Viral E protein neutralizes BET protein-mediated post-entry antagonism of SARS-CoV-2.
Viral E protein neutralizes BET protein-mediated post-entry antagonism of SARS-CoV-2.
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DOI：
10.1016/j.celrep.2022.111088
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发表时间：
2022-07-19
期刊：
影响因子：
8.8
通讯作者：
Ott, Melanie
中科院分区：
文献类型：
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作者：
Chen, Irene P.;Longbotham, James E.;McMahon, Sarah;Suryawanshi, Rahul K.;Khalid, Mir M.;Taha, Taha Y.;Tabata, Takako;Hayashi, Jennifer M.;Soveg, Frank W.;Carlson-Stevermer, Jared;Gupta, Meghna;Zhang, Meng Yao;Lam, Victor L.;Li, Yang;Yu, Zanlin;Titus, Erron W.;Diallo, Amy;Oki, Jennifer;Holden, Kevin;Krogan, Nevan;Fujimori, Danica Galonie;Ott, Melanie
溴域和端外域(BET)蛋白的抑制剂可能是抗SARS冠状病毒2(SARS-CoV-2)的预防药物，因为它们下调血管紧张素转换酶2(ACE2)。在这里，我们表明BET蛋白不应该被治疗灭活，因为它们在进入后的水平上可能是关键的抗病毒因子。过度表达ACE2的细胞中BRD3或BRD4的缺失会加剧SARS-CoV-2的感染；当内源性ACE2表达的细胞在感染期间而不是在感染前用BET抑制剂处理时，也会观察到同样的情况。在过度表达ACE2的BET抑制剂治疗的小鼠中，病毒复制和死亡率也得到了提高。BET灭活可抑制SARS-CoV-2诱导的干扰素产生，这一过程由包膜(E)蛋白表型复制，此前被认为是一种可能的组蛋白模拟物。E蛋白以乙酰化的形式直接与BBRD4的第二个溴结构域结合。我们的数据支持一种模型，在该模型中，SARS-CoV-2E蛋白进化为通过抑制BET蛋白来对抗干扰素反应；这种中和不应因BET抑制剂的治疗而进一步增强。Chen等人。发现BET灭活，通过抑制抗病毒反应，增强SARS-CoV-2感染。这种效应被病毒包膜(E)蛋白所复制，病毒包膜(E)蛋白在细胞中被乙酰化，并通过结合和抑制BET蛋白的溴域而进化成对抗干扰素反应的诱导。
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. Chen et al. find that BET inactivation, by suppressing antiviral responses, enhances SARS-CoV-2 infection. This effect is phenocopied by the viral envelope (E) protein, which is acetylated in cells and has evolved to antagonize induction of the interferon response by binding and inhibiting BET proteins through their bromodomains.
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DOI：
10.1126/science.aaz8455
发表时间：
2020-04-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gilan O;Rioja I;Knezevic K;Bell MJ;Yeung MM;Harker NR;Lam EYN;Chung CW;Bamborough P;Petretich M;Urh M;Atkinson SJ;Bassil AK;Roberts EJ;Vassiliadis D;Burr ML;Preston AGS;Wellaway C;Werner T;Gray JR;Michon AM;Gobbetti T;Kumar V;Soden PE;Haynes A;Vappiani J;Tough DF;Taylor S;Dawson SJ;Bantscheff M;Lindon M;Drewes G;Demont EH;Daniels DL;Grandi P;Prinjha RK;Dawson MA
通讯作者：
Dawson MA
影响因子：
3.7
作者：
Nieto-Torres JL;Dediego ML;Alvarez E;Jiménez-Guardeño JM;Regla-Nava JA;Llorente M;Kremer L;Shuo S;Enjuanes L
通讯作者：
Enjuanes L
影响因子：
5.9
作者：
Javorsky A;Humbert PO;Kvansakul M
通讯作者：
Kvansakul M
影响因子：
3.7
作者：
Conant, David;Hsiau, Tim;Stoner, Rich
通讯作者：
Stoner, Rich
微管相关脱乙酰酶 HDAC6 对 Tat 乙酰化和反式激活活性的调节
影响因子：
4.8
作者：
Huo, Lihong;Li, Dengwen;Zhou, Jun
通讯作者：
Zhou, Jun