The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

Abstract

<jats:title>Abstract</jats:title><jats:p>Type I interferons (IFN) initiate an antiviral state through a signal transduction cascade that leads to the induction of hundreds of IFN-stimulated genes (ISGs) to restrict viral infection. Recently, RNA modifications on both host and viral RNAs have been described as regulators of infection. However, the impact of host mRNA cap modifications on the IFN response and how this regulates viral infection is unknown. Here, we reveal that CMTR1, an ISG that catalyzes 2’O methylation of the first transcribed nucleotide in cellular mRNA (Cap 1), promotes the protein expression of specific ISGs that contribute to the antiviral response. Depletion of CMTR1 reduces the IFN-induced protein levels of ISG15, MX1, and IFITM1, without affecting their transcript abundance. However, CMTR1 depletion does not significantly affect the IFN-induced protein or transcript abundance of IFIT1 and IFIT3. Importantly, knockdown of IFIT1, which acts with IFIT3 to inhibit the translation of RNAs lacking Cap 1 2’O methylation, restores protein expression of ISG15, MX1, and IFITM1 in cells depleted of CMTR1. Finally, we found that CMTR1 plays a role in restricting RNA virus replication, likely by ensuring the expression of specific antiviral ISGs. Taken together, these data reveal that CMTR1 is required to establish an antiviral state by ensuring the protein expression of a subset of ISGs during the type I IFN response.</jats:p><jats:sec><jats:title>Importance</jats:title><jats:p>Induction of an efficient type I IFN response is important to control viral infection. We show that the host 2’O methyltransferase CMTR1 facilitates the protein expression of ISGs in human cells by preventing IFIT1 from inhibiting the translation of these mRNAs lacking cap 2’O methylation. Thus, CMTR1 promotes the IFN-mediated antiviral response.</jats:p></jats:sec>

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“…Mutations in RNaseH2 are thought to disrupt the degradation of immuno‐stimulating nucleic acids and cause innate immune activation (Reijns & Jackson, 2014). CMTR1 is a mRNA methyltransferase and a known regulator of protein expression of IFN‐stimulated genes to restrict viral infection (Williams et al, 2020). SETD3, also a methyltransferase, is a human host protein critical for infection of a wide range of viruses and participates in viral replication yet its mode of action is currently unknown (Diep et al, 2019).…”

Immune Sensing Mechanisms that Discriminate Self from Altered Self and Foreign Nucleic Acids

“…The capping process controls gene expression by modulating nuclear export, splicing, protein translation and mRNA turnover ( Dimitrova et al., 2019 ). Of note, 2’O-methylation coevolved with the IFN system and is even used to specifically regulate ISG expression ( Williams et al., 2020 ). In addition to the extensive modification of mRNA, small nuclear RNAs (snRNAs) receive methylguanosine caps which are hypermethylated into trimethylguanosine in the cytoplasm, and ribosomal RNA (rRNA) and transfer RNA(tRNA) are both generated via processing of precursors which creates 5′ monophosphate (5′P) termini and are extensively 2’O-methylated.…”

CMTR1 is recruited to transcription start sites and promotes ribosomal protein and histone gene expression in embryonic stem cells

“…Thus, we observed that CMTR1 controls RNA levels in a gene specific manner in ESCs, correlating with RNAPII binding and expression level. In neurons, CMTR1 was found to control expression of Camk2a (21), and in the innate immune response, CMTR1 was found to be required for upregulation of certain interferon stimulated genes (20). In both scenarios and presented here in ESCs, CMTR1 is controlling the expression of some of the most highly expressed genes in the cell.…”