Multi-level proteomics reveals host-perturbation strategies of SARS-CoV-2 and SARS-CoV

Stukalov, A.; Girault, V.; Grass, V.; Bergant, V.; Karayel, O.; Urban, C.; Haas, D. A.; Huang, Y.; Oubraham, L.; Wang, A.; Hamad, S. M.; Piras, A.; Tanzer, M.; Hansen, F. M.; Engleitner, T.; Reinecke, M.; Lavacca, T. M.; Ehmann, R.; Wölfel, R.; Jores, J.; Küster, B.; Protzer, U.; Rad, R.; Ziebuhr, J.; Thiel, V.; Scaturro, P.; Mann, M.; Pichlmair, A.

doi:10.1101/2020.06.17.156455

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bioRxiv · 10.1101/2020.06.17.156455

Multi-level proteomics reveals host-perturbation strategies of SARS-CoV-2 and SARS-CoV

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Abstract

The global emergence of SARS-CoV-2 urgently requires 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. We therefore conducted a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactome of both viruses, as well as their influence on transcriptome, proteome, ubiquitinome and phosphoproteome in a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon SARS-CoV-2 and SARS-CoV infections at different layers and identified unique and common molecular mechanisms of these closely related coronaviruses. The TGF-{beta} pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org) highlights many hotspots that can be targeted by existing drugs and it can guide rational design of virus- and host-directed therapies, which we exemplify by identifying kinase and MMPs inhibitors with potent antiviral effects against SARS-CoV-2.

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Stukalov, A., Girault, V., Grass, V., Bergant, V., Karayel, O., Urban, C., Haas, D. A., Huang, Y., Oubraham, L., Wang, A., Hamad, S. M., Piras, A., Tanzer, M., Hansen, F. M., Engleitner, T., Reinecke, M., Lavacca, T. M., Ehmann, R., Wölfel, R., Jores, J., Küster, B., Protzer, U., Rad, R., Ziebuhr, J., Thiel, V., Scaturro, P., Mann, M., Pichlmair, A.. 2020-06-17. Multi-level proteomics reveals host-perturbation strategies of SARS-CoV-2 and SARS-CoV. https://doi.org/10.1101/2020.06.17.156455

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