Nsp16 shields SARS-CoV-2 from efficient MDA5 sensing and IFIT1-mediated restriction.
EMBO Rep
; 23(12): e55648, 2022 Dec 06.
Article
in English
| MEDLINE | ID: covidwho-2091042
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Language:
English
Journal:
EMBO Rep
Journal subject:
Molecular Biology
Year:
2022
Document Type:
Article
Affiliation country:
Embr.202255648
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