Artikel ; Online: Viral E protein neutralizes BET protein-mediated post-entry antagonism of SARS-CoV-2.
2022 Band 40, Heft 3, Seite(n) 111088
Abstract: Inhibitors of bromodomain and extraterminal domain (BET) proteins are possible anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prophylactics as they downregulate angiotensin-converting enzyme 2 (ACE2). Here we show that BET proteins ... ...
Abstract | Inhibitors of bromodomain and extraterminal domain (BET) proteins are possible anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prophylactics as they downregulate angiotensin-converting enzyme 2 (ACE2). Here we show that BET proteins should not be inactivated therapeutically because they are critical antiviral factors at the post-entry level. Depletion of BRD3 or BRD4 in cells overexpressing ACE2 exacerbates SARS-CoV-2 infection; the same is observed when cells with endogenous ACE2 expression are treated with BET inhibitors during infection and not before. Viral replication and mortality are also enhanced in BET inhibitor-treated mice overexpressing ACE2. BET inactivation suppresses interferon production induced by SARS-CoV-2, a process phenocopied by the envelope (E) protein previously identified as a possible "histone mimetic." E protein, in an acetylated form, directly binds the second bromodomain of BRD4. Our data support a model where SARS-CoV-2 E protein evolved to antagonize interferon responses via BET protein inhibition; this neutralization should not be further enhanced with BET inhibitor treatment. |
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Mesh-Begriff(e) | Angiotensin-Converting Enzyme 2 ; Animals ; Antiviral Agents/pharmacology ; COVID-19 ; Interferons ; Mice ; Nuclear Proteins ; SARS-CoV-2 ; Transcription Factors ; Viral Proteins |
Chemische Substanzen | Antiviral Agents ; Nuclear Proteins ; Transcription Factors ; Viral Proteins ; Interferons (9008-11-1) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) |
Sprache | Englisch |
Erscheinungsdatum | 2022-06-27 |
Erscheinungsland | United States |
Dokumenttyp | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural |
ZDB-ID | 2649101-1 |
ISSN | 2211-1247 ; 2211-1247 |
ISSN (online) | 2211-1247 |
ISSN | 2211-1247 |
DOI | 10.1016/j.celrep.2022.111088 |
Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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