Multi-level inhibition of coronavirus replication by chemical ER stress.
Animals
Autophagy
/ drug effects
Bronchi
/ pathology
COVID-19
/ pathology
Cell Differentiation
/ drug effects
Cell Extracts
Cell Line
Cell Survival
/ drug effects
Chlorocebus aethiops
Coronavirus 229E, Human
/ physiology
Down-Regulation
/ drug effects
Endoplasmic Reticulum Chaperone BiP
Endoplasmic Reticulum Stress
/ drug effects
Endoplasmic Reticulum-Associated Degradation
/ drug effects
Epithelial Cells
/ drug effects
Heat-Shock Proteins
/ metabolism
Humans
Macrolides
/ pharmacology
Middle East Respiratory Syndrome Coronavirus
/ drug effects
Protein Biosynthesis
/ drug effects
Proteome
/ metabolism
RNA, Messenger
/ genetics
Reproducibility of Results
SARS-CoV-2
/ drug effects
Thapsigargin
/ pharmacology
Unfolded Protein Response
/ drug effects
Vero Cells
Virus Replication
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 09 2021
20 09 2021
Historique:
received:
07
09
2020
accepted:
02
08
2021
entrez:
21
9
2021
pubmed:
22
9
2021
medline:
29
9
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34545074
doi: 10.1038/s41467-021-25551-1
pii: 10.1038/s41467-021-25551-1
pmc: PMC8452654
doi:
Substances chimiques
Cell Extracts
0
Endoplasmic Reticulum Chaperone BiP
0
Heat-Shock Proteins
0
Macrolides
0
Proteome
0
RNA, Messenger
0
Thapsigargin
67526-95-8
bafilomycin A1
88899-55-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5536Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 284237345
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 268555672
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 197785619
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 416910386
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 390649896
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2021. The Author(s).
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