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Viral E Protein Neutralizes BET Protein-Mediated Post-Entry Antagonism of SARS-CoV-2. 2021
Irene P Chen, and
James E Longbotham, and
Sarah McMahon, and
Rahul K Suryawanshi, and
Jared Carlson-Stevermer, and
Meghna Gupta, and
Meng Yao Zhang, and
Frank W Soveg, and
Jennifer M Hayashi, and
Taha Y Taha, and
Victor L Lam, and
Yang Li, and
Zanlin Yu, and
Erron W Titus, and
Amy Diallo, and
Jennifer Oki, and
Kevin Holden, and
, and
Nevan Krogan, and
Danica Galonić Fujimori, and
Melanie Ott
Inhibitors of Bromodomain and Extra-terminal domain (BET) proteins are possible anti-SARS-CoV-2 prophylactics as they downregulate angiotensin-converting enzyme 2 (ACE2). Here, we show that BET proteins should not be inactivated therapeutically as they are critical antiviral factors at the post-entry level. Knockouts of BRD3 or BRD4 in cells overexpressing ACE2 exacerbate 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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