Multi-level inhibition of coronavirus replication by chemical ER stress

Mohammed Samer Shaban, Christin Müller, Christin Mayr-Buro, Hendrik Weiser, Johanna Meier-Soelch, Benadict Vincent Albert, Axel Weber, Uwe Linne, Torsten Hain, Ilya Babayev, Nadja Karl, Nina Hofmann, Stephan Becker, Susanne Herold, M. Lienhard Schmitz, John Ziebuhr () and Michael Kracht ()
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Mohammed Samer Shaban: Justus Liebig University
Christin Müller: Justus Liebig University
Christin Mayr-Buro: Justus Liebig University
Hendrik Weiser: Justus Liebig University
Johanna Meier-Soelch: Justus Liebig University
Benadict Vincent Albert: Justus Liebig University
Axel Weber: Justus Liebig University
Uwe Linne: Philipps University
Torsten Hain: Justus Liebig University
Ilya Babayev: Justus Liebig University
Nadja Karl: Justus Liebig University
Nina Hofmann: Justus Liebig University
Stephan Becker: Philipps University
Susanne Herold: Justus Liebig University, and Institute for Lung Health (ILH)
M. Lienhard Schmitz: German Center for Lung Research (DZL) and Universities of Giessen and Marburg Lung Center (UGMLC)
John Ziebuhr: Justus Liebig University
Michael Kracht: Justus Liebig University

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. The ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types including primary differentiated human bronchial epithelial cells, (partially) reverses the virus-induced translational shut-down, improves viability of infected cells and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide analyses revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including essential (HERPUD1) or novel (UBA6 and ZNF622) factors of ER quality control, and ER-associated protein degradation complexes. Additionally, thapsigargin blocks the CoV-induced selective autophagic flux involving p62/SQSTM1. The data show that thapsigargin hits several central mechanisms required for CoV replication, suggesting that this compound (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs.

Date: 2021
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DOI: 10.1038/s41467-021-25551-1

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