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

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  • معلومة اضافية
    • Contributors:
      Populations virales et Pathogenèse - Viral Populations and Pathogenesis; Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS); Criblage chémogénomique et biologique (Plateforme) - Chemogenomic and Biological Screening Platform (PF-CCB); Institut Pasteur Paris (IP); Virus et Immunité - Virus and immunity (CNRS-UMR3569); University of Liverpool; Buck Institute for Research on Aging; University of California San Francisco (UC San Francisco); University of California (UC); University of New South Wales Sydney (UNSW); This work was supported by the Laboratoire d’Excellence “Integrative Biology of Emerging Infectious Diseases” (grant ANR-10-LABX-62-IBEID) to M.V. S.G. is the recipient of a MESR/Ecole Doctorale BioSPC ED562, Université de Paris fellowship. L.A.C. is supported by Institut Pasteur TASK FORCE SARS COV-2 (Tropicoro project), DIM ELICIT Region Ile-de-France, and ANRS. E.E. is supported by startup funding from the University of Liverpool, as well as a Wellcome Trust ISSF Interdisciplinary & Industry Award. E.E. is grateful for the support of GoFundMe donors for sponsoring SARS-CoV-2 research in his laboratory.; ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
    • بيانات النشر:
      HAL CCSD
      Nature Publishing Group
    • الموضوع:
      2021
    • Collection:
      Institut Pasteur: HAL
    • نبذة مختصرة :
      International audience ; 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.
    • Relation:
      info:eu-repo/semantics/altIdentifier/pmid/34548480; pasteur-03654295; https://pasteur.hal.science/pasteur-03654295; https://pasteur.hal.science/pasteur-03654295/document; https://pasteur.hal.science/pasteur-03654295/file/s41467-021-25796-w.pdf; PUBMED: 34548480; PUBMEDCENTRAL: PMC8455558
    • الرقم المعرف:
      10.1038/s41467-021-25796-w
    • Rights:
      http://creativecommons.org/licenses/by/ ; info:eu-repo/semantics/OpenAccess
    • الرقم المعرف:
      edsbas.3765AF1A