Einzeltreffer — DigiBib

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.

Competing Interests: Declaration of interests The authors declare no competing interests.

Titel:	Binding of the SARS-CoV-2 envelope E protein to human BRD4 is essential for infection.
Autor/in / Beteiligte Person:	Vann, KR ; Acharya, A ; Jang, SM ; Lachance, C ; Zandian, M ; Holt, TA ; Smith, AL ; Pandey, K ; Durden, DL ; El-Gamal, D ; Côté, J ; Byrareddy, SN ; Kutateladze, TG
Zeitschrift:	Structure (London, England : 1993), Jg. 30 (2022-09-01), Heft 9, S. 1224-1232.e5
Veröffentlichung:	2000- : Cambridge, Mass. : Cell Press ; <i>Original Publication</i>: London : Current Biology, c1993-, 2022
Medientyp:	academicJournal
ISSN:	1878-4186 (electronic)
DOI:	10.1016/j.str.2022.05.020
Schlagwort:	Humans Nuclear Proteins metabolism Protein Binding Protein Domains COVID-19 virology Cell Cycle Proteins metabolism Coronavirus Envelope Proteins metabolism SARS-CoV-2 physiology Transcription Factors metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Structure] 2022 Sep 01; Vol. 30 (9), pp. 1224-1232.e5. <i>Date of Electronic Publication: </i>2022 Jun 17. MeSH Terms: COVID-19* / virology ; Cell Cycle Proteins / metabolism ; Coronavirus Envelope Proteins / metabolism ; SARS-CoV-2 / physiology ; Transcription Factors / metabolism ; Humans ; Nuclear Proteins / metabolism ; Protein Binding ; Protein Domains Grant Information: R01 GM125195 United States GM NIGMS NIH HHS; R01 CA252707 United States CA NCI NIH HHS; R01 GM135671 United States GM NIGMS NIH HHS; T32 NS105594 United States NS NINDS NIH HHS; R01 DA052845 United States DA NIDA NIH HHS; R01 AI129745 United States AI NIAID NIH HHS; R01 HL151334 United States HL NHLBI NIH HHS; R01 AG067664 United States AG NIA NIH HHS; R56 AG067664 United States AG NIA NIH HHS Contributed Indexing: Keywords: BRD4; ET domain; SARS-CoV-2; bromodomain; envelope E protein Substance Nomenclature: 0 (BRD4 protein, human) ; 0 (Cell Cycle Proteins) ; 0 (Coronavirus Envelope Proteins) ; 0 (Nuclear Proteins) ; 0 (Transcription Factors) ; 0 (envelope protein, SARS-CoV-2) Entry Date(s): Date Created: 20220618 Date Completed: 20220908 Latest Revision: 20240521 Update Code: 20240521 PubMed Central ID: PMC9212912

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