한빛사 논문
Roswell Park Comprehensive Cancer Center, State University of New York
Dae-Kyum Kim1,2,3,4,5,25, Benjamin Weller 6,25, Chung-Wen Lin6,25, Dayag Sheykhkarimli 1,2,3,4,25, Jennifer J. Knapp 1,2,3,4,25, Guillaume Dugied 7,8,9,25, Andreas Zanzoni 10, Carles Pons11, Marie J. Tofaute 12, Sibusiso B. Maseko13, Kerstin Spirohn 4,14,15, Florent Laval 4,13,14,15,16,17, Luke Lambourne 4,14,15, Nishka Kishore1,2,3,4, Ashyad Rayhan1,2,3,4, Mayra Sauer6, Veronika Young 6, Hridi Halder6, Nora Marín-de la Rosa6, Oxana Pogoutse1,2,3,4, Alexandra Strobel6, Patrick Schwehn6, Roujia Li1,2,3,4, Simin T. Rothballer6, Melina Altmann6, Patricia Cassonnet7,8,9, Atina G. Coté1,2,3,4, Lena Elorduy Vergara6, Isaiah Hazelwood1,2,3,4, Betty B. Liu1,2,3,4, Maria Nguyen1,2,3,4, Ramakrishnan Pandiarajan6, Bushra Dohai6, Patricia A. Rodriguez Coloma6, Juline Poirson 1,2,18, Paolo Giuliana 1,2,3,4, Luc Willems16,17, Mikko Taipale 1,2,13, Yves Jacob 7,8,9, Tong Hao 4,14,15, David E. Hill 4,14,15,26, Christine Brun 10,19,26, Jean-Claude Twizere4,13,16,26, Daniel Krappmann 12,26, Matthias Heinig20,21,26, Claudia Falter6,26, Patrick Aloy11,22,26, Caroline Demeret7,8,9,26 , Marc Vidal4,14,26 , Michael A. Calderwood 4,14,15,26 , Frederick P. Roth 1,2,3,4,23,26 and Pascal Falter-Braun 6,24,26
1Donnelly Centre for Cellular and Biomolecular Research (CCBR), University of Toronto, Toronto, Ontario, Canada.
2Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
3Lunenfeld-Tanenbaum Research Institute (LTRI), Sinai Health System, Toronto, Ontario, Canada.
4Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA.
5Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
6Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.
7Unité de Génétique Moléculaire des Virus à ARN, Département de Virologie, Institut Pasteur, Paris, France.
8UMR3569, Centre National de la Recherche Scientifique, Paris, France.
9Université de Paris, Paris, France.
10Aix-Marseille Université, Inserm, TAGC, Marseille, France.
11Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute for Science and Technology, Barcelona, Spain.
12Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Molecular Targets and Therapeutics Center (MTTC), Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.
13Laboratory of Viral Interactomes, GIGA Institute, University of Liège, Liège, Belgium.
14Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
15Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
16TERRA Teaching and Research Centre, University of Liège, Gembloux, Belgium.
17Laboratory of Molecular and Cellular Epigenetics, GIGA Institute, University of Liège, Liège, Belgium.
18Molecular Architecture of Life Program, Canadian Institute for Advanced Research (CIFAR), Toronto, ON, Canada.
19CNRS, Marseille, France.
20Institute of Computational Biology (ICB), Computational Health Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.
21Department of Informatics, Technische Universität München, Munich, Germany.
22Institució Catalana de Recerca I Estudis Avaçats (ICREA), Barcelona, Spain.
23Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
24Microbe-Host Interactions, Faculty of Biology, Ludwig-Maximilians-Universität (LMU) München, Planegg-Martinsried, Germany.
25These authors contributed equally: Dae-Kyum Kim, Benjamin Weller, Chung-Wen Lin, Dayag Sheykhkarimli, Jennifer J. Knapp, Guillaume Dugied.
26These authors jointly supervised this work: David E. Hill, Christine Brun, Jean-Claude Twizere, Daniel Krappmann, Matthias Heinig, Claudia Falter, Patrick Aloy, Caroline Demeret, Marc Vidal, Michael A. Calderwood, Frederick P. Roth, Pascal Falter-Braun
Abstract
Understanding the mechanisms of coronavirus disease 2019 (COVID-19) disease severity to efficiently design therapies for emerging virus variants remains an urgent challenge of the ongoing pandemic. Infection and immune reactions are mediated by direct contacts between viral molecules and the host proteome, and the vast majority of these virus–host contacts (the ‘contactome’) have not been identified. Here, we present a systematic contactome map of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the human host encompassing more than 200 binary virus–host and intraviral protein–protein interactions. We find that host proteins genetically associated with comorbidities of severe illness and long COVID are enriched in SARS-CoV-2 targeted network communities. Evaluating contactome-derived hypotheses, we demonstrate that viral NSP14 activates nuclear factor κB (NF-κB)-dependent transcription, even in the presence of cytokine signaling. Moreover, for several tested host proteins, genetic knock-down substantially reduces viral replication. Additionally, we show for USP25 that this effect is phenocopied by the small-molecule inhibitor AZ1. Our results connect viral proteins to human genetic architecture for COVID-19 severity and offer potential therapeutic targets.
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