Interferon induced circRNAs escape herpesvirus host shutoff and suppress lytic infection

• Published in: EMBO reports Vol. 25; no. 3; pp. 1541 - 1569
• Main Authors: Dremel, Sarah E, Tagawa, Takanobu, Koparde, Vishal N, Hernandez-Perez, Carmen, Arbuckle, Jesse H, Kristie, Thomas M, Krug, Laurie T, Ziegelbauer, Joseph M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.03.2024
• Subjects: Animals; Antiviral Agents; Biomedical and Life Sciences; EMBO19; EMBO23; EMBO36; Herpes Simplex; Herpesviridae; Humans; Interferons; Life Sciences; Mice; RNA, Circular; RNA, Messenger; Simplexvirus; Circular RNAs; Herpesviruses; Host Shutoff; Interferon-stimulated Genes
• ISSN: 1469-3178; 1469-221X; 1469-3178
• DOI: 10.1038/s44319-023-00051-z

To globally profile circRNAs, we employ RNA-Sequencing paired with chimeric junction analysis for alpha-, beta-, and gamma-herpesvirus infection. We find circRNAs are, as a population, resistant to host shutoff. We validate this observation using ectopic expression assays of human and murine herpesvirus endoribonucleases. During lytic infection, four circRNAs are commonly induced across all subfamilies of human herpesviruses, suggesting a shared mechanism of regulation. We test one such mechanism, namely how interferon-stimulation influences circRNA expression. 67 circRNAs are upregulated by either interferon-β or -γ treatment, with half of these also upregulated during lytic infection. Using gain and loss of function studies we find an interferon-stimulated circRNA, circRELL1, inhibits lytic Herpes Simplex Virus-1 infection. We previously reported circRELL1 inhibits lytic Kaposi sarcoma-associated herpesvirus infection, suggesting a pan-herpesvirus antiviral activity. We propose a two-pronged model in which interferon-stimulated genes may encode both mRNA and circRNA with antiviral activity. This is critical in cases of host shutoff, such as alpha- and gamma-herpesvirus infection, where the mRNA products are degraded but circRNAs escape. Synopsis Comparative profiling of circRNAs during alpha-, beta-, and gamma-herpesvirus infection establishes circRNAs as host shutoff escapees. circRELL1 inhibits herpesvirus replication and is induced by infection and interferon-stimulation. Levels of circRNAs are globally profiled during alpha-, beta-, and gamma-herpesvirus infection. circRNAs are resistant to herpesvirus endoribonucleases. 67 circRNAs are upregulated by either interferon-β or -γ treatment. Interferon-stimulated circRELL1 inhibits HSV-1 lytic infection. Comparative profiling of circRNAs during alpha-, beta-, and gamma-herpesvirus infection establishes circRNAs as host shutoff escapees. circRELL1 inhibits herpesvirus replication and is induced by infection and interferon-stimulation.