The mRNA Cap 2′-<italic toggle="yes">O</italic>-Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes

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 infecti...

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Autores principales:	Graham D. Williams, Nandan S. Gokhale, Daltry L. Snider, Stacy M. Horner
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	ISGs RNA modification antiviral interferon Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/03799356559a46dd974db83f9190f76f
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spelling	oai:doaj.org-article:03799356559a46dd974db83f9190f76f2021-11-15T15:30:15ZThe mRNA Cap 2′-<italic toggle="yes">O</italic>-Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes10.1128/mSphere.00202-202379-5042https://doaj.org/article/03799356559a46dd974db83f9190f76f2020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00202-20https://doaj.org/toc/2379-5042ABSTRACT 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.Graham D. WilliamsNandan S. GokhaleDaltry L. SniderStacy M. HornerAmerican Society for MicrobiologyarticleISGsRNA modificationantiviralinterferonMicrobiologyQR1-502ENmSphere, Vol 5, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	ISGs RNA modification antiviral interferon Microbiology QR1-502
spellingShingle	ISGs RNA modification antiviral interferon Microbiology QR1-502 Graham D. Williams Nandan S. Gokhale Daltry L. Snider Stacy M. Horner The mRNA Cap 2′-<italic toggle="yes">O</italic>-Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes
description	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.
format	article
author	Graham D. Williams Nandan S. Gokhale Daltry L. Snider Stacy M. Horner
author_facet	Graham D. Williams Nandan S. Gokhale Daltry L. Snider Stacy M. Horner
author_sort	Graham D. Williams
title	The mRNA Cap 2′-<italic toggle="yes">O</italic>-Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes
title_short	The mRNA Cap 2′-<italic toggle="yes">O</italic>-Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes
title_full	The mRNA Cap 2′-<italic toggle="yes">O</italic>-Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes
title_fullStr	The mRNA Cap 2′-<italic toggle="yes">O</italic>-Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes
title_full_unstemmed	The mRNA Cap 2′-<italic toggle="yes">O</italic>-Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes
title_sort	mrna cap 2′-<italic toggle="yes">o</italic>-methyltransferase cmtr1 regulates the expression of certain interferon-stimulated genes
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/03799356559a46dd974db83f9190f76f
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The mRNA Cap 2′-<italic toggle="yes">O</italic>-Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes

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