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

Chen, I.; Longbotham, J. E.; McMahon, S.; Suryawanshi, R.; Carlson-Stevermer, J.; Gupta, M.; Zhang, M. Y.; Soveg, F. W.; Hayashi, J. M.; Taha, T. Y.; Lam, V. L.; Li, Y.; Yu, Z.; Titus, E. W.; Diallo, A.; Oki, J.; Holden, K.; QCRG Structural Biology Consortium,; Krogan, N. J.; Fijimori, D. G.; Ott, M.

doi:10.1101/2021.11.14.468537

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bioRxiv · 10.1101/2021.11.14.468537

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

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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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Chen, I., Longbotham, J. E., McMahon, S., Suryawanshi, R., Carlson-Stevermer, J., Gupta, M., Zhang, M. Y., Soveg, F. W., Hayashi, J. M., Taha, T. Y., Lam, V. L., Li, Y., Yu, Z., Titus, E. W., Diallo, A., Oki, J., Holden, K., QCRG Structural Biology Consortium,, Krogan, N. J., Fijimori, D. G., Ott, M.. 2021-11-15. Viral E Protein Neutralizes BET Protein-Mediated Post-Entry Antagonism of SARS-CoV-2. https://doi.org/10.1101/2021.11.14.468537

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