In early 2020, the outbreak of SARS-CoV-2 caused laboratories to close and scientists to work from home. With a view to tackling the virus, we joined forces with labs across Europe to contribute to the growing research on SARS-CoV-2. We focused on SARS-CoV-2 papain-like protease, PLpro, and compared it to previously characterised PLpro from SARS. PLpro can cleave small proteins such as ubiquitin or ISG15 from target proteins. We found that SARS-CoV-2 PLpro specifically cleaves ISG15 from its substrates, compared to SARS PLpro that specifically cleaves ubiquitin.

We highlighted the structural differences that led to the alteration in their function. This function is particularly important in regulating the host innate immunity, as one of the ISG15 substrates affected by SARS-CoV-2 PLpro is IRF3, an important transcription factor involved in interferon signalling. Our findings show that SARS-CoV-2 PLpro cleaves ISG15 from its substrates, thereby inhibiting interferon response and allowing the virus to replicate and spread. Using a small-molecule inhibitor of SARS PLpro, we were able to rescue the interferon response, and therefore provided a very promising angle for therapeutic intervention in the fight against COVID-19. 

This work has been published in Nature in July 2020, and is available to read on the following link:

Shin, D., Mukherjee, R., Grewe, D. et al. Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature (2020).