junctions using algorithms such as findcirc or KNIFE [10,11,12,13]. These approaches revealed that approximately 5,000 to 25,000 circRNAs exist per cell, with 20% of transcribed genes producing unique circRNAs that can be expressed in a tissue-specific manner [10, 14]
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