塔普斯加尔金
细胞生物学
病毒复制
下调和上调
冠状病毒
重编程
未折叠蛋白反应
生物
蛋白质组
化学
细胞
病毒
病毒学
细胞内
2019年冠状病毒病(COVID-19)
遗传学
内质网
医学
传染病(医学专业)
病理
疾病
基因
作者
Mohammed Samer Shaban,Christoph 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,Michael Kracht
标识
DOI:10.1038/s41467-021-25551-1
摘要
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.
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