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

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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
    Munich Partner Site
    German Cancer Research Center (DKFZ))

  • Teresa M. Lavacca

    (Technical University of Munich, School of Medicine, Institute of Virology)

  • Rosina Ehmann

    (Bundeswehr Institute of Microbiology
    Munich Partner Site)

  • Roman Wölfel

    (Bundeswehr Institute of Microbiology
    Munich Partner Site)

  • Jörg Jores

    (University of Bern)

  • Bernhard Kuster

    (Technical University of Munich
    Munich Partner Site
    German Cancer Research Center (DKFZ))

  • Ulrike Protzer

    (Technical University of Munich, School of Medicine, Institute of Virology
    Munich Partner Site)

  • Roland Rad

    (Technical University of Munich)

  • John Ziebuhr

    (Justus Liebig University Giessen, Institute of Medical Virology)

  • Volker Thiel

    (Institute of Virology and Immunology (IVI)
    University of Bern)

  • Pietro Scaturro

    (Technical University of Munich, School of Medicine, Institute of Virology
    Leibniz Institute for Experimental Virology)

  • Matthias Mann

    (Max-Planck Institute of Biochemistry)

  • Andreas Pichlmair

    (Technical University of Munich, School of Medicine, Institute of Virology
    Munich Partner Site)

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.

Suggested Citation

  • 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., 2021. "Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV," Nature, Nature, vol. 594(7862), pages 246-252, June.
    • Handle: RePEc:nat:nature:v:594:y:2021:i:7862:d:10.1038_s41586-021-03493-4
    DOI: 10.1038/s41586-021-03493-4
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    Cited by:

    1. Sara Sunshine & Andreas S. Puschnik & Joseph M. Replogle & Matthew T. Laurie & Jamin Liu & Beth Shoshana Zha & James K. Nuñez & Janie R. Byrum & Aidan H. McMorrow & Matthew B. Frieman & Juliane Winkle, 2023. "Systematic functional interrogation of SARS-CoV-2 host factors using Perturb-seq," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Andrea Fossati & Deepto Mozumdar & Claire Kokontis & Melissa Mèndez-Moran & Eliza Nieweglowska & Adrian Pelin & Yuping Li & Baron Guo & Nevan J. Krogan & David A. Agard & Joseph Bondy-Denomy & Daniell, 2023. "Next-generation proteomics for quantitative Jumbophage-bacteria interaction mapping," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Debjit Khan & Fulvia Terenzi & GuanQun Liu & Prabar K. Ghosh & Fengchun Ye & Kien Nguyen & Arnab China & Iyappan Ramachandiran & Shruti Chakraborty & Jennifer Stefan & Krishnendu Khan & Kommireddy Vas, 2023. "A viral pan-end RNA element and host complex define a SARS-CoV-2 regulon," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    4. Solène Denolly & Alexey Stukalov & Uladzimir Barayeu & Alina N. Rosinski & Paraskevi Kritsiligkou & Sebastian Joecks & Tobias P. Dick & Andreas Pichlmair & Ralf Bartenschlager, 2023. "Zika virus remodelled ER membranes contain proviral factors involved in redox and methylation pathways," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    5. Friederike L. Pennemann & Assel Mussabekova & Christian Urban & Alexey Stukalov & Line Lykke Andersen & Vincent Grass & Teresa Maria Lavacca & Cathleen Holze & Lila Oubraham & Yasmine Benamrouche & En, 2021. "Cross-species analysis of viral nucleic acid interacting proteins identifies TAOKs as innate immune regulators," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    6. Thomas Kruse & Caroline Benz & Dimitriya H. Garvanska & Richard Lindqvist & Filip Mihalic & Fabian Coscia & Raviteja Inturi & Ahmed Sayadi & Leandro Simonetti & Emma Nilsson & Muhammad Ali & Johanna K, 2021. "Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    7. Filip Mihalič & Caroline Benz & Eszter Kassa & Richard Lindqvist & Leandro Simonetti & Raviteja Inturi & Hanna Aronsson & Eva Andersson & Celestine N. Chi & Norman E. Davey & Anna K. Överby & Per Jemt, 2023. "Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    8. Haris Babačić & Wanda Christ & José Eduardo Araújo & Georgios Mermelekas & Nidhi Sharma & Janne Tynell & Marina García & Renata Varnaite & Hilmir Asgeirsson & Hedvig Glans & Janne Lehtiö & Sara Gredma, 2023. "Comprehensive proteomics and meta-analysis of COVID-19 host response," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    9. Ma’ayan Israeli & Yaara Finkel & Yfat Yahalom-Ronen & Nir Paran & Theodor Chitlaru & Ofir Israeli & Inbar Cohen-Gihon & Moshe Aftalion & Reut Falach & Shahar Rotem & Uri Elia & Ital Nemet & Limor Klik, 2022. "Genome-wide CRISPR screens identify GATA6 as a proviral host factor for SARS-CoV-2 via modulation of ACE2," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Valter Bergant & Daniel Schnepf & Niklas Andrade Krätzig & Philipp Hubel & Christian Urban & Thomas Engleitner & Ronald Dijkman & Bernhard Ryffel & Katja Steiger & Percy A. Knolle & Georg Kochs & Rola, 2023. "mRNA 3’UTR lengthening by alternative polyadenylation attenuates inflammatory responses and correlates with virulence of Influenza A virus," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    11. Gianluca Baldanzi & Beatrice Purghè & Beatrice Ragnoli & Pier Paolo Sainaghi & Roberta Rolla & Annalisa Chiocchetti & Marcello Manfredi & Mario Malerba, 2023. "Circulating Peptidome Is Strongly Altered in COVID-19 Patients," IJERPH, MDPI, vol. 20(2), pages 1-15, January.
    12. Emilie Murigneux & Laurent Softic & Corentin Aubé & Carmen Grandi & Delphine Judith & Johanna Bruce & Morgane Le Gall & François Guillonneau & Alain Schmitt & Vincent Parissi & Clarisse Berlioz-Torren, 2024. "Proteomic analysis of SARS-CoV-2 particles unveils a key role of G3BP proteins in viral assembly," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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