Interferon induced circRNAs escape herpesvirus host shutoff and suppress lytic infection

Author:

Dremel, Sarah E

Tagawa, Takanobu [ORCID]

Koparde,Vishal [ORCID]

Hernandez-Perez, Carmen

Arbuckle, Jesse H [ORCID]

Kristie, Thomas M [ORCID]

Krug, Laurie T

Ziegelbauer, Joseph M [ORCID]
Author Address

HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, 20892, USA., CCR Collaborative Bioinformatics Resource, National Cancer Institute, Bethesda, 20892, USA., Frederick National Laboratory for Cancer Research Advanced Biomedical Computational Sciences, Leidos Biomedical Research, Inc., Frederick, 21701, USA., Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, 20892, USA., HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, 20892, USA. ziegelbauerjm@nih.gov.,

Abstract:

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-ß or -gamma 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. © 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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