[4] In addition to their protease activity, PLP domains function as deubiquitinating enzymes (DUBs) that can cleave the isopeptide bond found in ubiquitin chains.

[2][10] PLPro is a multifunctional enzyme with multiple roles in the viral life cycle, including protease, deubiquitinase, and deISGylating activities.

PLPro domains are responsible for proteolytic processing of the polyprotein to generate mature viral nonstructural proteins (nsps), many of which are components of the replicase-transcriptase complex.

[2][12] This prediction was later confirmed by in vitro experiments for a number of coronavirus and arterivirus PLP domains,[2][9] including that of SARS-CoV-2.

In addition to deubiquitinating activity, coronavirus and arterivirus PLP domains have been identified as deISGylase enzymes, capable of removing ISG15 from cellular proteins.