Journal Article

Multi-level inhibition of coronavirus replication by chemical ER stress

Weiser, Hendrik, Albert, Benadict Vincent, Linne, Uwe, Weber, Axel, Babayev, Ilya, Meier-Soelch, Johanna, Hofmann, Nina, Schmitz, M. Lienhard, Becker, Stephan, Hain, Torsten, Shaban, Mohammed Samer, Mayr-Buro, Christin, Kracht, Michael, Ziebuhr, John, Karl, Nadja, Herold, Susanne, Müller, Christin

2021

Overview

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. Here, Shaban et al. show that coronaviruses modulate ER stress and the unfolded protein response. The ER stress inducer thapsigargin exerts potent antiviral effects, partially reverses the virus-induced translational shut-down, reprograms the host proteome and suppresses autophagic flux, thereby inhibiting coronavirus replication at multiple levels.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/95 / 14/32 / 49/1 / 49/39 / 49/47 / 631/250/254 / 631/326/596/2097 / 631/326/596/2557 / 631/326/596/4130 / 692/699/255/2514 / 82/58 / 82/80 / 96/34 / 96/63 / Animals / Antiviral agents / Antiviral drugs / Antiviral state / Autophagy - drug effects / Biodegradation / Bronchi - pathology / Cell differentiation / Cell Differentiation - drug effects / Cell Extracts / Cell Line / Cell Survival - drug effects / Chlorocebus aethiops / Coronavirus 229E, Human - physiology / Coronaviruses / COVID-19 / COVID-19 - pathology / COVID-19 - virology / Down-Regulation - drug effects / Endoplasmic Reticulum Chaperone BiP / Endoplasmic Reticulum Stress - drug effects / Endoplasmic Reticulum Stress - genetics / Endoplasmic Reticulum-Associated Degradation - drug effects / Epithelial cells / Epithelial Cells - drug effects / Epithelial Cells - virology / Epithelium / Heat-Shock Proteins - metabolism / Humanities and Social Sciences / Humans / Macrolides - pharmacology / Middle East Respiratory Syndrome Coronavirus - drug effects / Middle East Respiratory Syndrome Coronavirus - physiology / multidisciplinary / Protein Biosynthesis - drug effects / Protein folding / Proteins / Proteome - metabolism / Proteomes / Quality control / Replication / Reproducibility of Results / RNA, Messenger - genetics / RNA, Messenger - metabolism / SARS-CoV-2 - drug effects / SARS-CoV-2 - physiology / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Shutdowns / Thapsigargin / Thapsigargin - pharmacology / Translation / Unfolded Protein Response - drug effects / Vero Cells / Viral diseases / Virus Replication - drug effects / Virus Replication - physiology / Viruses