Nsp16 shields SARS–CoV-2 from efficient MDA5 sensing and IFIT1-mediated restriction

Ruß A, Wittmann S, Tsukamoto Y, Herrmann A, Deutschmann J, Lagisquet J, Enßer A, Kato H, Gramberg T (2022)

Publication Type: Journal article

Publication year: 2022

Journal

EMBO Reports EMBO Press

Book Volume: 23

Pages Range: e55648

Journal Issue: 12

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.

Authors with CRIS profile

Alina Ruß Institute of Clinical and Molecular Virology Sabine Wittmann Institute of Clinical and Molecular Virology Alexandra Herrmann Institute of Clinical and Molecular Virology Janina Deutschmann Institute of Clinical and Molecular Virology Justine Lagisquet Institute of Clinical and Molecular Virology Armin Enßer Lehrstuhl für Klinische und Molekulare Virologie Thomas Gramberg Institute of Clinical and Molecular Virology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

A094: Host cell factors and nonstructural proteins of SARS-CoV-2 July 1, 2023 - Dec. 31, 2025 A095: The 2’-O-methylation of viral RNA regulates innate immune sensing by MDA5 Jan. 1, 2023 - June 30, 2025 A083: The role of SAMHD1 in CMV/ HIV coinfections Jan. 1, 2020 - Dec. 31, 2022

Involved external institutions

Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE)

How to cite

APA:

Ruß, A., Wittmann, S., Tsukamoto, Y., Herrmann, A., Deutschmann, J., Lagisquet, J.,... Gramberg, T. (2022). Nsp16 shields SARS–CoV-2 from efficient MDA5 sensing and IFIT1-mediated restriction. EMBO Reports, 23(12), e55648. https://doi.org/10.15252/embr.202255648

MLA:

Ruß, Alina, et al. "Nsp16 shields SARS–CoV-2 from efficient MDA5 sensing and IFIT1-mediated restriction." EMBO Reports 23.12 (2022): e55648.

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