CK2 phosphorylation of CMTR1 promotes RNA cap formation and influenza virus infection

The RNA cap methyltransferase CMTR1 methylates the first transcribed nucleotide of RNA polymerase II transcripts, impacting gene expression mechanisms, including during innate immune responses. Using mass spectrometry, we identify a multiply phosphorylated region of CMTR1 (phospho-patch [P-Patch]), which is a substrate for the kinase CK2 (casein kinase II). CMTR1 phosphorylation alters intramolecular interactions, increases recruitment to RNA polymerase II, and promotes RNA cap methylation. P-Patch phosphorylation occurs during the G1 phase of the cell cycle, recruiting CMTR1 to RNA polymerase II during a period of rapid transcription and RNA cap formation. CMTR1 phosphorylation is required for the expression of specific RNAs, including ribosomal protein gene transcripts, and promotes cell proliferation. CMTR1 phosphorylation is also required for interferon-stimulated gene expression. The cap-snatching virus, influenza A, utilizes host CMTR1 phosphorylation to produce the caps required for virus production and infection. We present an RNA cap methylation control mechanism whereby CK2 controls CMTR1, enhancing co-transcriptional capping. [Display omitted] •CK2 phosphorylates the RNA cap methyltransferase CMTR1, resulting in binding to RNA Pol II•CMTR1 P-Patch phosphorylation is required for RNA cap methylation and gene expression•Expression of interferon-stimulated genes (ISGs) is dependent on CMTR1 P-Patch phosphorylation•Influenza A, a cap-snatching virus, is dependent on CMTR1 phosphorylation for infection Lukozek et al. report that the RNA cap methyltransferase CMTR1 is phosphorylated by CK2, which promotes the interaction with RNA Pol II and RNA cap formation. CMTR1 phosphorylation is required for ribosomal protein gene expression and the interferon response. Propagation of the cap-snatching influenza virus depends on host CMTR1 phosphorylation.