tetano
Editor, Senior Moderator
Cell Rep
. 2022 Jun 27;111088.
doi: 10.1016/j.celrep.2022.111088. Online ahead of print.
Viral E protein neutralizes BET protein-mediated post-entry antagonism of SARS-CoV-2
Irene P Chen[SUP] 1 [/SUP], James E Longbotham[SUP] 2 [/SUP], Sarah McMahon[SUP] 1 [/SUP], Rahul K Suryawanshi[SUP] 3 [/SUP], Mir M Khalid[SUP] 3 [/SUP], Taha Y Taha[SUP] 3 [/SUP], Takako Tabata[SUP] 3 [/SUP], Jennifer M Hayashi[SUP] 3 [/SUP], Frank W Soveg[SUP] 3 [/SUP], Jared Carlson-Stevermer[SUP] 4 [/SUP], Meghna Gupta[SUP] 5 [/SUP], Meng Yao Zhang[SUP] 2 [/SUP], Victor L Lam[SUP] 6 [/SUP], Yang Li[SUP] 6 [/SUP], Zanlin Yu[SUP] 6 [/SUP], Erron W Titus[SUP] 6 [/SUP], Amy Diallo[SUP] 6 [/SUP], Jennifer Oki[SUP] 4 [/SUP], Kevin Holden[SUP] 4 [/SUP], Nevan Krogan[SUP] 7 [/SUP], Danica Galonić Fujimori[SUP] 8 [/SUP], Melanie Ott[SUP] 9 [/SUP]
Affiliations
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.
. 2022 Jun 27;111088.
doi: 10.1016/j.celrep.2022.111088. Online ahead of print.
Viral E protein neutralizes BET protein-mediated post-entry antagonism of SARS-CoV-2
Irene P Chen[SUP] 1 [/SUP], James E Longbotham[SUP] 2 [/SUP], Sarah McMahon[SUP] 1 [/SUP], Rahul K Suryawanshi[SUP] 3 [/SUP], Mir M Khalid[SUP] 3 [/SUP], Taha Y Taha[SUP] 3 [/SUP], Takako Tabata[SUP] 3 [/SUP], Jennifer M Hayashi[SUP] 3 [/SUP], Frank W Soveg[SUP] 3 [/SUP], Jared Carlson-Stevermer[SUP] 4 [/SUP], Meghna Gupta[SUP] 5 [/SUP], Meng Yao Zhang[SUP] 2 [/SUP], Victor L Lam[SUP] 6 [/SUP], Yang Li[SUP] 6 [/SUP], Zanlin Yu[SUP] 6 [/SUP], Erron W Titus[SUP] 6 [/SUP], Amy Diallo[SUP] 6 [/SUP], Jennifer Oki[SUP] 4 [/SUP], Kevin Holden[SUP] 4 [/SUP], Nevan Krogan[SUP] 7 [/SUP], Danica Galonić Fujimori[SUP] 8 [/SUP], Melanie Ott[SUP] 9 [/SUP]
Affiliations
- PMID: 35839775
- PMCID: PMC9234021
- DOI: 10.1016/j.celrep.2022.111088
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.