Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV

Nature. 2021 Jun;594(7862):246-252. doi: 10.1038/s41586-021-03493-4. Epub 2021 Apr 12.

Abstract

The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1-10. Integration of such datasets to obtain a holistic view of virus-host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-β pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org ) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Autophagy / drug effects
  • COVID-19 / immunology
  • COVID-19 / metabolism*
  • COVID-19 / virology
  • Cell Line
  • Datasets as Topic
  • Drug Evaluation, Preclinical
  • Host-Pathogen Interactions* / immunology
  • Humans
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Phosphorylation
  • Protein Interaction Maps
  • Protein Kinase Inhibitors / pharmacology
  • Protein Processing, Post-Translational
  • Proteome / chemistry
  • Proteome / metabolism*
  • Proteomics*
  • SARS Virus / immunology
  • SARS Virus / pathogenicity*
  • SARS-CoV-2 / immunology
  • SARS-CoV-2 / pathogenicity*
  • Severe Acute Respiratory Syndrome / immunology
  • Severe Acute Respiratory Syndrome / metabolism*
  • Severe Acute Respiratory Syndrome / virology
  • Transforming Growth Factor beta / metabolism
  • Ubiquitination
  • Viral Proteins / chemistry
  • Viral Proteins / metabolism
  • Viroporin Proteins / metabolism

Substances

  • Antiviral Agents
  • Matrix Metalloproteinase Inhibitors
  • ORF3a protein, SARS-CoV-2
  • ORF8 protein, SARS-CoV-2
  • Protein Kinase Inhibitors
  • Proteome
  • Transforming Growth Factor beta
  • Viral Proteins
  • Viroporin Proteins