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Mechanistic insights into COVID-19 by global analysis of the SARS-CoV-2 3CL substrate degradome. | LitMetric

Mechanistic insights into COVID-19 by global analysis of the SARS-CoV-2 3CL substrate degradome.

Cell Rep

Centre for Blood Research, Life Sciences Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address:

Published: October 2021

AI Article Synopsis

Article Abstract

The main viral protease (3CL) is indispensable for SARS-CoV-2 replication. We delineate the human protein substrate landscape of 3CL by TAILS substrate-targeted N-terminomics. We identify more than 100 substrates in human lung and kidney cells supported by analyses of SARS-CoV-2-infected cells. Enzyme kinetics and molecular docking simulations of 3CL engaging substrates reveal how noncanonical cleavage sites, which diverge from SARS-CoV, guide substrate specificity. Cleaving the interactors of essential effector proteins, effectively stranding them from their binding partners, amplifies the consequences of proteolysis. We show that 3CL targets the Hippo pathway, including inactivation of MAP4K5, and key effectors of transcription, mRNA processing, and translation. We demonstrate that Spike glycoprotein directly binds galectin-8, with galectin-8 cleavage disengaging CALCOCO2/NDP52 to decouple antiviral-autophagy. Indeed, in post-mortem COVID-19 lung samples, NDP52 rarely colocalizes with galectin-8, unlike in healthy lungs. The 3CL substrate degradome establishes a foundational substrate atlas to accelerate exploration of SARS-CoV-2 pathology and drug design.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501228PMC
http://dx.doi.org/10.1016/j.celrep.2021.109892DOI Listing

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