Binding of the SARS-CoV-2 envelope E protein to human BRD4 is essential for infection.

Structure (London, England : 1993) 2022 Sep 01

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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. Copyright © 2022 Elsevier Ltd. All rights reserved.

Citation

Kendra R Vann, Arpan Acharya, Suk Min Jang, Catherine Lachance, Mohamad Zandian, Tina A Holt, Audrey L Smith, Kabita Pandey, Donald L Durden, Dalia El-Gamal, Jacques Côté, Siddappa N Byrareddy, Tatiana G Kutateladze. Binding of the SARS-CoV-2 envelope E protein to human BRD4 is essential for infection. Structure (London, England : 1993). 2022 Sep 01;30(9):1224-1232.e5