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Cell Rep
. 2022 Jun 27;111088.
doi: 10.1016/j.celrep.2022.111088. Online ahead of print.
Viral E protein neutralizes BET protein-mediated post-entry antagonism of SARS-CoV-2
Irene P Chen 1 , James E Longbotham 2 , Sarah McMahon 1 , Rahul K Suryawanshi 3 , Mir M Khalid 3 , Taha Y Taha 3 , Takako Tabata 3 , Jennifer M Hayashi 3 , Frank W Soveg 3 , Jared Carlson-Stevermer 4 , Meghna Gupta 5 , Meng Yao Zhang 2 , Victor L Lam 6 , Yang Li 6 , Zanlin Yu 6 , Erron W Titus 6 , Amy Diallo 6 , Jennifer Oki 4 , Kevin Holden 4 , Nevan Krogan 7 , Danica Galonić Fujimori 8 , Melanie Ott 9
Affiliations
- PMID: 35839775
- PMCID: PMC9234021
- DOI: 10.1016/j.celrep.2022.111088
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 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.
Keywords: BET inhibitors; BET proteins; BRD2; BRD3; BRD4; COVID-19; CP: Microbiology; SARS-CoV-2; antiviral response; histone mimetic; viral replication.