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

• DOI: 10.1016/j.celrep.2022.111088
• Publication Date: 2022-06-27T06:00:25Z
• Authors: Irene P. Chen; James E. Longbotham; Sarah McMahon; Rahul K. Suryawanshi; Mir M. Khalid; Taha Y. Taha; Takako Tabata; Jennifer M. Hayashi; Frank W. Soveg; Jared Carlson-Ste...; Meghna Gupta; Meng Yao Zhang; Victor L. Lam; Yang Li; Zanlin Yu; Erron W. Titus; Amy Diallo; Jennifer Oki; Kevin Holden; Nevan Krogan; Danica Galonić Fu...; Melanie Ott
• Keywords: 570; Coronaviruses; Medical Physiology; 610; Antiviral Agents; Article; antiviral response; Mice; Viral Proteins; Biodefense; BET proteins; Animals; BET inhibitors; SARS-CoV-2; CP: Microbiology; COVID-19; Nuclear Proteins; Biological Sciences; 3. Good health; Biological sciences; Infectious Diseases; Emerging Infectious Diseases; Good Health and Well Being; histone mimetic; BRD2; BRD4; viral replication; BRD3; Biochemistry and Cell Biology; Angiotensin-Converting Enzyme 2; Interferons; Infection; Transcription Factors

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.