Journal article

Publication year: 2021

Journal: Nature Communications

Volume number: 12

Issue number: 1

eISSN: 2041-1723

Open access status: Gold

DOI Link: https://doi.org/10.1038/s41467-021-25551-1

Publisher: Nature Research

Abstract: 

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.

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 IRE1 alpha 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.

Harvard Citation style: Shaban, M., Mueller, C., Mayr-Buro, C., Weiser, H., Meier-Soelch, J., Albert, B., et al. (2021) Multi-level inhibition of coronavirus replication by chemical ER stress, Nature Communications, 12(1), Article 5536. https://doi.org/10.1038/s41467-021-25551-1

APA Citation style: Shaban, M., Mueller, C., Mayr-Buro, C., Weiser, H., Meier-Soelch, J., Albert, B., Weber, A., Linne, U., Hain, T., Babayev, I., Karl, N., Hofmann, N., Becker, S., Herold, S., Schmitz, M., Ziebuhr, J., & Kracht, M. (2021). Multi-level inhibition of coronavirus replication by chemical ER stress. Nature Communications. 12(1), Article 5536. https://doi.org/10.1038/s41467-021-25551-1