Journal
CELL REPORTS
Volume 37, Issue 4, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109892
Keywords
-
Categories
Funding
- Canada Research Chairs program [950-01-126, 950-231595]
- Canadian Institutes of Health Research (CIHR) Foundation [FDN-148408]
- CIHR 2019 Novel Coronavirus (COVID-19) Rapid Research grant program [OV3-170636, FRN-170645]
- CIHR [OV4-170645, PJT-173318, MM1-174898, MOP-130408, PJT-153270, 388726, 201911 FBD-434976-268115]
- Canada Foundation for Innovation [31059]
- Michael Smith Foundation for Health Research (MSRF) [IN-NPG-00105, 17905]
- Knut and Alice Wallenberg Foundation
- Stockholms Lans Landsting [929362]
- Natural Sciences and En-gineering Research Council (NSERC) [RGPIN-2016-03811, RGPIN-2018-03828, 532117-2019]
- Pol-ish Medical Research Agency [2020/ABM/SARS/1]
- National Sci-ence Centre in Poland [2020/01/0/NZ1/00063]
- ALS-Canada/Brain-Canada Doctoral Fellowship
Ask authors/readers for more resources
Research on the main viral protease of SARS-CoV-2 and its relationship with human protein substrates has revealed a large group of substrates, accelerating the exploration of pathophysiology and drug design. The study also demonstrates the interactions between 3CL(pro) and the Hippo pathway and other key effector proteins in human cells.
The main viral protease (3CL(pro)) is indispensable for SARS-CoV-2 replication. We delineate the human protein substrate landscape of 3CL(pro) 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(pro) 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(pro) 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(pro) substrate degradome establishes a foundational substrate atlas to accelerate exploration of SARSCoV-2 pathology and drug design.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available