Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

, David E. Gordon, Joseph Hiatt, Mehdi Bouhaddou, Veronica V. Rezelj, Svenja Ulferts, Hannes Braberg, Alexander S. Jureka, Kirsten Obernier, Jeffrey Z. Guo, Jyoti Batra, Robyn M. Kaake, Andrew R. Weckstein, Tristan W. Owens, Meghna Gupta, Sergei Pourmal, Erron W Titus, Merve Cakir, Margaret Soucheray, Michael McGregorZeynep Cakir, Gwendolyn Jang, Matthew J. O'Meara, Tia A. Tummino, Ziyang Zhang, Helene Foussard, Ajda Rojc, Yuan Zhou, Dmitry Kuchenov, Ruth Hüttenhain, Jiewei Xu, Manon Eckhardt, Danielle L. Swaney, Jacqueline M. Fabius, Manisha Ummadi, Beril Tutuncuoglu, Ujjwal Rathore, Maya Modak, Paige Haas, Kelsey M. Haas, Daniel M. Williams, C. James Hastie, Matthew Elliott, Fiona Brown, Kerry A. Burness, Elaine Reid, Carla Baillie, Samantha Raggett, Rachel Toth, Dario R. Alessi, Paul Davies, Adolfo García-Sastre, Jeremy A. Rassen, Robert Grosse, Oren S. Rosenberg, Kliment A. Verba, Christopher F. Basler, Marco Vignuzzi, Andrew A. Peden, Pedro Beltrao, Nevan J. Krogan

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Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human proteinprotein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARSCoV- 2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.

Original languageEnglish
Article numbereabe9403
Number of pages28
JournalScience (New York, N.Y.)
Volume370
Issue number6521
Early online date15 Oct 2020
DOIs
Publication statusPublished - 4 Dec 2020

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