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Binding of the SARS-CoV-2 envelope E protein to human BRD4 is essential for infection.
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.
  • Vann KR; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
  • Acharya A; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68131, USA.
  • Jang SM; Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division, Québec City, QC G1R 3S3, Canada.
  • Lachance C; Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division, Québec City, QC G1R 3S3, Canada.
  • Zandian M; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
  • Holt TA; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
  • Smith AL; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68131, USA.
  • Pandey K; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68131, USA.
  • Durden DL; Division of Hematology and Oncology, Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, CA 92130, USA.
  • El-Gamal D; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68131, USA.
  • Côté J; Laval University Cancer Research Center, CHU de Québec-UL Research Center-Oncology Division, Québec City, QC G1R 3S3, Canada. Electronic address: jacques.cote@crchudequebec.ulaval.ca.
  • Byrareddy SN; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68131, USA. Electronic address: sid.byrareddy@unmc.edu.
  • Kutateladze TG; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: tatiana.kutateladze@cuanschutz.edu.
Structure ; 30(9): 1224-1232.e5, 2022 09 01.
Article in English | MEDLINE | ID: covidwho-1895449
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Transcription Factors / Cell Cycle Proteins / Coronavirus Envelope Proteins / SARS-CoV-2 / COVID-19 Topics: Variants Limits: Humans Language: English Journal: Structure Journal subject: Molecular Biology / Biochemistry / Biotechnology Year: 2022 Document Type: Article Affiliation country: J.str.2022.05.020

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Transcription Factors / Cell Cycle Proteins / Coronavirus Envelope Proteins / SARS-CoV-2 / COVID-19 Topics: Variants Limits: Humans Language: English Journal: Structure Journal subject: Molecular Biology / Biochemistry / Biotechnology Year: 2022 Document Type: Article Affiliation country: J.str.2022.05.020