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 M 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 Krogan; Danica Galonić Fujimori; Melanie Ott

doi:10.1016/j.celrep.2022.111088

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

Cell Rep. 2022 Jul 19;40(3):111088. doi: 10.1016/j.celrep.2022.111088. Epub 2022 Jun 27.

Authors

Irene P Chen¹, James E Longbotham², Sarah McMahon¹, Rahul K Suryawanshi³, Mir M Khalid³, Taha Y Taha³, Takako Tabata³, Jennifer M Hayashi³, Frank W Soveg³, Jared Carlson-Stevermer⁴, Meghna Gupta⁵, Meng Yao Zhang², Victor L Lam⁶, Yang Li⁶, Zanlin Yu⁶, Erron W Titus⁶, Amy Diallo⁶, Jennifer Oki⁴, Kevin Holden⁴, Nevan Krogan⁷, Danica Galonić Fujimori⁸, Melanie Ott⁹

Affiliations

¹ Gladstone Institutes, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA.
² Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Gladstone Institutes, San Francisco, CA 94158, USA.
⁴ Synthego Corporation, 3696 Haven Avenue, Suite A, Menlo Park, CA 94063, USA.
⁵ Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA.
⁶ Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA.
⁷ Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: danica.fujimori@ucsf.edu.
⁹ Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: melanie.ott@gladstone.ucsf.edu.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Angiotensin-Converting Enzyme 2
Animals
Antiviral Agents / pharmacology
COVID-19*
Interferons
Mice
Nuclear Proteins
SARS-CoV-2*
Transcription Factors
Viral Proteins

Substances

Antiviral Agents
Nuclear Proteins
Transcription Factors
Viral Proteins
Interferons
Angiotensin-Converting Enzyme 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding