Characterising proteolysis during SARS-CoV-2 infection identifies viral cleavage sites and cellular targets with therapeutic potential

Bjoern Meyer, Jeanne Chiaravalli, Stacy Gellenoncourt, Philip Brownridge, Dominic P. Bryne, Leonard A. Daly, Arturas Grauslys, Marius Walter, Fabrice Agou, Lisa A. Chakrabarti, Charles S. Craik, Claire E. Eyers, Patrick A. Eyers, Yann Gambin, Andrew R. Jones, Emma Sierecki, Eric Verdin, Marco Vignuzzi and Edward Emmott ()
Additional contact information
Bjoern Meyer: Viral Populations and Pathogenesis Unit, CNRS, UMR 3569, Institut Pasteur
Jeanne Chiaravalli: Chemogenomic and Biological Screening Core Facility, C2RT, Departments of Cell Biology & Infection and of Structural Biology & Chemistry, Institut Pasteur
Stacy Gellenoncourt: CIVIC Group, Virus & Immunity Unit, Institut Pasteur and CNRS
Philip Brownridge: University of Liverpool
Dominic P. Bryne: University of Liverpool
Leonard A. Daly: University of Liverpool
Arturas Grauslys: University of Liverpool
Marius Walter: Buck Institute for Research on Aging
Fabrice Agou: Chemogenomic and Biological Screening Core Facility, C2RT, Departments of Cell Biology & Infection and of Structural Biology & Chemistry, Institut Pasteur
Lisa A. Chakrabarti: CIVIC Group, Virus & Immunity Unit, Institut Pasteur and CNRS
Charles S. Craik: University of California, San Francisco
Claire E. Eyers: University of Liverpool
Patrick A. Eyers: University of Liverpool
Yann Gambin: The University of New South Wales
Andrew R. Jones: University of Liverpool
Emma Sierecki: The University of New South Wales
Eric Verdin: Buck Institute for Research on Aging
Marco Vignuzzi: Viral Populations and Pathogenesis Unit, CNRS, UMR 3569, Institut Pasteur
Edward Emmott: University of Liverpool

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract SARS-CoV-2 is the causative agent behind the COVID-19 pandemic, responsible for over 170 million infections, and over 3.7 million deaths worldwide. Efforts to test, treat and vaccinate against this pathogen all benefit from an improved understanding of the basic biology of SARS-CoV-2. Both viral and cellular proteases play a crucial role in SARS-CoV-2 replication. Here, we study proteolytic cleavage of viral and cellular proteins in two cell line models of SARS-CoV-2 replication using mass spectrometry to identify protein neo-N-termini generated through protease activity. We identify previously unknown cleavage sites in multiple viral proteins, including major antigens S and N: the main targets for vaccine and antibody testing efforts. We discover significant increases in cellular cleavage events consistent with cleavage by SARS-CoV-2 main protease, and identify 14 potential high-confidence substrates of the main and papain-like proteases. We show that siRNA depletion of these cellular proteins inhibits SARS-CoV-2 replication, and that drugs targeting two of these proteins: the tyrosine kinase SRC and Ser/Thr kinase MYLK, show a dose-dependent reduction in SARS-CoV-2 titres. Overall, our study provides a powerful resource to understand proteolysis in the context of viral infection, and to inform the development of targeted strategies to inhibit SARS-CoV-2 and treat COVID-19.

Date: 2021
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DOI: 10.1038/s41467-021-25796-w

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