Viral E Protein Neutralizes BET Protein-Mediated Post-Entry Antagonism of SARS-CoV-2

Irene P. Chen; James E. Longbotham; Sarah McMahon; Rahul K. Suryawanshi; Mir Mubashir Khalid; Taha Y. Taha; Takako Tabata; Jennifer M. Hayashi; Frank W. Soveg; Jared Carlson-Stevermer; Meghna Gupta; Meng Yao Zhang; Victor L. Lam; Yang Li; Zanlin Yu; Erron W. Titus; Amy Diallo; Jennifer Oki; Kevin Holden; Nevan J. Krogan; Danica Galonić Fujimori; Mélanie Ott

doi:10.1016/j.celrep.2022.111088

Molecular BiologyCell ReportsJun 27, 2022

Peer-reviewed journal article

Viral E Protein Neutralizes BET Protein-Mediated Post-Entry Antagonism of SARS-CoV-2

Irene P. Chen iD, James E. Longbotham iD, Sarah McMahon iD, Rahul K. Suryawanshi iD, Mir Mubashir Khalid iD, Taha Y. Taha iD, Takako Tabata iD, Jennifer M. Hayashi iD, Frank W. Soveg iD, Jared Carlson-Stevermer iD, Meghna Gupta iD, Meng Yao Zhang iD, Victor L. Lam iD, Yang Li iD, Zanlin Yu iD, Erron W. Titus iD, Amy Diallo iD, Jennifer Oki iD, Kevin Holden iD, Nevan J. Krogan iD, Danica Galonić Fujimori iD, Mélanie Ott iD

Abstract

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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