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

• Published in: Science (American Association for the Advancement of Science) Vol. 370; no. 6521
• Main Authors: Gordon, David E., Hiatt, Joseph, Bouhaddou, Mehdi, Rezelj, Veronica V., Ulferts, Svenja, Braberg, Hannes, Jureka, Alexander S., Obernier, Kirsten, Guo, Jeffrey Z., Batra, Jyoti, Kaake, Robyn M., Weckstein, Andrew R., Owens, Tristan W., Gupta, Meghna, Pourmal, Sergei, Titus, Erron W., Cakir, Merve, Soucheray, Margaret, McGregor, Michael, Cakir, Zeynep, Jang, Gwendolyn, O’Meara, Matthew J., Tummino, Tia A., Zhang, Ziyang, Foussard, Helene, Rojc, Ajda, Zhou, Yuan, Kuchenov, Dmitry, Hüttenhain, Ruth, Xu, Jiewei, Eckhardt, Manon, Swaney, Danielle L., Fabius, Jacqueline M., Ummadi, Manisha, Tutuncuoglu, Beril, Rathore, Ujjwal, Modak, Maya, Haas, Paige, Haas, Kelsey M., Naing, Zun Zar Chi, Pulido, Ernst H., Shi, Ying, Barrio-Hernandez, Inigo, Memon, Danish, Petsalaki, Eirini, Dunham, Alistair, Marrero, Miguel Correa, Burke, David, Koh, Cassandra, Vallet, Thomas, Silvas, Jesus A., Azumaya, Caleigh M., Billesbølle, Christian, Brilot, Axel F., Campbell, Melody G., Diallo, Amy, Dickinson, Miles Sasha, Diwanji, Devan, Herrera, Nadia, Hoppe, Nick, Kratochvil, Huong T., Liu, Yanxin, Merz, Gregory E., Moritz, Michelle, Nguyen, Henry C., Nowotny, Carlos, Puchades, Cristina, Rizo, Alexandrea N., Schulze-Gahmen, Ursula, Smith, Amber M., Sun, Ming, Young, Iris D., Zhao, Jianhua, Asarnow, Daniel, Biel, Justin, Bowen, Alisa, Braxton, Julian R., Chen, Jen, Chio, Cynthia M., Chio, Un Seng, Deshpande, Ishan, Doan, Loan, Faust, Bryan, Flores, Sebastian, Jin, Mingliang, Kim, Kate, Lam, Victor L., Li, Fei, Li, Junrui, Li, Yen-Li, Li, Yang, Liu, Xi, Lo, Megan, Lopez, Kyle E., Melo, Arthur A., Moss, Frank R., Nguyen, Phuong, Paulino, Joana, Pawar, Komal Ishwar, Peters, Jessica K.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 04.12.2020; American Association for the Advancement of Science (AAAS); American Association for the Advancement of Science
• Subjects: Antipsychotics; Comparative Analysis; Conserved Sequence; Coronaviridae; Coronavirus Nucleocapsid Proteins - genetics; Coronavirus Nucleocapsid Proteins - metabolism; Coronaviruses; COVID-19; COVID-19 - metabolism; Cryoelectron Microscopy; Data integration; Drugs; Electron microscopy; Engineering; Genetic screening; Genome-wide association studies; Genotypes; Global economy; Host Microbial Interactions; Humans; Immune response; Life Sciences; Microbio; Middle East respiratory syndrome; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Precursor Protein Import Complex Proteins; Multidisciplinary; Narcotics; Online; Pandemics; Perturbation; Phosphoproteins - genetics; Phosphoproteins - metabolism; Protein Conformation; Protein Interaction Maps; Proteins; Psychotropic drugs; Public health; Receptors; Respiratory diseases; Risk assessment; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome; Severe Acute Respiratory Syndrome - metabolism; Severe acute respiratory syndrome-related coronavirus - metabolism; Therapeutic targets; Viral diseases; Viruses; Middle East
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abe9403

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is closely related to the deadly coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Considerable efforts are focused on developing treatments, and therapies that work across coronaviruses would be particularly valuable. Shedding light on the host factors hijacked by the viruses, Gordon et al. mapped the interactions between viral and human proteins for SARS-CoV-2, SARS-CoV-1, and MERS-CoV; analyzed the localization of viral proteins in human cells; and used genetic screening to identify host factors that either enhance or inhibit viral infection. For a subset of the interactions essential for the virus life cycle, the authors determined the cryo–electron microscopy structures and mined patient data to understand how targeting host factors may be relevant to clinical outcomes. Science , this issue p. eabe9403 Comparison of host interactions of three lethal coronaviruses identifies commonly hijacked pathways and potential drug targets. 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 protein-protein 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 SARS-CoV-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.