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

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. [Display omitted] •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 Chen et al. find that BET inactivation, by suppressing antiviral responses, enhances SARS-CoV-2 infection. This effect is phenocopied by the viral envelope (E) protein, which is acetylated in cells and has evolved to antagonize induction of the interferon response by binding and inhibiting BET proteins through their bromodomains.