SARS Virus Papain-Like Protease: A Mysterious Weapon

Papain-like protease (PLpro) of SARS-CoV in association with 3Chemotrypsin-like protease (3CLpro or Mpro) are two proteases which auto-proteolyze replicase polyproteins pp1a/pp1ab. These poly-proteins are translated from ORF1a/ORF1b of the virus genome. Cleavage of pp1a/pp1ab releases non-structural proteins of the virus which orchestrate viral replication. In addition, PLpro as a deubiquitinase and deISGylase modifies the proteins involved in recognition of the virus by the sensors of host cell innate immunity system. In this manner, the virus reforms the ubiquitination and ISGylation of the cell proteins to progress its own replication without any interference from host cell restrictive strategies against the viruses. Furthermore, PLpro blocks IRF3 activation independent of deubiquinating processes. Besides, PLpro induces pulmonary fibrosis through pathways involving ROS and MAPK.

Inhibition of PLpro allows innate immunity to sense and react against the invasion of SARS-CoV and to activate IRF3 to induce type I IFN expression. Thenceforth, proper development and signaling of innate immunity result in a long-term efficient cell/humoral adaptive immunity. Moreover, suppression of PLpro prevents cleavage of nsp3 and hence replication of the virus and through abolishing ubiquitin-proteasome/MAPK/ERK- and ROS/MAPK-mediated pathways prevent pulmonary fibrosis.