@article{2152858856cf46cc9db1ef75eae1203b,
title = "Binding of the SARS-CoV-2 envelope E protein to human BRD4 is essential for infection",
abstract = "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.",
keywords = "BRD4, ET domain, SARS-CoV-2, bromodomain, envelope E protein",
author = "Vann, {Kendra R.} and Arpan Acharya and Jang, {Suk Min} and Catherine Lachance and Mohamad Zandian and Holt, {Tina A.} and Smith, {Audrey L.} and Kabita Pandey and Durden, {Donald L} and Dalia El-Gamal and Jacques C{\^o}t{\'e} and Byrareddy, {Siddappa N.} and Kutateladze, {Tatiana G.}",
note = "Funding Information: This work was supported in part by grants from NIH : HL151334 , CA252707 , GM125195 , GM135671 , and AG067664 to T.G.K. and AI129745 and DA052845 to S.N.B., and a foundation grant from the CIHR to J.C. ( FDN-143314 ). S.N.B. acknowledges independent research and development (IRAD) funding from the National Strategic Research Institute (NSRI) at the University of Nebraska . J.C. holds the Canada Research Chair on Chromatin Biology and Molecular Epigenetics. We acknowledge the UNMC BSL-3 core facility at DRC-1 where experiments involving live SARS-CoV-2 were performed and St Patrick Reid laboratory for the use of Operetta CLS. UNMC BSL-3 core facility is administered by the Office of the Vice-Chancellor for Research and supported by the Nebraska Research Initiative (NRI). Funding Information: This work was supported in part by grants from NIH: HL151334, CA252707, GM125195, GM135671, and AG067664 to T.G.K. and AI129745 and DA052845 to S.N.B. and a foundation grant from the CIHR to J.C. (FDN-143314). S.N.B. acknowledges independent research and development (IRAD) funding from the National Strategic Research Institute (NSRI) at the University of Nebraska. J.C. holds the Canada Research Chair on Chromatin Biology and Molecular Epigenetics. We acknowledge the UNMC BSL-3 core facility at DRC-1 where experiments involving live SARS-CoV-2 were performed and St Patrick Reid laboratory for the use of Operetta CLS. UNMC BSL-3 core facility is administered by the Office of the Vice-Chancellor for Research and supported by the Nebraska Research Initiative (NRI). K.R.V. A.A. S.M.J. C. L. M.Z. T.A.H. A.L.S. and K.P. performed experiments and, together with D.L.D. D.E.G. J.C. S.N.B. and T.G.K. discussed and analyzed the data. K.R.V. and T.G.K. wrote the manuscript with input from all authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",
year = "2022",
month = sep,
day = "1",
doi = "10.1016/j.str.2022.05.020",
language = "English (US)",
volume = "30",
pages = "1224--1232.e5",
journal = "Structure with Folding & design",
issn = "0969-2126",
publisher = "Cell Press",
number = "9",
}