Binding of the SARS-CoV-2 envelope E protein to human BRD4 is essential for infection.
Structure
; 30(9): 1224-1232.e5, 2022 09 01.
Article
de En
| MEDLINE
| ID: mdl-35716662
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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Facteurs de transcription
/
Protéines du cycle cellulaire
/
Protéines d'enveloppe des coronavirus
/
SARS-CoV-2
/
COVID-19
Limites:
Humans
Langue:
En
Journal:
Structure
Sujet du journal:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
BIOTECNOLOGIA
Année:
2022
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique