tetano
Editor, Senior Moderator
EMBO Rep
. 2022 Oct 26;e55648.
doi: 10.15252/embr.202255648. Online ahead of print.
Nsp16 shields SARS-CoV-2 from efficient MDA5 sensing and IFIT1-mediated restriction
Alina Russ[SUP] #[/SUP][SUP] 1 [/SUP], Sabine Wittmann[SUP] #[/SUP][SUP] 1 [/SUP], Yuta Tsukamoto[SUP] 2 [/SUP], Alexandra Herrmann[SUP] 1 [/SUP], Janina Deutschmann[SUP] 1 [/SUP], Justine Lagisquet[SUP] 1 [/SUP], Armin Ensser[SUP] 1 [/SUP], Hiroki Kato[SUP] 2 [/SUP], Thomas Gramberg[SUP] 1 [/SUP]
Affiliations
Abstract
Methylation of the mRNA 5' cap by cellular methyltransferases enables efficient translation and avoids recognition by innate immune factors. Coronaviruses encode viral 2'-O-methyltransferases to shield their RNA from host factors. Here, we generate recombinant SARS-CoV-2 harboring a catalytically inactive 2'-O-methyltransferase Nsp16, Nsp16mut, and analyze viral replication in human lung epithelial cells. Although replication is only slightly attenuated, we find SARS-CoV-2 Nsp16mut to be highly immunogenic, resulting in a strongly enhanced release of type I interferon upon infection. The elevated immunogenicity of Nsp16mut is absent in cells lacking the RNA sensor MDA5. In addition, we report that Nsp16mut is highly sensitive to type I IFN treatment and demonstrate that this strong antiviral effect of type I IFN is mediated by the restriction factor IFIT1. Together, we describe a dual role for the 2'-O-methyltransferase Nsp16 during SARS-CoV-2 replication in avoiding efficient recognition by MDA5 and in shielding its RNA from interferon-induced antiviral responses, thereby identifying Nsp16 as a promising target for generating attenuated and highly immunogenic SARS-CoV-2 strains and as a potential candidate for therapeutic intervention.
Keywords: 2′-O-methyltransferase; IFIT1; MDA5; Nsp16; SARS-CoV-2.
. 2022 Oct 26;e55648.
doi: 10.15252/embr.202255648. Online ahead of print.
Nsp16 shields SARS-CoV-2 from efficient MDA5 sensing and IFIT1-mediated restriction
Alina Russ[SUP] #[/SUP][SUP] 1 [/SUP], Sabine Wittmann[SUP] #[/SUP][SUP] 1 [/SUP], Yuta Tsukamoto[SUP] 2 [/SUP], Alexandra Herrmann[SUP] 1 [/SUP], Janina Deutschmann[SUP] 1 [/SUP], Justine Lagisquet[SUP] 1 [/SUP], Armin Ensser[SUP] 1 [/SUP], Hiroki Kato[SUP] 2 [/SUP], Thomas Gramberg[SUP] 1 [/SUP]
Affiliations
- PMID: 36285486
- DOI: 10.15252/embr.202255648
Abstract
Methylation of the mRNA 5' cap by cellular methyltransferases enables efficient translation and avoids recognition by innate immune factors. Coronaviruses encode viral 2'-O-methyltransferases to shield their RNA from host factors. Here, we generate recombinant SARS-CoV-2 harboring a catalytically inactive 2'-O-methyltransferase Nsp16, Nsp16mut, and analyze viral replication in human lung epithelial cells. Although replication is only slightly attenuated, we find SARS-CoV-2 Nsp16mut to be highly immunogenic, resulting in a strongly enhanced release of type I interferon upon infection. The elevated immunogenicity of Nsp16mut is absent in cells lacking the RNA sensor MDA5. In addition, we report that Nsp16mut is highly sensitive to type I IFN treatment and demonstrate that this strong antiviral effect of type I IFN is mediated by the restriction factor IFIT1. Together, we describe a dual role for the 2'-O-methyltransferase Nsp16 during SARS-CoV-2 replication in avoiding efficient recognition by MDA5 and in shielding its RNA from interferon-induced antiviral responses, thereby identifying Nsp16 as a promising target for generating attenuated and highly immunogenic SARS-CoV-2 strains and as a potential candidate for therapeutic intervention.
Keywords: 2′-O-methyltransferase; IFIT1; MDA5; Nsp16; SARS-CoV-2.