The Main Protease of Middle East Respiratory Syndrome Coronavirus Induces Cleavage of Mitochondrial Antiviral Signaling Protein to Antagonize the Innate Immune Response

Mitochondrial antiviral signaling protein (MAVS) is a crucial signaling adaptor in the sensing of positive-sense RNA viruses and the subsequent induction of the innate immune response. Coronaviruses have evolved multiple mechanisms to evade this response, amongst others, through their main protease (M-pro), which is responsible for the proteolytic cleavage of the largest part of the viral replicase polyproteins pp1a and pp1ab. Additionally, it can cleave cellular substrates, such as innate immune signaling factors, to dampen the immune response. Here, we show that MAVS is cleaved in cells infected with Middle East respiratory syndrome coronavirus (MERS-CoV), but not in cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This cleavage was independent of cellular negative feedback mechanisms that regulate MAVS activation. Furthermore, MERS-CoV M-pro expression induced MAVS cleavage upon overexpression and suppressed the activation of the interferon-beta (IFN-beta) and nuclear factor-kappa B (NF-kappa B) response. We conclude that we have uncovered a novel mechanism by which MERS-CoV downregulates the innate immune response, which is not observed among other highly pathogenic coronaviruses.