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eSymposia | RNA Editing and Modifications: From Biology to Therapy


Cap-proximal N6-methylation protects viral mRNA against interferon beta pretreatment


Sep 30, 2020 12:00am ‐ Sep 30, 2020 12:00am

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Cap-proximal N6-methylation protects viral mRNA against interferon beta pretreatment Abstract: Vesicular stomatitis virus (VSV) mRNAs contain a 5’ cap structure m7GpppAm synthesized by the viral large polymerase protein (L). A host enzyme further N6-methylates viral mRNA cap structures to produce m7Gpppm6Am during infection. We report that the cellular methyltransferase PCIF1 carries out this modification on viral mRNA cap structures, modifying most of the viral mRNA in cells. We define cis acting requirements for modification of viral mRNA and demonstrate that neither mRNA stability nor translation are affected by this methylation. However, pretreatment of cells with interferon uncovered an advantage for viral mRNA in the presence of PCIF1. The suppressive effect of interferon on viral replication was blunted for PCIF1 modified viral mRNAs, facilitating ongoing viral gene expression. This study identifies a role for cap-proximal m6Am in countering innate immune effectors induced upon interferon beta treatment of cells in culture. Continuing work will uncover whether m6Am mediates the direct targeting of viral mRNA, or indirectly modifies the host ISG response. Authors and Affiliations: Michael A. Tartell 1,2, Konstantinos Boulias 3, Eric Lieberman Greer 3 and Sean P. J. Whelan 2 1: Program in Virology, Harvard Medical School, Boston MA, USA 2: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA 3: Department of Pediatrics, Boston Children’s Hospital, Boston MA, USA

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