TY - JOUR
T1 - Interferon induced circRNAs escape herpesvirus host shutoff and suppress lytic infection
AU - Dremel, Sarah E
AU - Tagawa, Takanobu
AU - Koparde, Vishal N
AU - Hernandez-Perez, Carmen
AU - Arbuckle, Jesse H
AU - Kristie, Thomas M
AU - Krug, Laurie T
AU - Ziegelbauer, Joseph M
N1 - This work was supported by the Intramural Research Program of the National Cancer Institute (JMZ; 1ZIABC011176, LTK; 1ZIABC011953) and National Institute of Allergy and Infectious Diseases (TMK; 1ZIAAI000712). TT was funded by a research fellowship from the Japan Society for the Promotion of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank the Center for Cancer Research Sequencing Facility (Frederick, MD) for their assistance in sequencing libraries. The resources of the NIH High-Performance Computing BIOWULF Cluster were utilized for all our computational needs. We thank Mandy Muller (University of Massachusetts Amherst) for plasmids containing viral endonucleases. We thank Neal DeLuca (University of Pittsburgh) for HSV-1 (strain KOS). We thank Bill Sugden (University of Wisconsin Madison) for providing B cell lymphoma cell lines.
PY - 2024/3/12
Y1 - 2024/3/12
N2 - 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 SimplexVirus-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
AB - 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 SimplexVirus-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
KW - Circular RNAs
KW - Herpesviruses
KW - Host Shutoff
KW - Interferon-stimulated Genes
UR - https://doi.org/10.1038/s44319-023-00051-z
U2 - 10.1038/s44319-023-00051-z
DO - 10.1038/s44319-023-00051-z
M3 - Article
SN - 1469-221X
VL - 25
SP - 1541
EP - 1569
JO - EMBO Reports
JF - EMBO Reports
IS - 3
ER -