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

Alexey Stukalov, Virginie Girault, Vincent Grass, Ozge Karayel, Valter Bergant, Christian Urban, Darya A. Haas, Yiqi Huang, Lila Oubraham, Anqi Wang, M. Sabri Hamad, Antonio Piras, Fynn M. Hansen, Maria C. Tanzer, Igor Paron, Luca Zinzula, Thomas Engleitner, Maria Reinecke, Teresa M. Lavacca, Rosina Ehmann, Roman Wölfel, Jörg Jores, Bernhard Kuster, Ulrike Protzer, Roland Rad, John Ziebuhr, Volker Thiel, Pietro Scaturro, Matthias Mann and Andreas Pichlmair ()
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Alexey Stukalov: Technical University of Munich, School of Medicine, Institute of Virology
Virginie Girault: Technical University of Munich, School of Medicine, Institute of Virology
Vincent Grass: Technical University of Munich, School of Medicine, Institute of Virology
Ozge Karayel: Max-Planck Institute of Biochemistry
Valter Bergant: Technical University of Munich, School of Medicine, Institute of Virology
Christian Urban: Technical University of Munich, School of Medicine, Institute of Virology
Darya A. Haas: Technical University of Munich, School of Medicine, Institute of Virology
Yiqi Huang: Technical University of Munich, School of Medicine, Institute of Virology
Lila Oubraham: Technical University of Munich, School of Medicine, Institute of Virology
Anqi Wang: Technical University of Munich, School of Medicine, Institute of Virology
M. Sabri Hamad: Technical University of Munich, School of Medicine, Institute of Virology
Antonio Piras: Technical University of Munich, School of Medicine, Institute of Virology
Fynn M. Hansen: Max-Planck Institute of Biochemistry
Maria C. Tanzer: Max-Planck Institute of Biochemistry
Igor Paron: Max-Planck Institute of Biochemistry
Luca Zinzula: Max-Planck Institute of Biochemistry
Thomas Engleitner: Technical University of Munich
Maria Reinecke: Technical University of Munich
Teresa M. Lavacca: Technical University of Munich, School of Medicine, Institute of Virology
Rosina Ehmann: Bundeswehr Institute of Microbiology
Roman Wölfel: Bundeswehr Institute of Microbiology
Jörg Jores: University of Bern
Bernhard Kuster: Technical University of Munich
Ulrike Protzer: Technical University of Munich, School of Medicine, Institute of Virology
Roland Rad: Technical University of Munich
John Ziebuhr: Justus Liebig University Giessen, Institute of Medical Virology
Volker Thiel: Institute of Virology and Immunology (IVI)
Pietro Scaturro: Technical University of Munich, School of Medicine, Institute of Virology
Matthias Mann: Max-Planck Institute of Biochemistry
Andreas Pichlmair: Technical University of Munich, School of Medicine, Institute of Virology

Nature, 2021, vol. 594, issue 7862, 246-252

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03493-4

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