Methylation of viral mRNA cap structures by PCIF1 attenuates the antiviral activity of interferon-β.

Michael A Tartell, Konstantinos Boulias, Gabriela Brunsting Hoffmann, Louis-Marie Bloyet, Eric Lieberman Greer, Sean P J Whelan

Proceedings of the National Academy of Sciences of the United States of America 2021 Jul 20

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Interferons induce cell-intrinsic responses associated with resistance to viral infection. To overcome the suppressive action of interferons and their effectors, viruses have evolved diverse mechanisms. Using vesicular stomatitis virus (VSV), we report that the host cell N6-adenosine messenger RNA (mRNA) cap methylase, phosphorylated C-terminal domain interacting factor 1 (PCIF1), attenuates the antiviral response. We employed cell-based and in vitro biochemical assays to demonstrate that PCIF1 efficiently modifies VSV mRNA cap structures to m7Gpppm6Am and define the substrate requirements for this modification. Functional assays revealed that the PCIF1-dependent modification of VSV mRNA cap structures is inert with regard to mRNA stability, translation, and viral infectivity but attenuates the antiviral effects of the treatment of cells with interferon-β. Cells lacking PCIF1 or expressing a catalytically inactive PCIF1 exhibit an augmented inhibition of viral replication and gene expression following interferon-β treatment. We further demonstrate that the mRNA cap structures of rabies and measles viruses are also modified by PCIF1 to m7Gpppm6Am This work identifies a function of PCIF1 and cap-proximal m6Am in attenuation of the host response to VSV infection that likely extends to other viruses.

Citation

Michael A Tartell, Konstantinos Boulias, Gabriela Brunsting Hoffmann, Louis-Marie Bloyet, Eric Lieberman Greer, Sean P J Whelan. Methylation of viral mRNA cap structures by PCIF1 attenuates the antiviral activity of interferon-β. Proceedings of the National Academy of Sciences of the United States of America. 2021 Jul 20;118(29)