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Cell Reports

Volume 40, Issue 3, 19 July 2022, 111088

Viral E protein neutralizes BET protein-mediated post-entry antagonism of SARS-CoV-2

Author links open overlay panelhttps://doi.org/10.1016/j.celrep.2022.111088

Highlights

 

Inactivation of BET protein aggravates SARS-CoV-2 infection in cells and mice

Viral envelope (E) protein is acetylated in cells and binds bromodomain 2 of BRD4

E protein antagonizes BET protein-mediated antiviral responses during infection

 

Summary

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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