ORF3c is expressed in SARS-CoV-2-infected cells and inhibits innate sensing by targeting MAVS

Müller M, Herrmann A, Fujita S, Uriu K, Kruth C, Strange A, Kolberg JE, Schneider M, Ito J, Müller MA, Drosten C, Enßer A, Sato K, Sauter D (2023)

Publication Type: Journal article

Publication year: 2023

Journal

EMBO Reports EMBO Press

DOI: 10.15252/embr.202357137

Abstract

Most SARS-CoV-2 proteins are translated from subgenomic RNAs (sgRNAs). While the majority of these sgRNAs are monocistronic, some viral mRNAs encode more than one protein. One example is the ORF3a sgRNA that also encodes ORF3c, an enigmatic 41-amino-acid peptide. Here, we show that ORF3c is expressed in SARS-CoV-2-infected cells and suppresses RIG-I- and MDA5-mediated IFN-β induction. ORF3c interacts with the signaling adaptor MAVS, induces its C-terminal cleavage, and inhibits the interaction of RIG-I with MAVS. The immunosuppressive activity of ORF3c is conserved among members of the subgenus sarbecovirus, including SARS-CoV and coronaviruses isolated from bats. Notably, however, the SARS-CoV-2 delta and kappa variants harbor premature stop codons in ORF3c, demonstrating that this reading frame is not essential for efficient viral replication in vivo and is likely compensated by other viral proteins. In agreement with this, disruption of ORF3c does not significantly affect SARS-CoV-2 replication in CaCo-2, CaLu-3, or Rhinolophus alcyone cells. In summary, we here identify ORF3c as an immune evasion factor of SARS-CoV-2 that suppresses innate sensing in infected cells.

Authors with CRIS profile

Alexandra Herrmann Institute of Clinical and Molecular Virology Armin Enßer 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

Involved external institutions

Universitätsklinikum Tübingen DE Germany (DE) University of Tokyo JP Japan (JP) Berliner Institut für Gesundheitsforschung (BIH) DE Germany (DE)

How to cite

APA:

Müller, M., Herrmann, A., Fujita, S., Uriu, K., Kruth, C., Strange, A.,... Sauter, D. (2023). ORF3c is expressed in SARS-CoV-2-infected cells and inhibits innate sensing by targeting MAVS. EMBO Reports. https://doi.org/10.15252/embr.202357137

MLA:

Müller, Martin, et al. "ORF3c is expressed in SARS-CoV-2-infected cells and inhibits innate sensing by targeting MAVS." EMBO Reports (2023).

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