Evade to invade: how nidovirus proteases manipulate host antiviral responses to facilitate infection

Nidoviruses, which include arteri- and coronaviruses, have evolved many mechanisms to manipulate host antiviral responses, some of which are exerted by the viral proteases that are essential for processing the viral replicase polyproteins. We found that the main protease of MERS-CoV induces cleavage of MAVS, a crucial mediator of the innate immune response against RNA viruses. Furthermore, the papain-like protease (PLP2 or PLpro) can remove ubiquitin and ISG15 from substrates by its deubiquitinating (DUB) and deISGylating activities, which are believed to contribute to immune evasion. To gain insight into the role of these activities during virus infection, we generated SARS-CoV-2 mutants that lack DUB activity. Disruption of the DUB activity did not affect virus replication in cell culture or in vivo. Furthermore, immune responses were not affected in vivo. To further elucidate the substrates that are deubiquitinated by the nidovirus papain-like protease, we characterized the ubiquitinated proteome of cells infected with wild-type or DUB mutant EAV. We found that EAV PLP2 deubiquitinates both cellular and viral proteins. Cellular proteins targeted by EAV PLP2 were involved in diverse processes, such as mRNA translation, and cytoskeleton and nucleoskeleton organization. Understanding these virus-host interactions contributes essential knowledge to designing innovative antiviral intervention strategies.