期刊
STRUCTURE
卷 30, 期 9, 页码 1224-+出版社
CELL PRESS
DOI: 10.1016/j.str.2022.05.020
关键词
-
资金
- CIHR [FDN-143314]
- National Strategic Research Institute (NSRI) at the University of Nebraska
- Nebraska Research Initiative (NRI)
- [NIH: HL151334]
- [CA252707]
- [GM125195]
- [GM135671]
- [AG067664]
- [AI129745]
- [DA052845]
This study describes how the E protein of SARS-CoV-2 hijacks the human transcriptional regulator BRD4 and identifies BRD4 as a potential anti-COVID-19 target. Inhibitors of BRD4 can decrease the infectivity of SARS-CoV-2, providing a new strategy to block the virus.
Emerging new variants of SARS-CoV-2 and inevitable acquired drug resistance call for the continued search of new pharmacological targets to fight the potentially fatal infection. Here, we describe the mechanisms by which the E protein of SARS-CoV-2 hijacks the human transcriptional regulator BRD4. We found that SARS-CoV-2 E is acetylated in vivo and co-immunoprecipitates with BRD4 in human cells. Bromodomains (BDs) of BRD4 bind to the C-terminus of the E protein, acetylated by human acetyltransferase p300, whereas the ET domain of BRD4 recognizes the unmodified motif of the E protein. Inhibitors of BRD4 BDs, JQ1 or OTX015, decrease SARS-CoV-2 infectivity in lung bronchial epithelial cells, indicating that the acetyllysine binding function of BDs is necessary for the virus fitness and that BRD4 represents a potential anti-COVID-19 target. Our findings provide insight into molecular mechanisms that contribute to SARS-CoV-2 pathogenesis and shed light on a new strategy to block SARS-CoV-2 infection.
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