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

Significance The cap structure present at the 5′ end of eukaryotic messenger RNAs (mRNAs) regulates RNA stability, translation, and marks mRNA as self, thereby impeding recognition by the innate immune system. Cellular transcripts beginning with adenosine are additionally modified at the N6 position of the 2’-O methylated cap-proximal residue by the methyltransferase PCIF1 to m7Gpppm6Am. We define a function for this N6-adenosine methylation in attenuating the interferon-β–mediated suppression of viral infection. Cells lacking PCIF1, or defective in its enzymatic activity, augment the cell-intrinsic suppressive effect of interferon-β treatment on vesicular stomatitis virus (VSV) and rabies virus (RABV) gene expression. VSV and RABV mRNAs are efficiently methylated by PCIF1, suggesting this contributes to viral evasion of innate immune suppression. 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.