Mechanistic insights into COVID-19 by global analysis of the SARS-CoV-2 3CL(pro) substrate degradome [Elektronisk resurs]

• 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. 

Ämnesord

Medical and Health Sciences  (hsv)

Medical Biotechnology  (hsv)

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)  (hsv)

Medicin och hälsovetenskap  (hsv)

Medicinsk bioteknologi  (hsv)

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)  (hsv)

Genre

government publication  (marcgt)