1. Academic Validation
  2. The mRNA Cap 2'- O-Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes

The mRNA Cap 2'- O-Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes

  • mSphere. 2020 May 13;5(3):e00202-20. doi: 10.1128/mSphere.00202-20.
Graham D Williams 1 Nandan S Gokhale 1 Daltry L Snider 1 Stacy M Horner 2 3
Affiliations

Affiliations

  • 1 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.
  • 2 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA stacy.horner@duke.edu.
  • 3 Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Abstract

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 are 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.IMPORTANCE 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 those mRNAs lacking cap 2'-O-methylation. Thus, CMTR1 promotes the IFN-mediated Antiviral response.

Keywords

ISGs; RNA modification; antiviral; interferon.

Figures
Products