SARS-CoV-2 ORF3c suppresses immune activation by inhibiting innate sensing (preprint)

ABSTRACT

SARS-CoV-2 proteins are translated from subgenomic RNAs (sgRNAs). While most of these sgRNAs are monocistronic, some viral mRNAs encode more than one protein. For example, the ORF3a sgRNA also encodes ORF3c, an enigmatic 41-amino acid peptide. Here, we show that ORF3c suppresses RIG-I- and MDA5-mediated immune activation and interacts with the signaling adaptor MAVS. In line with this, ORF3c inhibits IFN-{beta} induction. This 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. In agreement with this, disruption of ORF3c did not significantly affect SARS-CoV-2 replication in CaCo-2 or CaLu-3 cells. In summary, we here identify ORF3c as an immune evasion factor that suppresses IFN-{beta} induction, but is dispensable for efficient replication of SARS-CoV-2.