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

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. W...

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Detalles Bibliográficos
Autores principales: Vann, Kendra R., Acharya, Arpan, Jang, Suk Min, Lachance, Catherine, Zandian, Mohamad, Holt, Tina A., Smith, Audrey L., Pandey, Kabita, Durden, Donald L., El-Gamal, Dalia, Côté, Jacques, Byrareddy, Siddappa N., Kutateladze, Tatiana G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Ltd. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9212912/
https://www.ncbi.nlm.nih.gov/pubmed/35716662
http://dx.doi.org/10.1016/j.str.2022.05.020
Descripción
Sumario: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.